The Effect Of Nucleos(t)ide Analogues On Hepatitis B Virus-related Acute-on-chronic Liver Failure And The Influence On Change Of Lymphocytes And Cytokines

Background & Aims: Acute decompensation of Cirrhosis is a clinical presentation with high mortality. The incidence of acute decompensation of Cirrhosis on the basis of chronic hepatitis is high in China and Asian, high. There is not model developed to predict mortality risk of acute decompensation of Cirrhosis in chronic hepatitis B(CHB) patients. We aimed to establish a clinical scoring model for mortality risk in patients with acute decompensation of chronic hepatitis B Cirrhosis, using patients′ data that are routinely collected and easily obtained at the time of initial presentation.Methods: A retrospective multicenter study was conducted. 509 in-patients with acute decompensation of chronic hepatitis B Cirrhosis were recruited from October 2008 to February 2014 in Beijing Ditan Hospital, Capital Medical University, China. These patients′ clinical data were assigned to risk-model derivation. Univariate risk factors associated with the outcome were entered into a multivariate logistic regression model for screening independent risk factors. Each variable was assigned an integer value based on the regression coefficients, and the final score was the sum of these values in the derivation set. 620 patients of acute decompensation of chronic hepatitis B Cirrhosis from January 2005 to February 2011 in Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China were assigned model validation. Cumulative mortality rates were analyzed by Kaplan–Meier curves and log rank test, and Model discrimination were assessed by Cox regression analysis.Results:1. 509 patients were diagnosed acute decompensation of chronic hepatitis B Cirrhosis on admission and 56 patients(11.0%) died by the end of 4 weeks. 35 of 56(62.5%) patients and 53 of 56(94.6%) patients died of acute-on-chronic liver failure(ACLF) according to APASL and EASL-CLIF criteria. 2. Clinical mortality risk factors for patients with acute decompensation of chronic hepatitis B Cirrhosis were age>65 years, spontaneous bacterial peritonitis, hepatic encephalopathy grade III-IV, total bilirubin > 171 μmol/L, serum sodium < 135 mmol/L. Patients were categorized into low(0-1), intermediate(2-3), and high(4-8) risk group by score model based on these 5 factors. There were significant 28-day death rate differences between low, intermediate, and high risk groups both in derivation and validation population(0.9% vs 16.3% vs 63.5%, log-rank P for all<0.0001; 13.0% vs 50.5% vs 75.9%, log-rank log-rank P for all <0.0001, respectively). In the derivation and validation population, the model had good discrimination(AUC = 0.918, 95% CI: 0.882-0.953 and AUC = 0.792, 95% CI: 0.754-0.831, respectively).Conclusions: 1. Acute-on-chronic liver failure is the most important cause of death for patients with acute decompensation of chronic hepatitis B Cirrhosis.2. The simple score model based on readily obtainable clinical characteristics could be helpful in predicting the prognosis of acute decompensation of chronic hepatitis B cirrhosis patients.Background & Aims: Hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF) is a clinical presentation with significant morbidity and mortality. There is no standard approach for managing HBV-related ACLF with nucleos(t)ide analogues(NAs). Our objective is to compare the short-term mortality between entecavir(ETV) and lamivudine(LAM) in patients with HBV-related ACLF.Methods: 311 in-patients with HBV-related ACLF were recruited from December 2002 to January 2015. The patients were treated with entecavir and lamivudine respectively. The primary endpoint was mortality rate at week 8. Virological and biochemical responses were also studied.Results: 143 and 168 patients with HBV-ACLF were treated with entecavir and lamivudine respectively. By week 8, 53(37.1%) patients in the ETV group, 57(33.9%) patients in the LAM group died. The ETV group had similar mortality to the LAM group(p=0.414). Multivariate analysis showed that age, TBIL, INR and end-stage liver disease(MELD) scores were independent factors for mortality at week 8. The best cut-off value of MELD scores was 24.5 for 8-week mortality. Among the 170 patients with MELD scores <24.5, 29(17.1%) patients died at week 8, the ETV group and the LAM group had similar mortality(p=0.743); among the 141 patients with MELD scores ≥24.5, 81(57.4%) patients died at week 8, the LAM group had lower mortality rate than the ETV group(p=0.039), and two groups had similar virological and biochemical responses in 4 weeks.Conclusions: Lamivudine significantly reduces 8-week mortality rate in patients with HBV-related ACLF who had MELD scores ≥24.5.Objective: To observe the changes of lymphocytes and cytokines with lamivudine and enticavir on Con A or LPS combind with D-galactosamine(D-Gal N) induced acute liver failure(ALF). To explore the role of lamivudine and enticavir to survival rate of ALF mice and its possible mechanism.Methods: Con A and LPS/D-Gal N were intravenous injectionrd or intraperitoneally injected into C57BL/6J mice to induce ALF, respectively. Simultaneously, dd H2 O, entecavir(ETV) or lamivudine(LAM) were orally administered. Transaminase levels in plasma and hepatic tissue histology by HE staining were detected; Survival rates of ALF mice were observed; Flow cytometry was used to analyzed frequencies of T cell, B cell, granulocyte and mononuclear cell; Cytometric Bead Array(CBA) were performed to detect cytokines(IL-6、IL-10、MCP-1、IFN-γ、TNF-α and IL-12p70) and evaluate the effects of different nucleos(t)ide analogues.Results: 1. There were no differences of the levels of ALT and AST among the model group, LAM and ETV groups in peripheral blood of mice injected with Con A or LPS/D-Gal N.2. Oral administration of LAM or ETV significantlly aggravated injury of liver histopathology and ETV caused most severe impairment in liver histopathology of mice injected with Con A; Of mice injected with LPS/D-Gal N, there were similar severe impairment of liver histopathology in model group, LAM and ETV groups.3. The survival rates of Con A challenged mice model, oral administration of LAM or ETV were 90%, 70% and 40% respectively at the 24 hour. All mice injected with LPS/D-Gal N dead in 6 hours and there were no differences of survival rates among three groups.4. Oral administration of LAM or ETV significantlly increased frequencies of T cell in peripheral blood of mice injected with Con A, the frequencies of T cell in ETV group was higher than model group and it was statistical significance(t=2.454,p=0.040). There were no differences of the frequencies of T celll, B cell, granulocyte and mononuclear cell among three groups in peripheral blood of mice model injected with LPS/D-Gal N.5. Oral administration of ETV significantlly decreased level of IL-6 in peripheral blood of mice injected with Con A, the level of IL-6 in ETV group was lower than model group and it was statistical significance( t=2.634, p=0.025). Oral administration of LAM or ETV significantlly increased level of IL-12 in peripheral blood of mice injected with Con A, the level of IL-12 in LAM group was higher than model group and it was statistical significance(t=2.939,p=0.012). There were no differences of the levels of IL-10、MCP-1、IFN-γ、TNF-α among three groups in peripheral blood of mice injected with Con A; There were no differences of the levels of TNF-α、MCP-1、IL-10、IFN-γ among three groups in peripheral blood of mice injected with LPS/D-Gal N.Conclusions: 1. Oral administration of LAM or ETV significantlly exacerbated the situation and death of mice injected with Con A, especially ETV.2. It might be a reason of liver injury or death that frequencies of T cell and the level of IL-12 in peripheral blood increased by LAM or ETV for mice injected with Con A.