Hepatitis C-related liver cirrhosis-strategies for the prevention of hepatic decompensation,hepatocarcinogenesis,and mortality

Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of β-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.

Hepatic decompensation/serious adverse events in post-liver transplantation recipients on sofosbuvir for recurrent hepatitis C virus

AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection.METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome.RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m2, 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases.CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.

Evolution of care in cirrhosis: Preventing hepatic decompensation through pharmacotherapy

Cirrhosis is a leading cause of morbidity and mortality,impacting more than 120 million people worldwide.Although geographic differences exist,etiologic factors such as alcohol use disorder,chronic viral hepatitis infections,and non-alcoholic fatty liver disease are prevalent in nearly every region.Historically,significant effort has been devoted to modifying these risks to prevent disease progression.Nevertheless,more than 11%of patients with compensated cirrhosis experience hepatic decompensation each year.This transition signifies the most important prognostic factor in the natural history of the disease,corresponding to a decline in median survival to below 2 years.Over the past decade,the need for pharmacotherapies aimed at reducing the risk for hepatic decompensation has been emphasized,and non-selective beta-blockers have emerged as the most effective option to date.However,a critical therapeutic gap still exists,and additional therapies have been proposed,including statins,rifaximin,and sodium-glucose cotransporter-2 inhibitors.Based on the results of innovative retrospective analyses and small-scale prospective trials,these pharmacotherapies represent promising options,but further studies,including randomized controlled trials,are necessary before they can be incorporated into clinical use.This report highlights the potential impact of these agents and others in preventing hepatic decompensation and discusses how this paradigm shift may pave the way for guideline-directed medical therapy in cirrhosis.

Road to recompensation:BavenoⅦcriteria and transjugular intrahepatic portosystemic shunt in liver cirrhosis

Liver cirrhosis has long been considered a point of no return,with limited hope for recovery.However,recent advancements,particularly the Baveno VII criteria and the utilization of transjugular intrahepatic portosystemic shunt(TIPS),have illuminated the concept of hepatic recompensation.In this editorial we comment on the article by Gao et al published in the recent issue.This editorial provides a comprehensive overview of the evolution of understanding cirrhosis,the criteria for recompensation,and the efficacy of TIPS in achieving recompensation.We discuss key findings from recent studies,including the promising outcomes observed in patients who achieved recompensation post-TIPS insertion.While further research is needed to validate these findings and elucidate the mechanisms underlying recompensation,the insights presented here offer renewed hope for patients with decompensated cirrhosis and highlight the potential of TIPS as a therapeutic option in their management.

Validation of the albumin-bilirubin score for identifying decompensation risk in patients with compensated cirrhosis

BACKGROUND The albumin-bilirubin(ALBI)score is an index of liver function recently developed to assess prognosis in patients with hepatocellular carcinoma(HCC).It can detect small changes in liver dysfunction and has been successfully applied to the prediction of survival in patients with non-malignant liver diseases of various etiologies.AIM To investigate the ALBI score for identifying decompensation risk at the 3-year follow-up in patients with compensated cirrhosis.METHODS One-hundred and twenty-three patients with compensated cirrhosis without HCC in King Chulalongkorn Memorial Hospital diagnosed by imaging were retrospectively enrolled from January 2016 to December 2020.A total of 113 patients(91.9%)had Child A cirrhosis with a median model for end-stage liver disease(MELD)score of less than 9.Baseline clinical and laboratory variables and decompensation events were collected.The ALBI score was calculated and validated to classify decompensation risk into low-,middle-,and high-risk groups using three ALBI grade ranges(ALBI grade 1:≤-2.60;grade 2:>-2.60 but≤-1.39;grade 3:>-1.39).Decompensation events were defined as ascites development,variceal bleeding,or grade 3 or 4 hepatic encephalopathy.RESULTS Among 123 cirrhotic patients enrolled,13.8%(n=17)developed decompensating events at a median time of 25[95%confidence interval(CI):17-31]mo.Median baseline ALBI score in compensated cirrhosis was significantly lower than that of patients who developed decompensation events[-2.768(-2.956 to-2.453)vs-2.007(-2.533 to-1.537);P=0.01].Analysis of decompensation risk at 3 years showed that ALBI score had a time-dependent area under the curve(tAUC)of 0.86(95%CI:0.78-0.92),which was significantly better than that of ALBI-Fibrosis-4(ALBI-FIB4)score(tAUC=0.77),MELD score(tAUC=0.66),Child-Pugh score(tAUC=0.65),and FIB-4 score(tAUC=0.48)(P<0.05 for all).The 3-year cumulative incidence of decompensation was 3.1%,22.6%,and 50%in the low-,middle-,and high-risk groups,respectively(P<0.001).The odds ratio for decompensation in patients of the high-risk group was 23.33(95%CI:3.88-140.12,P=0.001).CONCLUSION The ALBI score accurately identifies decompensation risk at the 3-year follow-up in patients with compensated cirrhosis.Those cirrhotic patients with a high-risk grade of ALBI score showed a 23 times greater odds of decompensation.

