Lymphocyte-to-white blood cell ratio is associated with outcome in patients with hepatitis B virus-related acute-on-chronic liver failure

BACKGROUND The lymphocyte-to-white blood cell ratio(LWR)is a blood marker of the systemic inflammatory response.The prognostic value of LWR in patients with hepatitis B virus-associated acute-on-chronic liver failure(HBV-ACLF)remains unclear.AIM To explore whether LWR could stratify the risk of poor outcomes in HBV-ACLF patients.METHODS This study was conducted by recruiting 330 patients with HBV-ACLF at the Department of Gastroenterology in a large tertiary hospital.Patients were divided into survivor and non-survivor groups according to their 28-d prognosis.The independent risk factors for 28-d mortality were calculated by univariate and multivariate Cox regression analyses.Patients were divided into low-and high-LWR groups according to the cutoff values.Kaplan-Meier analysis was performed according to the level of LWR.RESULTS During the 28-d follow-up time,135 patients died,and the mortality rate was 40.90%.The LWR level in non-surviving patients was significantly decreased compared to that in surviving patients.A lower LWR level was an independent risk factor for poor 28-d outcomes(hazard ratio=0.052,95%confidence interval:0.005-0.535).The LWR level was significantly negatively correlated with the Child-Turcotte-Pugh,model for end-stage liver disease,and Chinese Group on the Study of Severe Hepatitis B-ACLF II scores.In addition,the 28-d mortality was higher for patients with LWR<0.11 than for those with LWR≥0.11.CONCLUSION LWR may serve as a simple and useful tool for stratifying the risk of poor 28-d outcomes in HBVACLF patients.

Differential expression and significance of 5-hydroxymethylcytosine modification in hepatitis B virus carriers and patients with liver cirrhosis and liver cancer

BACKGROUND The relationship between hepatitis B surface antigen(HBsAg)-positive carrier status and liver cancer has been extensively studied.However,the epigenetic changes that occur during progression from HBsAg-positive carrier status or cirrhosis to liver cancer are unknown.The epigenetic modification of DNA hydroxymethylation is critical in tumor development.Further,5-hydroxymethylcytosine(5hmC)is an important base for DNA demethylation and epigenetic regulation.It is also involved in the assembly of chromosomes and the regulation of gene expression.However,the mechanism of action of 5hmC in HBsAgpositive carriers or patients with cirrhosis who develop liver cancer has not been fully elucidated.AIM To investigate the possible epigenetic mechanism of HBsAg-positive carriers and hepatocellular carcinoma(HCC)progression from cirrhosis.METHODS Forty HBsAg-positive carriers,forty patients with liver cirrhosis,and forty patients with liver cancer admitted to the First People's Hospital of Yongkang between March 2020 and November 2021 were selected as participants.Free DNA was extracted using a cf-DNA kit.cfDNA was extracted by 5hmC DNA sequencing for principal component analysis,the expression profiles of the three groups of samples were detected,and the differentially expressed genes(DEGs)modified by hydroxymethylation were screened.Bioinformatic analysis was used to enrich DEGs,such as in biological pathways.RESULTS A total of 16455 hydroxymethylated genes were identified.Sequencing results showed that 32 genes had significant 5hmC modification differences between HBsAg carriers and liver cancer patients,of which 30 were upregulated and 2 downregulated in patients with HCC compared with HBsAg-positive carriers.Significant 5hmC modification differences between liver cirrhosis and liver cancer patients were identified in 20 genes,of which 17 were upregulated and 3 were downregulated in patients with HCC compared with those with cirrhosis.These genes may have potential loci that are undiscovered or unelucidated,which contribute to the development and progression of liver cancer.Analysis of gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes showed that the major signaling pathways involved in the differential genes were biliary secretion and insulin secretion.The analysis of protein interactions showed that the important genes in the protein-protein interaction network were phosphoenolpyruvate carboxykinase and solute carrier family 2.CONCLUSION The occurrence and development of liver cancer involves multiple genes and pathways,which may be potential targets for preventing hepatitis B carriers from developing liver cancer.

