Detoxification Slow Cool Blood Treatment For Hepatitis B And Acute Liver Failure Mechanism Of Curative Effect Evaluation And Research

Acute-on-chronic liver failure (ACLF) is a severe life-threatening clinical syndrome. It has been defined as "an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within4weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease". Hepatitis B virus (HBV) infection is a leading cause of ACLF in Asia, and HBV associate acute-on-chronic liver failure (HBV-ACLF) account for more than70%. Acute hepatic deterioration often results in multiple complications (bacterial infection, hepatorenal syndrome, hepatic encephalopathy and so on) and multisystem organ failure, and short-term mortality is up to50-90%in ACLF patients. ACLF is charactered by rapid progress, dangerous disease, severe complications and high mortality of patients. It is important to understand its clinical features and make a more detailed description on prognosis and outcome of ACLF. Thus, accurately and objectively determine the prognosis of ACLF patients and explore effective therapy in early stage become an important research topic in HBV-ACLF.[objective]1. Systematically understanding predisposing factors, clinical features, overall mortality and mortality in different stages of patients with HBV-ACLF.2. Evaluating efficacy and safety of integrative medicine measure basing on the method of detoxification and cooling blood for HBV-ACLF by randomized controlled clinical study.3. Exploring expression differential proteomics in HBV-ACLF, HBV-ACLF patients with different prognosis and integrative medicine treatment, in order to reveal the pathogenesis of HBV-ACLF, find biomarkers of disease prognostic as well as further study pathways and mechanisms of the cooling blood detoxification treating HBV-ACLF.[Methods]1. Collecting patients admitted with HBV-associated ACLF at the Capital Medical University, Beijing Ditan Hospital were entered in this study. All patients with available clinical information and baseline laboratory parameters were enrolled from from September2008to December2012. Establishing Epidata database and descriptively analysing age, sex, predisposing factors, stage of disease and laboratory examination in patients with different prognosis. Single factors and multivariate analysis were performed to screen prognostic indicators associated with HBV-ACLF, and assessing accuracy and value of the marker by prospective validation cohort.2. Evaluating efficacy and safety of integrative medicine measure basing on the method of detoxification and cooling blood for HBV-ACLF by randomized controlled clinical study. All patients were randomly assigned to the Integrative Medicine group and Western medicine group. Western medicine group was treated by the comprehensive treatment of Western medicine, and Integrative Medicine group was given Western medicine treatment and jiedu liangxue prescriptions. All patients was treated8weeks and followed up40weeks.3. basing on theITRAQ techniques in proteomics, we Explored expression of differential proteomics in HBV-ACLF, IIBV-ACLF patients with different prognosis and integrative medicine treatment, Using gel electrophores to separate and remove the high abundance of albumin and immunoglobulin, marking each group by ITRAQ reagents and detectoring peptide signal by Q-EXACTIVE mass spectrometer. Protein Discovery software was used to analyes mass spectrometry data qualitatively and quantitatively, and the biological information database was used to retrieve specific biological function of Protein.[Results]1. A total of316patients with HBV-ACLF were enrolled in the second part of the study. The ratio was5.58:lmale to female. Incorrect use of the antiviral drugs is a main cause to induce HBV-ACLF, and the fatality rate was up to68.27%in HBV-ACLF patients with decomponsated cirrhosis.2.131cases of316were dead, and overall mortality in two months was41.5%.184cases in the early stage died and the fatality rate was27.17%; the fatality rate was55.26%in the mid-stage;56patients died of advanced disease and the mortality was69.64%.3. Single factor analysis showed that baseline TBTL, PTA, NC, LC, NLR and MELD score exist differences between the survival group and death group (P<0.01). Multi-factor analysis show age, TBIL NLR and MELD score of patients affect the prognosis of HBV-ACLF patients. Area under the curve (AUC) of Age, TBIL, NLR and MELD score was0.615,0.691,0.781and0.744, respectively. There was no significant difference between NLR and MELD score (P=0.945).4. Baseline NLR≤2.36was the negative threshold and NLR>6.12was positive threshold for retrospective cohort with a90.1%specificity and91.6%sensitivity; the survival rate was86.0%(49/57cases) in57HBV-ACLF patients with baseline NLR≤2.36at the end of8weeks, and the survival rate was19.7%(12/61cases) in61cases with NLR>6.12; the survival rate was61.22%(60/98cases) in HBV-ACLF patients with NLR ratio ranged from2.36to6.12. Log-rank test showed that the survival rate among the three groups were significantly different (P=0.004).5. A total of105patients with HBV-ACLF were enrolled in our randomized controlled clinical study. Integrative Medicine group consisted of64cases, and Western medicine group consisted of41patients. After48Weeks, the overall fatality rate of two groups were21.88%and-39.02%, respectively(P=0.026). Integrative measure basing on the cooling blood and detoxification can significantly reduce the mortality in medium-term patients with HBV-ACLF (25%vs.64.7%, χ2=8.749, P=0.003).6. There was statistical difference in total bilirubin (at8th week) and PTA (at4th week and6th week) between Integrative Medicine group and Western medicine group.(Total bilirubin:Integrative group:64.54±79.76vs Western medicine group:168.44±114.80, P=0.04).7. About40down-regulated proteins and10up-regulated proteins were identified between Chronic hepatitis B and HBV-ACLF groups; comparing to HBV-ACLF survival group, the death group had24up-regulated proteins and24down-regulated proteins, which involved in energy metabolism, cytoskeleton, oxidative stress and transforming regulation. Integrative Medicine group comparing with Western medicine group, there are four kinds of proteins up-regulated and2proteins down-regulated after treatment in Integrative Medicine group, and three kinds of proteins disappeared.[Conclusion] 1. Baseline NLR may be a potential marker to predict the short-term prognosis of patients with HBV-ACLF, which is as accuracy as the MELD score.2. The overall mortality was41.5%of patients with HBV-ACLF in two months, and the case fatality rate in terminal patients was significantly greater than patients in the early and middle stages. Thus, early diagnosis and reasonable treatment is the key to reducing mortality of HBV-ACLF patients.3."Cooling blood, detoxification, fu-unblocking therapy and invigorating spleen to re solve dampness" is the important rule for the treatment of HBV-ACLF, which can significantly reduce the mortality of patients, improve the synthetic function of the liver and reduce the level of total bilirubin.4. The α1-acid glycoprotein was significantly lowered in patients of the death group, which can be as a sign for liver reserve function and prognosis in patients with liver failure; sulfated glycoproteins significantly down-regulated in the death group patients may inhibit apoptosis of liver cells; the a2-macroglobul in expression was raised in Integrative group, suggesting method of detoxification and cooling blood may have a role to promote regeneration for liver cell.