Low level of hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in compensated cirrhotic patients

BACKGROUND Whether patients with compensated cirrhosis and low-level viremia(LLV)of hepatitis B should receive antiviral therapy(AVT)is still controversial,and published results are inconsistent.AIM To investigate the link between LLV in compensated cirrhosis and prognosis concerning hepatocellular carcinoma(HCC),decompensation,and liver-related events.METHODS The PubMed,EMBASE,and Cochrane Library databases were searched up to March 5,2023.Outcomes of interest were assessed by pooled hazard ratios(HRs).The study was registered with PROSPERO(CRD42023405345).RESULTS Six cohort studies representing 3155 patients were included.Compared with patients with undetectable HBV DNA,patients with LLV was associated with increased risk of HCC(HR:2.06,95%CI:1.36-3.13;Q-statistic-P=0.07,I^(2)=51%)regardless of receiving AVT or not(AVT group:HR:3.14;95%CI:1.73-5.69;Qstatistic-P=0.60,I2=0%;un-AVT group:HR:1.73,95%CI:1.09-2.76;Q-statistic-P=0.11,I2=50%).The pooled results showed no statistical association between LLV and decompensation of cirrhosis(HR:2.06,95%CI:0.89-4.76;Q-statistic-P=0.04,I2=69%),and liver-related events(HR:1.84,95%CI:0.92-3.67;Q-statistic-P=0.03,I2=72%),respectively.Grading of Recommendations Assessment,Development and Evaluation assessment indicated moderate certainty for HCC,very low certainty for decompensation of cirrhosis and liver-related clinical events.CONCLUSION LLV in compensated cirrhotic patients is associated with increased risk of HCC,higher tendency for hepatic decompensation and liver-related events.Closer screening of HCC should be conducted in this population.

Immunoglobulin G in non-alcoholic steatohepatitis predicts clinical outcome:A prospective multi-centre cohort study

BACKGROUND Autoimmune markers including plasma cells(PC),anti-smooth-muscle antibody(ASMA),anti-nuclear antibody(ANA),and raised immunoglobulin G(IgG)are commonly observed in non-alcoholic steatohepatitis(NASH),however their clinical significance is unknown.AIM To determine if autoimmune markers in NASH patients are independently associated with poorer clinical outcomes.METHODS Consecutive patients with biopsy proven NASH from Christchurch Hospital,New Zealand and Singapore General Hospital(SGH)were included between 2005 to 2016 in a prospective multi-centre cohort study.Patients with other causes of chronic liver disease were excluded.IgG>14 g/L or globulin fraction>50%,ANA≥1:40,SMA≥1:40 were considered positive.Multivariate analysis was performed to assess which markers were independently associated with mortality and hepatic decompensation.RESULTS Total 261 patients were included of which 201 were from SGH.The median age was 53 and 51.9%were male.Advanced fibrosis was present in 31.4%at diagnosis.PC,ASMA,ANA and raised IgG were observed in 13.1%,4.9%,27.8%and 30.1%of patients respectively.After multivariate analysis,elevated IgG[Hazard Ratio(HR)6.79,95%CI:2.93-17.15]and fibrosis stage(HR 1.37,95%CI:1.03-1.87)were found to be independently associated with increased risk of liver decompensation.Age(HR 1.06,95%CI:1.02-1.10)and elevated IgG(HR 3.79,95%CI:1.90-7.68)were independent factors associated with higher mortality risk.CONCLUSION Elevated IgG,rather than ANA,ASMA or plasma cells,is independently associated with increased risk of hepatic decompensation and mortality in NASH.It could hence be important for prognostication.

De novo combination therapy with lamivudine and adefovir dipivoxil in chronic hepatitis B patients