Clinical significance of serum oxidative stress and serum uric acid levels before surgery for hepatitis B-related liver cancer

BACKGROUND The incidence and mortality of liver cancer are among the highest of all malignant tumors in China.The high recurrence rate after conventional hepatectomy is worrying.There is a lack of effective prognostic indicators for liver cancer.AIM To explore the clinical significance of preoperative serum oxidative stress and serum uric acid(UA)levels in hepatitis B-related liver cancer.METHODS The medical records of 110 hepatitis B-related liver cancer patients who under-went hepatectomy in Gansu Provincial Hospital were retrospectively analyzed.Recurrence in patients within 3 years after surgery was determined.The logistic regression model and Pearson or Spearman correlation were used to analyze the correlation between oxidative stress level and UA,and the recurrence of hepatitis B-related liver cancer.RESULTS Compared with the non-recurrence group,the levels of superoxide dismutase(SOD)and glutathione(GSH)in the recurrence group were lower and the levels of malondialdehyde(MDA)and UA were higher(all P<0.05).UA,SOD,MDA,and GSH were risk factors for postoperative recurrence in hepatitis B-related liver cancer patients(P<0.05).UA was positively correlated with MDA(r=0.395,P<0.001)and negatively correlated with GSH(r=-0.204,P=0.032).The area under the receiver operating characteristic curve(AUC)of SOD,MDA,GSH,and UA in predicting the prognosis was 0.276,0.910,0.199,and 0.784,respectively(all P<0.001).CONCLUSION The preoperative serum SOD,GSH,MDA,and UA levels had significant predictive effects on postoperative recurrence of hepatitis B-related liver cancer.

Influence of nonalcoholic fatty liver disease on response to antiviral treatment in patients with chronic hepatitis B:A meta-analysis

BACKGROUND Although hepatitis B virus infection is the leading cause of chronic liver injury globally,nonalcoholic fatty liver disease(NAFLD)is gradually gaining attention as another major chronic liver disease.The number of patients having chronic hepatitis B(CHB)with concomitant hepatic steatosis has increased.AIM To analyze the effect of NAFLD on the response to antiviral treatment in patients with CHB.METHODS Relevant English studies were systematically searched across PubMed,EMBASE,Web of Science,and Cochrane Library until October 2023.Studies in which the treatment outcomes were compared between patients with CHB only and those with CHB and hepatic steatosis were included.RESULTS Of the 2502 retrieved studies,11 articles were finally included.Biochemical response until 48 wk(OR=0.87,95%CI:0.50–1.53,P=0.000)and 96 wk(OR=0.35,95%CI:0.24–0.53,P=0.24)and virological response until 96 wk(OR=0.80,95%CI:0.43–1.49,P=0.097)were lower in patients with hepatic steatosis than in patients with CHB alone.CONCLUSION Hepatic steatosis lowers the biochemical response to antiviral treatment in patients with CHB.

Perilipin 2 inhibits replication of hepatitis B virus deoxyribonucleic acid by regulating autophagy under high-fat conditions

Hepatitis B virus(HBV)infection poses a global health concern without a definitive cure;however,antiviral medications can effectively suppress viral replication.This study delves into the intricate interplay between lipid metabo-lism and HBV replication,implicating molecular mechanisms such as the stearoyl coenzyme A desaturase 1 autophagy pathway,SAC1-like phosphatidylinositol phosphatase,and galectin-9 mediated selective autophagy of viral core proteins in regulating HBV replication.Within lipid droplets,perilipin 2(PLIN2)emerges as a pivotal guardian,with its overexpression protecting against autophagy and downregulation stimulating triglyceride catabolism through the autophagy pathway.This editorial discusses the correlation between hepatic steatosis and HBV replication,emphasizing the role of PLIN2 in this process.The study underscores the multifaceted roles of lipid metabolism,autophagy,and perilipins in HBV replication,shedding light on potential therapeutic avenues.

Outcomes of ABO-incompatible liver transplantation in end-stage liver disease patients co-infected with hepatitis B and human immunodeficiency virus

BACKGROUND Human immunodeficiency virus(HIV)-positive patients coinfected with hepatitis B virus(HBV)are eligible for liver transplantation(LT)in Africa and Southeast Asia,particularly China.However,the outcome of HIV-HBV coinfected patients referred for ABO-incompatible LT(ABOi-LT)is unknown.AIM To clarify the outcome of ABOi-LT for HIV-HBV coinfected patients with endstage liver disease(ESLD).METHODS We report on two Chinese HIV-HBV coinfected patients with ESLD who underwent A to O brain-dead donor LT and reviewed the literature on HIV-HBV coinfected patients treated with ABO-compatible LT.The pretransplantation HIV viral load was undetectable,with no active opportunistic infections.Induction therapy consisted of two sessions of plasmapheresis and a single dose of rituximab in two split doses,followed by an intraoperative regimen of intravenous immunoglobulin,methylprednisolone,and basiliximab.Post-transplant maintenance immunosuppressive agents consisted of tacrolimus and mycophenolate mofetil,and prednisone.RESULTS At the intermediate-term follow-up,patients showed undetectable HIV viral load,CD4(+)T cell counts greater than 150 cells/μL,no HBV recurrence,and stable liver function.A liver allograft biopsy showed no evidence of acute cellular rejection.Both patients survived at 36-42 mo of follow-up.CONCLUSION This is the first report of ABOi-LT in HIV-HBV recipients with good intermediate-term outcomes,suggesting that ABOi-LT may be feasible and safe for HIV-HBV coinfected patients with ESLD.

