Baseline metabolites could predict responders with hepatitis B virus-related liver fibrosis for entecavir or combined with FuzhengHuayu tablet

BACKGROUND After receiving entecavir or combined with FuzhengHuayu tablet(FZHY)treatment,some sufferers with hepatitis B virus(HBV)-related liver fibrosis could achieve a histological improvement while the others may fail to improve even worsen.Serum metabolomics at baseline in these patients who were effective in treatment remain unclear.AIM To explore baseline serum metabolites characteristics in responders.METHODS A total of 132 patients with HBV-related liver fibrosis and 18 volunteers as healthy controls were recruited.First,all subjects were divided into training set and validation set.Second,the included patients were subdivided into entecavir responders(E-R),entecavir no-responders(E-N),FZHY+entecavir responders(FR),and FZHY+entecavir no-responders(F-N)following the pathological histological changes after 48 wk’treatments.Then,Serum samples of all subjects before treatment were tested by high performance liquid chromatographytandem mass spectrometry(LC-MS)high-performance LC-MS.Data processing was conducted using multivariate principal component analysis and orthogonal partial least squares discriminant analysis.Diagnostic tests of selected differential metabolites were used for Boruta analyses and logistic regression.RESULTS As for the intersection about differential metabolic pathways between the groups E-R vs E-N and F-R vs F-N,results showed that 4 pathways including linoleic acid metabolism,aminoacyl-tRNA biosynthesis,cyanoamino acid metabolism,alanine,aspartate and glutamate metabolism were screened out.As for the differential metabolites,these 7 intersected metabolites including hydroxypropionic acid,tyrosine,citric acid,taurochenodeoxycholic acid,benzoic acid,2-Furoic acid,and propionic acid were selected.CONCLUSION Our findings showed that 4 metabolic pathways and 7 differential metabolites had potential usefulness in clinical prediction of the response of entecavir or combined with FZHY on HBV fibrotic liver.

Metabonomic window into hepatitis B virus-related hepatic diseases

Metabonomics has recently been widely used todiscover the pathogenesis and find potential metabolic markers with high sensitivity and specificity. Furthermore, it develops new diagnosis and treatment methods, increases early phase diagnosis rates of certain diseases and provides a new basis for targeted therapy. This review mainly analyzes the research progress of the metabonomics of hepatitis B virus(HBV)-related hepatic diseases, hoping to discover some potential metabolic markers for identification of HBVrelated hepatic diseases from other etiologies and for HBV-related hepatitis, liver cirrhosis and hepatocellular carcinoma. This can contribute to early discovery, diagnosis and treatment, eventually increasing the survival rate of HBV-related hepatic diseases.

Progress in hepatitis B virus-related acute-on-chronic liver failure treatment in China:A large,multicenter,retrospective cohort study using a propensity score matching analysis

Background:Hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF)has a high short-term mortality.However,the treatment progression for HBV-ACLF in China in the past decade has not been well characterized.The present study aimed to determine whether the HBV-ACLF treatment has significantly improved during the past decade.Methods:This study retrospectively compared short-term(28/56 days)survival rates of two different nationwide cohorts(cohort I:2008-2011 and cohort II:2012-2015).Eligible HBV-ACLF patients were enrolled retrospectively.Patients in the cohorts I and II were assigned either to the standard medical therapy(SMT)group(cohort I-SMT,cohort II-SMT)or artificial liver support system(ALSS)group(cohort IALSS,cohort II-ALSS).Propensity score matching analysis was conducted to eliminate baseline differences,and multivariate logistic regression analysis was used to explore the independent factors for 28-day survival.Results:Short-term(28/56 days)survival rates were significantly higher in the ALSS group than those in the SMT group(P<0.05)and were higher in the cohort II than those in the cohort I(P<0.001).After propensity score matching,short-term(28/56 days)survival rates were higher in the cohort II than those in the cohort I for both SMT(60.7%vs.53.0%,50.0%vs.39.8%,P<0.05)and ALSS(66.1%vs.56.5%,53.0%vs.44.4%,P<0.05)treatments.The 28-day survival rate was higher in patients treated with nucleos(t)ide analogs than in patients without such treatments(P=0.046).Multivariate logistic regression analysis revealed that ALSS(OR=0.962,95%CI:0.951-0.973,P=0.038),nucleos(t)ide analogs(OR=0.927,95%CI:0.871-0.983,P=0.046),old age(OR=1.028,95%CI:1.015-1.041,P<0.001),total bilirubin(OR=1.002,95%CI:1.001-1.003,P=0.004),INR(OR=1.569,95%CI:1.044-2.358,P<0.001),COSSH-ACLF grade(OR=2.683,95%CI:1.792-4.017,P<0.001),and albumin(OR=0.952,95%CI:0.924-0.982,P=0.002)were independent factors for 28-day mortality.Conclusions:The treatment for patients with HBV-ACLF has improved in the past decade.