AIM:To investigate the appropriate time for combination therapy in HBeAg positive chronic hepatitis B(CHB) patients with decompensated cirrhosis.METHODS:Thirty HBeAg positive CHB patients with decompensated cirrhosis were enrolled in the study.All of the patients were given 48 wk combination therapy with lamivudine(LAM) and adefovir dipivoxil(ADV) .Briefly,10 patients were given the de novo combination therapy with LAM and ADV,whereas the other 20 patients received ADV in addition to LAM after hepatitis B virus(HBV) genetic mutation.RESULTS:Serum alanine aminotransferase and total bilirubin were both improved in the two groups at 4,12,24 and 48 wk after treatment.Serum albumin was also improved at 24 and 48 wk after combination therapy in both groups.The serum HBV DNA level wasstill detectable in every patient in the two groups at 4 and 12 wk after combination treatment.However,in the de novo combination group,serum HBV DNA levels in 4(40%) and 9(90%) patients was decreased to below 1×10 3 copies/mL at 24 and 48 wk after the combination treatment,respectively.In parallel,serum HBV DNA levels in 2(20%) and 8(40%) patients in the add-on combination group became undetectable at 24 and 48 wk after combination treatment,respectively.Furthermore,6(60%) patients in the de novo combination group achieved HBeAg seroconversion after 48 wk treatment,whereas only 4(20%) patients in the add-on combination group achieved seroconversion.Child-Pugh score of patients in the de novo combination group was better than that of patients in the add-on combination group after 48 wk treatment.Moreover,patients in the de novo combination group had a significantly decreased serum creatinine level and elevated red blood cell counts.CONCLUSION:De novo combination therapy with LAM and ADV was better than add-on combination therapy in terms of Child-Pugh score,virus inhibition and renal function.

Acute-on-chronic liver failure：recent update

Acute on chronic liver failure（ACLF） was first described in 1995 as a clinical syndrome distinct to classic acute decompensation.Characterized by complications of decompensation,ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between45%and 90%.Despite the clinical relevance of the condition,it still remains largely undefined with continued disagreement regarding its precise etiological factors,clinical course,prognostic criteria and management pathways.It is concerning that,despite our relative lack of understanding of the condition,the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%.This paper highlights our current understanding of ACLF,including its etiology,diagnostic and prognostic criteria and pathophysiology.It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates.The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters,while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.

Short Term Efficacy of Entecavir in the Treatment of Decompensated Chronic Hepatitis B Cirrhosis

Objective:To explore the effect of entecavir on patients with decompensated chronic hepatitis B cirrhosis.Methods:From October 2007 to December 2019,100 patients with decompensated chronic hepatitis B cirrhosis who were treated in our hospital were selected to carry out this study.The clinical data of the patients were analyzed.According to whether entecavir treatment was carried out,100 patients were divided into two groups,50 cases in the control group and 50 cases in the observation group.The control group was treated with conventional drugs,and the observation group was treated with entecavir.Liver function indexes,liver fibrosis indexes,HBV-DNA negative conversion rate and incidence of adverse reactions were compared between the two groups.Results:Compared with the control group,the liver function indexes of the observation group were lower,P<0.05;Compared with the control group,the observation group was better,P<0.05;The negative rate of HBV-DNA in the observation group was lower than that in the control group(P<0.05);There was no difference in the incidence of adverse reactions between the two groups,P>0.05.Conclusion:Entecavir can not only improve the liver function,but also enhance the shortterm treatment effect,without increasing adverse reactions,and has high safety,which is worthy of recommendation.

Analysis of Serum Cys-C,TBA,and Routine Blood Parameters of Patients with Hepatitis B-Related Decompensated Cirrhosis

Objective:To study the levels of serum cystatin C(Cys-C),total bile acid(TBA),and other routine blood parameters on patients with decompensated hepatitis B cirrhosis.Methods:Study group 1 consisted of 30 patients with hepatitis B-related decompensated cirrhosis,and study group 2 consisted of 30 patients with hepatitis B;while the control group consisted of 30 healthy people who underwent physical examination.The blood parameters were used to evaluate the clinical treatment effect of patients.Results:The TBA,Cys-C,alanine transaminase(ALT),total bilirubin(TBIL),aspartate aminotransferase(AST),and international normalized ratio(INR)in study group 1 were significantly higher than those of study group 2 and the control group;while the platelet count(PLT),hemoglobin(Hb),albumin(ALB),and estimated glomerular filtration rate(eGFR)were significantly lower in the study group 1 compared to the control group and study group 2(P<0.05).The Cys-C,PLT,TBA,AST,TBIL,and INR of patients in study group 1 who were successfully treated were significantly lower than the patients who were not successfully treated(P<0.05).Conclusion:Serum Cys-C,TBA,and routine blood parameters are useful in predicting the condition and the prognosis of patients of hepatitis B-related decompensated cirrhosis.

Impact of low alcohol consumption in the natural history of cirrhosis

Alcohol-related liver disease(ALD)and metabolic dysfunction-associated steatotic liver disease(MASLD)are the most common causes of chronic liver disease worldwide(1).Daily alcohol consumption thresholds(<20 g/day for women and<30 g/day for men)are used to arbitrarily differentiate MASLD from ALD(2).However,“safe”levels of alcohol intake are difficult to define because of wide variations in the factors that contribute to its susceptibility and multiple effect modifiers.In MASLD,conflicting results on whether light alcohol intake is detrimental or beneficial.

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.