Serum thymosin β4 levels in patients with hepatitis B virus-related liver failure

AIM:To investigate whether serum thymosinβ4 can provide diagnostic or prognostic information in liver failure patients caused by chronic hepatitis B virus(HBV) infection. METHODS:Serum thymosinβ4 levels were measured in 30 patients with acute-on-chronic liver failure(ACLF), 31 patients with chronic liver failure(CLF),30 patients with compensated liver cirrhosis(CR)and 32 patients with chronic hepatitis B and 30 healthy controls.Serum thymosinβ4 levels were measured by enzyme-linked immunosorbent assay and Child-Pugh and model for end-stage liver disease(MELD)scores were calculated for each patient on admission.RESULTS:Compared with healthy controls,serum thymosinβ4 levels in ACLF,CLF,CR and chronic hepatitis B patients were significantly lower,6.5047 (4.7879-10.5314)μg/mL vs 0.4632(0.2759-0.8768) μg/mL,0.6981(0.5209-1.2008)μg/mL,1.8053 (0.8110-2.3397)μg/mL,3.7803(1.8570-6.4722)μg/mL, respectively(P<0.001).The levels of thymosinβ4 in liver failure(ACLF or CLF)patients were markedly lower than that in CR(P<0.001),and a difference was also found between CLF and ACLF patients(P=0.038).In patients with chronic liver disease,there was a positive relationship between thymosinβ4 levels and albumin, choline esterase,and platelet(P<0.001),and negative relationship with alanine aminotransferase(P=0.020), aspartate aminotransferase,total bilirubin,international normalized ratio of prothrombin time,and Child-Pugh and MELD scores(P<0.001).Of the 61 liver failure patients,the thymosinβ4 levels of non-survivors were significantly lower than that of survivors(P=0.007). Receiver operating characteristics analysis identified a thymosinβ4 cutoff level of 0.5708μg/mL for predicting poor prognosis in all liver failure patients.The serial thymosinβ4 values were observed in 13 liver failure inpatients.Lower initial values were observed in the death.While greater improvement in thymosinβ4 value was found in those who recovered from the disease. CONCLUSION:Serum thymosinβ4 can be used as an important potential predictor for liver failure caused by chronic HBV infection.

Combined glucocorticoid and antiviral therapy of hepatitis B virus-related liver failure

Acute hepatic failure due to hepatitis B virus(HBV)can occur both during primary infection as well as after reactivation of chronic infection.Guidelines recommend considering antiviral therapy in both situations,although evidence supporting this recommendation is weak.Since HBV is not directly cytopathic,the mechanism leading to fulminant hepatitis B is thought to be primarily immunemediated.Therefore,immunosuppression combined with antiviral therapy might be a preferred therapeutic intervention in acute liver failure in hepatitis B.Here wereport our favourable experience in three hepatitis B patients with fulminant hepatic failure who were treated by combining high-dose steroid therapy with standard antiviral treatment,which resulted in a rapid improvement of clinical and liver parameters.

Modified model for end-stage liver disease improves shortterm prognosis of hepatitis B virus-related acute-on-chronic liver failure