Hepatitis E virus-related acute liver failure associated with pure red cell aplasia

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Immune Control Strategies for Vaccinia Virus-related Laboratory-acquired Infections

While presenting biological characteristics of vaccinia virus and laboratory-acquired infections during related research processes, this paper focuses on benefits and risks of vaccinia virus immunization in relation to laboratory-acquired infections, describes characteristics and the adaptation of vaccinia virus vaccine, analyses the role vaccinia virus immunization plays in the prevention and control of laboratory-acquired infections, and finally proposes solutions and countermeasures to further promote and implement immune control strategies. The problem related to immune strategy and laboratory- acquired infections which is being raised, analyzed and explored plays an active and instructive role in vaccinia virus related researches and laboratory- acquired infections, and also helps to recommend and develop relevant immune strategy for future vaccine control of such infections.

Comprehensive identification of key biomarkers and pathways in hepatitis B virus-related hepatocellular carcinoma using bioinformatic analyses

Objective:The aim of the present study was to explore the potential biomarkers and pathways in hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC)using bioinformatic analyses.Methods:GSE14520,a whole-genome expression profile dataset of HBV-related HCC,was downloaded from the gene expression omnibus database.Data of HCC patients from The Cancer Genome Atlas(TCGA)database were used as the validation cohort.

Pathogenesis and treatment of hepatitis C virus-related liver diseases

BACKGROUND: Few comprehensive reviews on the pa- thogenesis of hepatitis C virus (HCV)-related liver diseases have been presented to the present. This article was to re- view the pathogenesis and treatment of HCV-related liver diseases. DATA SOURCES: Data presented here are mostly taken from Japanese studies. RESULTS: HCV infection is characterized by persistent in- flammation of the liver and frequent development of hepa- tocellular carcinoma (HCC) in most cases. These charac- teristic evidences could be explained by immunological al- terations and oxidative stress in the hepatocyte caused by HCV infection. Interferon (IFN) treatment is carried out, at present, not only for the elimination of infected HCV for the treatment of chronic liver diseases, but also for both the prevention of HCC and the treatment of advanced HCC with chemotherapy. The treatment for oxidative stress is al- so important for non-responders to IFN. CONCLUSION: It is important to understand the pathoge- nesis of HCV-related liver diseases for a successful treat- ment.

Predictive value of the Chinese group on the study of severe hepatitis B-acute-on-chronic liver failure score in the short-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure

Background:As a large,prospective,multicenter study-based prognostic score for hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF),the Chinese group on the study of severe hepatitis B-acute-on-chronic liver failure score(COSSH-ACLFs),has been approved by some foreign scholars;however,its predictive value needs to be verified.This study investigated the predictive value of COSSH-ACLFs for short-term prognosis in Chinese patients with HBV-ACLF.Methods:This retrospective cohort study included 751 patients with HBV-ACLF admitted to the Fifth Medical Center of Chinese PLA General Hospital between January 2011 and December 2014.Spearman method was used to assess the correlation of COSSHACLFs with classical scores.Different COX multivariate regression models were used to confirm the relationship between COSSHACLFs and short-term prognosis in patients with HBV-ACLF,and stratified analysis was used to further verify the stability of this relationship.We compared the predictive powers of COSSH-ACLFs and other classical scores using area under the receiver operating characteristic curve(AUROC)and Z-test.Results:A total of 975 patients with HBV-ACLF were screened,and 751 were analyzed(623 male and 128 female).COSSH-ACLFs was the highest in patients with end-stage ACLF,followed by those with middle-and early-stage ACLF(H=211.8,P<0.001).In the fully adjusted model,COX multivariate regression analysis revealed that COSSH-ACLFs(as a continuous variable)was independently and positively correlated with mortality risk in patients with HBV-ACLF at 28 days(hazard ratio[HR]:1.37[1.22,1.53],P<0.001)and 90 days(HR:1.43[1.29,1.58],P<0.001).The same trend could be observed in the crude model and minimally adjusted model.The AUROCs of COSSH-ACLFs for 28-day and 90-day prognoses in patients with HBV-ACLF were 0.807 and 0.792,respectively,indicating a stronger predictive accuracy than those of classic models.Conclusions:COSSH-ACLFs,with a superior predictive accuracy compared with other classical scores,can strongly predict shortterm prognosis in Chinese patients with HBV-ACLF.