AIM To investigate whether the short-term prognosis of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF) could be improved by using a modified model for end-stage liver disease(MELD) including serum lactate.METHODS This clinical study was conducted at the First Affiliated Hospital, Fujian Medicine University, China. From 2009 to 2015, 236 patients diagnosed with HBV-related ACLF at our center were recruited for this 3-month followup study. Demographic data and serum lactate levels were collected from the patients. The MELD scores with or without serum lactate levels from survival and nonsurvival groups were recorded and compared.RESULTS Two hundred and thirty-six patients with HBV-ACLF were divided into two groups: survival group(S) andnon-survival group(NS). Compared with the NS group, the patients in survival the S group had a significantly lower level of serum lactate(3.11 ± 1.98 vs 4.67 ± 2.43, t = 5.43, P < 0.001) and MELD score(23.33 ± 5.42 vs 30.37 ± 6.58, t = 9.01, P = 0.023). Furthermore, serum lactate level was positively correlated with MELD score(r = 0.315, P < 0.001). Therefore, a modified MELD including serum lactate was developed by logistic regression analysis(0.314 × lactate + 0.172 × MELD-5.923). In predicting 3-month mortality using the MELD-LAC model, the patients from the S group had significantly lower baseline scores(-0.930 ± 1.34) when compared with those from the NS group(0.771 ± 1.32, t = 9.735, P < 0.001). The area under the receiver operating characteristic curve(AUROC) was 0.859 calculated by using the MELD-LAC model, which was significantly higher than that calculated by using the lactate level(0.790) or MELD alone(0.818). When the cutoff value was set at-0.4741, the sensitivity, specificity, positive predictive value and negative predictive value for predicting short-term mortality were 91.5%, 80.10%, 94.34% and 74.62%, respectively. When the MELD-LAC scores at baseline level were set at-0.5561 and 0.6879, the corresponding mortality rates within three months were 75% and 90%, respectively.CONCLUSION The short-term prognosis of HBV-related ACLF was improved by using a modified MELD including serum lactate from the present 6-year clinical study.

Clinical management of hepatitis B virus infection correlated with liver transplantation

BACKGROUND: As a radical cure for post-hepatitis B virus (HBV)-related liver cirrhosis and hepatocellular carcinoma, liver transplantation has been applied in many medical centers. Before the use of effective measures, hepatitis B recurrence and the existence of HBsAg(+) donors, patients with hepatitis B-related diseases are contraindicated for liver transplantation. Application of interferon, hepatitis B immunoglobulin (HBIG), and nucleotide analogues (e.g., lamivudine) has made great progress in the clinical care of HBV. However, there are still many shortcomings such as low viral suppression rate, rising expense, and the induction of HBV tyrosine-methionine-aspartate-aspartate (YMDD) mutation. This article systematically reviews the current evidence that immunotherapy, conventional drug combinations, and some special fields of HBV infection correlate with liver transplantation. DATA SOURCES: Studies were identified by searching MEDLINE and PubMed for articles using the keywords 'hepatitis B virus', 'hepatitis B vaccination', 'lamivudine', 'adefovir', 'entecavir', 'tenofovir', 'HBV genotype', and 'liver transplantation' up to October 2009. Additional papers were identified by a manual search of the references from the key articles. RESULTS: Hepatitis B vaccine and human monoclonal antibody have very good clinical prospects. Compared with traditional therapies, the new medical regimens have many benefits such as boosting viral suppression rate and decreasing medical expenses. The triple therapy for YMDD mutation also has an excellent therapeutic effect and a low barrier to resistance. New nucleos(t)ide analogues (entecavir and tenofovir) eliminate virus more effectively with few adverse reactions, and may replace lamivudine or HBIG in future. CONCLUSIONS: Hepatitis B vaccine needs further large-scale and rigorous randomized controlled trials to confirm its effective dose and injection frequency. Monoclonal antibody is still experimental, and the next step is to carry out the relevant animal and human studies. A consensus standard regimen for the treatment of hepatitis B should be developed.

Epidemiological and clinical features of hepatitis B virus related liver failure in China

AIM:To examine the epidemiologic and clinical characteristics of hepatitis B virus (HBV) related liver failure in patients in China.METHODS:This study was conducted with a retrospective design to examine 1066 patients with HBVrelated liver failure in the southwest of China.RESULTS:There were more male than female patients.Young and middle-aged people comprised most of the patients.Farmers and laborers comprised the largest proportion (63.09%).Han Chinese accounted for 98.12%,while minority ethnic groups only accounted for 0.88% of patients.A total of 43.47% patients had a family history of HBV-related liver failure and 56.66% patients had a history of drinking alcohol.A total of 42.59% patients with HBV-related liver failure had definite causes.With regard to the clinical manifestation of HBV-related liver failure,the symptoms were:hypodynamia,anorexia and abdominal distension.Total bilirubin (TBIL) and alanine aminotransferase (ALT) levels were altered in 46.23% of patients with evident damage of the liver.Univariate logistic regression analysis showed that the patients' prognoses were correlated with ALT,aspartate aminotransferase,albumin,TBIL,prothrombin activity (PTA),and alpha-fetoprotein levels,and drinking alcohol,ascites,hepatorenal syndrome,infection and ≥ 2 complications.Multifactor logistic regression analysis showed that the activity of thrombinogen and the number of complications were related to the prognosis.CONCLUSION:Alcohol influences the patients' prognosis and condition.PTA and complications are independent factors that can be used for estimating the prognosis of HBV-related liver failure.

Clinical characteristics and 28-d outcomes of bacterial infections in patients with hepatitis B virus-related acute-on-chronic liver failure

BACKGROUND Acute-on-chronic liver failure(ACLF),which includes hepatic and multiple extrahepatic organ failure,is a severe emergency condition that has high mortality.ACLF can rapidly progress and requires an urgent assessment of condition and referral for liver transplantation.Bacterial infections(BIs)trigger ACLF and play pivotal roles in the deterioration of clinical course.AIM To investigate the clinical characteristics and 28-d outcomes of first BIs either at admission or during hospitalization in patients with hepatitis B virus(HBV)-ACLF as defined by the Chinese Group on the Study of Severe Hepatitis B(COSSH).METHODS A total of 159 patients with HBV-ACLF and 40 patients with acute decompensation of HBV-related chronic liver disease combined with first BIs were selected for a retrospective analysis between October 2014 and March 2016.The characteristics of BIs,the 28-d transplant-free survival rates,and the independent predictors of the 28-d outcomes were evaluated.RESULTS A total of 194 episodes of BIs occurred in 159 patients with HBV-ACLF.Among the episodes,13.4%were community-acquired,46.4%were healthcare-associated,and 40.2%belonged to nosocomial BIs.Pneumonia(40.7%),spontaneous bacterial peritonitis(SBP)(34.5%),and bloodstream infection(BSI)(13.4%)were the most prevalent.As the ACLF grade increased,the incidence of SBP showed a downward trend(P=0.021).Sixty-one strains of bacteria,including 83.6%Gramnegative bacteria and 29.5%multidrug-resistant organisms,were cultivated from 50 patients with ACLF.Escherichia coli(44.3%)and Klebsiella pneumoniae(23.0%)were the most common bacteria.As the ACLF grade increased,the 28-d transplant-free survival rates showed a downward trend(ACLF-1,55.7%;ACLF-2,29.3%;ACLF-3,5.4%;P<0.001).The independent predictors of the 28-d outcomes of patients with HBV-ACLF were COSSH-ACLF score(hazard ratio[HR]=1.371),acute kidney injury(HR=2.187),BSI(HR=2.339),prothrombin activity(HR=0.967),and invasive catheterization(HR=2.173).CONCLUSION For patients with HBV-ACLF combined with first BIs,pneumonia is the most common form,and the incidence of SBP decreases with increasing ACLF grade.COSSH-ACLF score,acute kidney injury,BSI,prothrombin activity,and invasive catheterization are the independent predictors of 28-d outcomes.

Negative impact of hepatitis B surface seroclearance on prognosis of hepatitis B-related primary liver cancer

AIM To assess the impact of hepatitis B surface(HBs Ag) seroclearance on survival outcomes in hepatitis B-related primary liver cancer.METHODS Information from patients with hepatitis B-related liver cancer admitted in our hospital from 2008-2017 was retrieved. Cases diagnosed with HBs Ag(-) and HBc Ab(+) liver cancer were included in the HBs Ag seroclearance(SC) group. HBs Ag(+) liver cancer patients strictly matched for liver cancer stage(AJCC staging system, 8 th edition), Child-Pugh score, and first diagnosis/treatment method(surgery, ablation and TACE) were assigned to the HBsA g non-seroclearance(NSC) group. Then, clinical, pathological and survival data in both groups were assessed.RESULTS The SC and NSC groups comprised of 72 and 216 patients, respectively. Patient age(P < 0.001) and platelet count(P = 0.001) in the SC group were significantly higher than those of the NSC group. SC group patients who underwent surgery had more intrahepatic cholangiocarcinoma(ICC) and combined HCC-CC(CHC) cases than the NSC group, but no significant differences in tumor cell differentiation and history of liver cirrhosis were found between the two groups. The numbers of interventional treatments were similar in both groups(4.57 vs 5.07, P > 0.05). Overall survival was lower in the SC group than the NSC group(P = 0.019), with 1-,3-, and 5-year survival rates of 82.1% vs 85.1%, 43.2%vs 56.8%, and 27.0% vs 45.2%, respectively. Survival of patients with AJCC stage Ⅰ disease in the SC group was lower than that of the NSC group(P = 0.029).CONCLUSION Seroclearance in patients with hepatitis B-related primary liver cancer has protective effects with respect to tumorigenesis, cirrhosis, and portal hypertension but confers worse prognosis, which may be due to the frequent occurrence of highly malignant ICC and CHC.