Prognosis of 153 patients with decompensated hepatitis B virus-related cirrhosis is improved after 3-year continuous lamivudine treatment

Background The long-term effectiveness and safety of lamivudine in patients with decompensated hepatitis B virus-related cirrhosis are still not clear. The present study attempted to describe the clinical outcomes of lamivudine therapy in these special patients over three years. Methods This study was a retrospective, controlled cohort study which involved 153 patients with decompensated hepatitis B virus-related cJrrhosJs. Of these, 86 patients received lamJvudJne 100 mg daily accompanied with general internal treatment, and the other 67 were given general internal treatment only. Significant clinical responses were recorded after years of antiviral treatment. Results The patients in both groups were matched in terms of age, sex and laboratory results at baseline. After years of therapy, the Child-Pugh-Turcotte scores and laboratory values of the patients receiving lamivudine were remarkably improved compared to the patients in the control group. The mortality rate and the incidence of cirrhosis-related complications were much lower in the lamivudine group than in the control group. Genotypic resistance tyrosine, methionine, aspartate, aspartate mutations developed in 26.7 percent of the patients during 3-year lamivudine treatment, and cirrhosis-related death and the hepatocellular carcinoma were more likely to occur in patients with these mutations than in the other patients who were treated with lamivudine. Conclusions Continuous long-term lamivudine treatment in patients with decompensated hepatitis B virus-related cirrhosis delays clinical progression, and significantly improves hepatic function and prognosis. However, the use of a retrospective control cohort precludes drawin（~ definitive conclusions.

Short-Term Efficacy of Treating Hepatitis B Virus-Related Acute-on-Chronic Liver Failure Based on Cold Pattern Differentiation with Hot Herbs: A Randomized Controlled Trial

Objective： To evaluate the clinical efficacy and safety of Yinchen Zhufu Decoction（茵陈术附汤, YCZFD） in the treatment of acute-on-chronic liver failure caused by hepatitis B virus（HBV-ACLF） with cold pattern in Chinese medicine（CM）. Methods： This is a multi-center randomized controlled trial of integrative treatment of CM and Western medicine（WM） for the management of HBV-ACLF patients. A total of 200 HBV-ACLF patients with cold pattern were equally randomly assigned to receive YCZFD and WM（integrative treatment） or WM conventional therapy alone respectively for 4 weeks. The primary end point was the mortality for HBV-ACLF patients. Secondary outcome measures included Model for End-Stage Liver disease（MELD） score, liver biochemical function, coagulation function and complications. Adverse events during treatment were reported. Results： The mortality was decreased 14.28% in the integrative treatment group compared with WM group（χ^2=6.156, P=0.013）. The integrative treatment was found to significantly improve the MELD score（t=2.353, P=0.020）. There were statistically significant differences in aspartate transaminase, total bilirubin, indirect bilirubin, direct bilirubin and prothrombin time between the two groups（P〈0.05 or P〈0.01）. The complications of ascites（χ^2=9.033, P=0.003） and spontaneous bacteria peritonitis（χ^2=4.194, P=0.041） were improved significantly in the integrative treatment group. No serious adverse event was reported. Conclusions： The integrative treatment of CM and WM was effective and safe for HBV-ACLF patients with cold pattern in CM. The Chinese therapeutic principle ＂treating cold pattern with hot herbs＂ remains valuable to the clinical therapy.（Trial registration No. Chi CTR-TRC-10000766）

The possible role and clinical implication of myeloid-derived suppressor cells in the peripheral blood of patients with hepatitis B virus-related acute-on-chronic liver failure

Objective To explore the possible role and clinical implications of myeloid-derived suppressor cells(MDSC)in the peripheral blood of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBVACLF).Methods A total of 25 HBV-ACLF patients

Prognostic value of keratin 18 for the patients with hepatitis B virus-related acute-on-chronic liver failure

Objective To analyze the serum keratin 18(K18)level of patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(HBV-ACLF)and its correlation with prognosis.Methods From December 2012 to October 2014,120 patients who visited Fuzhou Infectious Diseases Hospital and were diagnosed with HBV-ACLF were enrolled,and 20 chronic hepatitis B(CHB)pa-

Hepatocellular carcinoma in viral and autoimmune liver diseases:Role of CD4+CD25+Foxp3+regulatory T cells in the immune microenvironment