Mucosal-associated invariant T cells in hepatitis B virus-related liver failure

BACKGROUND Liver failure has high mortality and poor prognosis,and establishing new reliable markers for predicting its prognosis is necessary.Mucosal-associated invariant T(MAIT)cells are a novel population of innate-like lymphocytes involved in inflammatory liver disease,and their potential role in liver failure remains unclear.AIM To investigate alteration of circulating MAIT cells and assess its prognostic value in patients with hepatitis B virus(HBV)-related liver failure.METHODS We recruited 55 patients with HBV-related liver failure,48 patients with chronic hepatitis B and 40 healthy controls(HCs)from Nantong Third People’s Hospital Affiliated to Nantong University.Peripheral blood mononuclear cells were isolated,and the percentage and number of circulating MAIT cells were detected by flow cytometry.Plasma levels of interleukin(IL)-7,IL-12p70,IL-18 and interferon-αwere measured by Luminex assay.RESULTS Circulating MAIT cells were significantly decreased in HBV-related liver failure patients(percentage:2.00±1.22 vs 5.19±1.27%,P<0.0001;number:5.47±4.93 vs 84.43±19.59,P<0.0001)compared with HCs.More importantly,there was a significant reduction of MAIT cells in patients with middle/late-stage compared with early-stage liver failure.Circulating MAIT cells partially recovered after disease improvement,both in percentage(4.01±1.21 vs 2.04±0.95%,P<0.0001)and in cell count(17.24±8.56 vs 7.41±4.99,P<0.0001).The proportion(2.29±1.01 vs 1.58±1.38%,P<0.05)and number(7.30±5.70 vs 2.94±1.47,P<0.001)of circulating MAIT cells were significantly higher in the survival group than in the dead/liver transplantation group,and the Kaplan–Meier curve showed that lower expression of circulating MAIT cells(both percentage and cell count)predicted poor overall survival(P<0.01).Also,the levels of IL-12(20.26±5.42 pg/mL vs 17.76±2.79 pg/mL,P=0.01)and IL-18(1470.05±1525.38 pg/mL vs 362.99±109.64 pg/mL,P<0.0001)were dramatically increased in HBV-related liver failure patients compared with HCs.CONCLUSION Circulating MAIT cells may play an important role in the process of HBV-related liver failure and can be an important prognostic marker.

Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure

AIM:To investigate the survival rates and prognostic factors in patients with hepatitis B virus-related acuteon-chronic liver failure(HBV-ACLF).METHODS:Clinical data in hospitalized patients with HBV-ACLF admitted from 2006 to 2009 were retrospectively analyzed.Their general conditions and survival were analyzed by survival analysis and Cox regression analysis.RESULTS:A total of 190 patients were included in this study.The overall 1-year survival rate was 57.6%.Patients not treated with antiviral drugs had a significantly higher mortality[relative risk(RR)=0.609,P=0.014].The highest risk of death in patients with ACLF was associated with hepatorenal syndrome(HRS)(RR=2.084,P=0.026),while other significant factors were electrolyte disturbances(RR=2.062,P=0.010),and hepatic encephalopathy(HE)(RR=1.879,P<0.001).CONCLUSION:Antiviral therapy has a strong effect on the prognosis of the patients with HBV-ACLF by improving their 1-year survival rate.HRS,electrolyte disturbances,and HE also affect patient survival.

Short-term prognostic factors for hepatitis B virus-related acute-onchronic liver failure

BACKGROUND Acute-on-chronic liver failure(ACLF)is the abrupt exacerbation of declined hepatic function in patients with chronic liver disease.AIM To explore the independent predictors of short-term prognosis in patients with hepatitis B virus(HBV)-related ACLF and to establish a predictive short-term prognosis model for HBV-related ACLF.METHODS From January 2016 to December 2019,207 patients with HBV-related ACLF attending the 910^(th) Hospital of Chinese People's Liberation Army were continuously included in this retrospective study.Patients were stratified based on their survival status 3 mo after diagnosis.Information was collected regarding gender and age;coagulation function in terms of prothrombin time and international normalized ratio(INR);hematological profile in terms of neutrophil-tolymphocyte ratio(NLR)and platelet count(PLT);blood biochemistry in terms of alanine aminotransferase,aspartate aminotransferase,total bilirubin(Tbil),albumin,cholinesterase,blood urea nitrogen(BUN),creatinine,blood glucose,and sodium(Na);tumor markers including alpha-fetoprotein(AFP)and Golgi protein 73(GP73);virological indicators including HBV-DNA,HBsAg,HBeAg,Anti-HBe,and Anti-HBc;and complications including hepatic encephalopathy,hepatorenal syndrome,spontaneous peritonitis,gastrointestinal bleeding,and pulmonary infection.RESULTS There were 157 and 50 patients in the survival and death categories,respectively.Univariate analysis revealed significant differences in age,PLT,Tbil,BUN,NLR,HBsAg,AFP,GP73,INR,stage of liver failure,classification of liver failure,and incidence of complications(pulmonary infection,hepatic encephalopathy,spontaneous bacterial peritonitis,and upper gastrointestinal bleeding)between the two groups(P<0.05).GP73[hazard ratio(HR):1.009,95%confidence interval(CI):1.005-1.013,P=0.000],middle stage of liver failure(HR:5.056,95%CI:1.792-14.269,P=0.002),late stage of liver failure(HR:22.335,95%CI:8.544-58.388,P=0.000),pulmonary infection(HR:2.056,95%CI:1.145-3.690,P=0.016),hepatorenal syndrome(HR:6.847,95%CI:1.930-24.291,P=0.003),and HBsAg(HR:0.690,95%CI:0.524-0.908,P=0.008)were independent risk factors for short-term prognosis in patients with HBV-related ACLF.Following binary logistics regression analysis,we arrived at the following formula for predicting short-term prognosis:Logit(P)=Ln(P/1-P)=0.013×(GP73 ng/mL)+1.907×(middle stage of liver failure)+4.146×(late stage of liver failure)+0.734×(pulmonary infection)+22.320×(hepatorenal syndrome)-0.529×(HBsAg)-5.224.The predictive efficacy of the GP73-ACLF score was significantly better than that of the Model for End-Stage Liver Disease(MELD)and MELD-Na score models(P<0.05).CONCLUSION The stage of liver failure,presence of GP73,pulmonary infection,hepatorenal syndrome,and HBsAg are independent predictors of short-term prognosis in patients with HBV-related ACLF,and the GP73-ACLF model has good predictive value among these patients.

Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure

AIM:To determine the prognostic value of circulating indicators of cell death in acute-on-chronic liver failure(ACLF)patients with chronic hepatitis B virus(HBV)infection as the single etiology.METHODS:Full length and caspase cleaved cytokeratin 18(detected as M65 and M30 antigens)represent circulating indicators of necrosis and apoptosis.M65and M30 were identified by enzyme-linked immunosorbent assay in 169 subjects including healthy controls(n=33),patients with chronic hepatitis B(CHB,n=55)and patients with ACLF(n=81).According to the 3-mo survival period,ACLF patients were defined as having spontaneous recovery(n=33)and non-spontaneous recovery which included deceased patients and those who required liver transplantation(n=48).RESULTS:Both biomarker levels significantly increased gradually as liver disease progressed(for M65:P<0.001 for all;for M30:control vs CHB,P=0.072;others:P<0.001 for all).In contrast,the M30/M65 ratio was significantly higher in controls compared with CHB patients(P=0.010)or ACLF patients(P<0.001).In addition,the area under receiver operating characteristic curve(AUC)analysis demonstrated that both biomarkers had diagnostic value(AUC≥0.80)in identifying ACLF from CHB patients.Interestingly,it is worth noting that the M30/M65 ratio was significantly different between spontaneous and non-spontaneous recovery in ACLF patients(P=0.032).The prognostic value of the M30/M65 ratio was compared with the Model for End-Stage Liver Disease(MELD)and Child-Pugh scores at the 3-mo survival period,the AUC of the M30/M65ratio was 0.66 with a sensitivity of 52.9%and the highest specificity of 92.6%(MELD:AUC=0.71;sensitivity,79.4%;specificity,63.0%;Child-Pugh:AUC=0.77;sensitivity,61.8%;specificity,88.9%).CONCLUSION:M65 and M30 are strongly associated with liver disease severity.The M30/M65 ratio may be a potential prognostic marker for spontaneous recovery in patients with HBV-related ACLF.