More than 90%of cases of hepatocellular carcinoma(HCC)occurs in patients with cirrhosis,of which hepatitis B virus and hepatitis C virus are the leading causes,while the tumor less frequently arises in autoimmune liver diseases.Advances in understanding tumor immunity have led to a major shift in the treatment of HCC,with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells.Regulatory T cells(Tregs)are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression,invasiveness,as well as metastasis.Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function.Notably,Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor(ICI)immunotherapy.Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity,it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events(irAEs).Since the use of ICI becomes common in oncology,with an increasing number of new ICI currently under clinical trials for cancer treatment,the occurrence of irAEs is expected to dramatically rise.Herein,we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease,and we discuss their involvement in irAEs due to the new immunotherapies.

Evaluation of Helicobacter pylori Infection in Patients with Chronic Hepatic Disease

Background： The ^13C urea breath test （^13C-UBT） is the gold standard for detecting Helicobacterpylori infection. H. pylori pathogenesis in patients with hepatitis B virus （HBV） and related diseases remains obscure. We used ^13C-UBT to detect H. p.vlori infection in patients with chronic HBV infection, HBV-related cirrhosis, HBV-related hepatic carcinoma, and other chronic hepatic diseases. Methods： A total of 131 patients with chronic hepatitis B （HB）, 179 with HBV-related cirrhosis, 103 with HBV-related hepatic carcinoma, 45 with HBV-negative hepatic carcinoma, and 150 controls were tested for H. pylori infection using ^13C-UBT. We compared H. pylori infection rate, liver function, complications of chronic hepatic disease, serum HBV-DNA, serum alpha-fetoprotein （AFP）, and portal hypertensive gastropathy （PHG） incidence among groups. Results： HBV-related cirrhosis was associated with the highest H. pylori infection rate （79.3%）. H. pylori infection rate in chronic HB was significantly higher than in the HBV-negative hepatic carcinoma and control groups （P 〈 0.001 ）. 11. pylori infection rate in patients with HBV-DNA ≥10^3 copies/ml was significantly higher than in those with HBV-DNA 〈103 copies/ml （76.8% vs. 52.4%, P 〈 0.001）. Prothrombin time （21.3 ± 3.5 s vs. 18.8 ±4.3 s）, total bilirubin （47.3±12.3 μmol/L vs. 26.6±7.9 μmol/L）, aspartate aminotransferase （ 184.5 ±37.6 U/L vs. 98.4 ± 23.5 U/L）, blood ammonia （93.4 ± 43.6 μmol/L vs. 35.5 ± 11.7 μmol/L）, and AFP （203.4±62.6 μg/L vs. 113.2± 45.8 μg/L） in the ^13C-UBT-positive group were significantly higher than in the ^13C-UBT-negative group （P 〈 0.01）. The incidence rates of esophageal fundus variceal bleeding （25.4% vs. 16.0%）, ascites （28.9% vs. 17.8%）, and hepatic encephalopathy （24.8% vs. 13.4%） in the ^13C-UBT-positive group were significantly higher than in the 13C-UBT-negative group （P 〈 0.01 ）. The percentages of patients with liver function in Child-Pugh Grade C （29.6% vs. 8.1%） and PHG （43.0% vs. 24.3%） in the ^13C-UBT-positive group were significantly higher than in the ^13C-UBT-negative group （P 〈 0.05）. Conclusions： It is possible that H. pylori infection could increase liver damage caused by HBV. 1t. pylori eradication should be performed in patients with complicating H. pylori infection to delay hepatic disease progression.

The “Traditional Chinese medicine regulating liver regeneration” treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data

On the basis of real-world clinical data,the study aimed to explore the effect and mechanisms of the treatment plan of“traditional Chinese medicine(TCM)regulating liver regeneration.”A total of 457 patients with HBV-related liver failure were retrospectively collected.The patients were divided into three groups:the modern medicine control group(MMC group),patients treated with routine medical treatment;the control group combining traditional Chinese and Western medicine(CTW),patients treated with routine medical treatment plus the common TCM formula;and the treatment group of“TCM regulating liver regeneration”(RLR),patients treated with both routine medical treatment and the special TCM formula of RLR.After 8 weeks of treatment,the mortality of patients in the RLR group(12.31%)was significantly lower than those in the MMC(50%)and CTW(29.11%)groups.Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups(P<0.05).In addition,there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group.RLR treatment can decrease jaundice,improve liver function,and significantly reduce the mortality in patients with HBV-related liver failure.The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.