Diabetes mellitus may affect the long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after liver transplantation

AIM to determine whether diabetes mellitus(DM) affects prognosis/recurrence after liver transplantation(Lt) for hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC). METHODS A retrospective study was conducted between January 2000 and August 2013 on 1631 patients with HBV-related HCC who underwent Lt with antiviral prophylaxis. Patient data were obtained from the China Liver transplant Registry(https://www.cltr.org/). to compare the outcomes and tumor recurrence in the HBV-related HCC patients with or without DM, statistical analyses were conducted using χ2 tests, Mann-Whitney tests, the Kaplan-Meier method, log-rank tests and multivariate step-wise Cox regression analysis. RESULTS Univariate analysis of 1631 patients who underwent Lt found overall 1-, 3- and 5-year survival rates of 79%, 73% and 71% respectively in the DM patients, and 84%, 78% and 76% in the non-DM patients respectively. Overall survival rate differences after Lt between the two groups were significant(P = 0.041), but recurrence-free survival rates were not(P = 0.096). By stratified analysis, the overall survival rates in DM patients for age > 50 years(P = 0.002), the presence of vascular invasion(P = 0.096), tumors ≤ 3 cm(P = 0.047), two to three tumor nodules(P = 0.007), Child-Pugh grade B(P = 0.018), and preLt alanine aminotransferase levels between 40 and 80 IU/L(P = 0.017) were significantly lower than in non-DM patients. Additionally, serum α-fetoprotein level > 2000 ng/m L(P = 0.052) was associated with a significant survival difference trend between DM and non-DM patients. Multivariate analysis showed that the presence of DM(P < 0.001, HR = 1.591; 95%CI: 1.239-2.041) was an independent predictor associated with poor survival after Lt. CONCLUSION HBV-related HCC patients with DM have decreased long-term overall survival and poor Lt outcomes. Prevention strategies for HCC patients with DM are recommended.

Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

This review describes woodchucks chronically infected with the woodchuck hepatitis virus(WHV)as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma(HCC)induced by the hepatitis B virus(HBV).Since laboratory animal models susceptible to HBV infection are limited,woodchucks experimentally infected with WHV,a hepatitis virus closely related to HBV,are increasingly used to enhance our understanding of virus-host interactions,immune response,and liver disease progression.A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established,which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans.HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size,morphology,and molecular gene signature to those of HBV-infected patients.Accordingly,woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC.In addition,drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs,alone or in combination with other compounds,minimizes the risk of liver disease progression to HCC.More recently,woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute,self-limited and chronic infections.Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae,including the onset of HCC.Therefore,woodchucks with chronic WHV infection constitute a well-characterized,fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities,which are based on chemo,gene,and immune therapy,for the prevention and treatment of HCC in patients for which current treatment options are dismal.

Long-term results of liver transplantation for over 60 years old patients with hepatitis B virus-related end-stage liver disease

BACKGROUND： Hepatitis B virus（HBV）-related end-stage liver disease is the leading indication for liver transplantation in China, but long-term results of liver transplantation in patients aged over 60 years are not clear. The present study was to reveal the natural history of liver recipients with hepatitis B older than60 years.METHODS： The recipients who had received liver transplantation between December 2003 and December 2005 were divided into two groups： those equal or older than 60 years（older group,n60） and those younger than 60 years（younger group, n305）.Risk factors for poor long-term outcome in patients aged over 60 years were also analyzed.RESULTS： Except for age and preexisting chronic disease（P0.05）,no significant differences were observed in perioperative characteristics between the two groups. There was also no significant difference in HBV and hepatocellular carcinoma recurrence（P0.05）. The actuarial 1-, 3-, 5- and 8-year survival rates were 81.6%, 71.6%, 66.7% and 63.3% respectively for the older group vs 84.9%, 77.7%, 70.8% and 65.6% for the younger group（P0.05）. Multivariate analyses showed that pre-liver transplant renal insufficiency was a risk factor for poor outcome in the older group（odds ratio=3.615, P0.014）.CONCLUSIONS： Liver transplantation is safe and feasible for patients with HBV-related end-stage liver disease aged over 60years. Older patients with renal insufficiency should undergo transplantation earlier than younger patients.