sTREM-1 as promising prognostic biomarker for acute-on-chronic liver failure and mortality in patients with acute decompensation of cirrhosis

BACKGROUND Acute decompensation(AD)of cirrhosis is associated with high short-term mortality,mainly due to the development of acute-on-chronic liver failure(ACLF).Thus,there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality.Soluble triggering receptor expressed on myeloid cells-1(sTREM-1)is released from activated innate immune cells and correlated with various inflammatory processes.AIM To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis.METHODS A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort(n=309)and validation cohort(n=133).Demographic and clinical data were collected,and serum sTREM-1 was measured at admission.All enrolled patients were followed-up for at least 1 year.RESULTS In patients with AD and cirrhosis,serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver,coagulation,cerebral and kidney failure.A new prognostic model of AD(P-AD)incorporating sTREM-1,blood urea nitrogen(BUN),total bilirubin(TBil),international normalized ratio(INR)and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease(MELD),MELD-sodium(MELD-Na),chronic liver failure-consortium(CLIF-C)ACLF and CLIF-C AD scores.Additionally,sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up.The ACLF risk score incorporating serum sTREM-1,BUN,INR,TBil and aspartate aminotransferase levels was established and significantly superior to MELD,MELD-Na,CLIF-C ACLF,CLIF-C AD and P-AD in predicting risk of ACLF development.CONCLUSION Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.

Evaluation of G3BP1 in the prognosis of acute and acute-on-chronic liver failure after the treatment of artificial liver support system

BACKGROUND The increased expression of G3BP1 was positively correlated with the prognosis of liver failure.AIM To investigate the effect of G3BP1 on the prognosis of acute liver failure(ALF)and acute-on-chronic liver failure(ACLF)after the treatment of artificial liver support system(ALSS).METHODS A total of 244 patients with ALF and ACLF were enrolled in this study.The levels of G3BP1 on admission and at discharge were detected.The validation set of 514 patients was collected to verify the predicted effect of G3BP1 and the viability of prognosis.RESULTS This study was shown that lactate dehydrogenase(LDH),alpha-fetoprotein(AFP)and prothrombin time were closely related to the prognosis of patients.After the ALSS treatment,the patient’amount of decreased G3BP1 index in difference of G3BP1 between the value of discharge and admission(difG3BP1)<0 group had a nearly 10-fold increased risk of progression compared with the amount of increased G3BP1 index.The subgroup analysis showed that the difG3BP1<0 group had a higher risk of progression,regardless of model for end-stage liver disease high-risk or low-risk group.At the same time,compared with the inflam matory marks[tumor necrosis factor-α,interleukin(IL)-1βand IL-18],G3BP1 had higher discrimination and was more stable in the model analysis and validation set.When combined with AFP and LDH,concordance index was respectively 0.84 and 0.8 in training and validation cohorts.CONCLUSION This study indicated that G3BP1 could predict the prognosis of ALF or ACLF patients treated with ALSS.The combination of G3BP1,AFP and LDH could accurately evaluate the disease condition and predict the clinical endpoint of patients.

Acute-on-chronic liver failure: Controversies and consensus

Acute-on-chronic liver failure(ACLF)is a poorly defined syndrome characterised by rapid clinical deterioration in patients with chronic liver disease.Consequences include high short-term morbidity,mortality,and healthcare resource utilisation.ACLF encompasses a dysregulated,systemic inflammatory response,which can precipitate extra hepatic organ failures.Common precipitants include infection,alcoholic hepatitis,and reactivation of viral hepatitis although frequently no cause is identified.Heterogenous definitions,diagnostic criteria,and treatment guidelines,have been proposed by international hepatology societies.This can result in delayed or missed diagnoses of ACLF,significant variability in clinical management,and under-estimation of disease burden.Liver transplantation may be considered but the mainstay of treatment is organ support,often in the intensive care unit.This review will provide clarity around where are the controversies and consensus in ACLF including:Epidemiology and resource utilisation,key clinical and diagnostic features,strategies for management,and research gaps.

Impact of cirrhosis-related complications on posttransplant survival in patients with acute-on-chronic liver failure

Background:Acute-on-chronic liver failure(ACLF)is a life-threatening syndrome defined as acute decompensation in patients with chronic liver disease.Liver transplantation(LT)is the most effective treatment.We aimed to assess the impact of cirrhosis-related complications pre-LT on the posttransplant prognosis of patients with ACLF.Methods:This was an observational cohort study conducted between January 2018 and December 2020.Clinical characteristics,cirrhosis-related complications at LT and patient survival post-LT were collected.All liver recipients with ACLF were followed for 1 year post-LT.Results:A total of 212 LT recipients with ACLF were enrolled,including 75(35.4%)patients with ACLF-1,64(30.2%)with ACLF-2,and 73(34.4%)with ACLF-3.The median waiting time for LT was 11(4-24)days.The most prevalent cirrhosis-related complication was ascites(78.8%),followed by hepatic encephalopathy(57.1%),bacterial infections(48.1%),hepatorenal syndrome(22.2%)and gastrointestinal bleeding(11.3%).Survival analyses showed that patients with complications at LT had a significantly lower survival probability at both 3 months and 1 year after LT than those without complications(all P<0.05).A simplified model was developed by assigning one point to each complication:transplantation for ACLF with cirrhosis-related complication(TACC)model.Risk stratification of TACC model identified 3 strata(≥4,=3,and≤2)with high,median and low risk of death after LT(P<0.001).Moreover,the TACC model showed a comparable ability for predicting the outcome post-LT to the other four prognostic models(chronic liver failure-consortium ACLF score,Chinese Group on the Study of Severe Hepatitis B-ACLF score,model for end-stage liver disease score and Child-Turcotte-Pugh score).Conclusions:The presence of cirrhosis-related complications pre-LT increases the risk of death post-LT in patients with ACLF.The TACC model based on the number of cirrhosis-related complications pre-LT could stratify posttransplant survival,which might help to determine transplant timing for ACLF.

Fecal cytolysin does not predict disease severity in acutely decompensated cirrhosis and acute-on-chronic liver failure

Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with mortality in alcohol-associated hepatitis(AH).It is unclear whether cytolysin also contributes to disease severity in AD and ACLF.Methods:We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF.Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction(PCR)was performed.The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed.Results:Fecal cytolysin and E.faecalis abundance did not predict chronic liver failure(CLIF-C)AD and ACLF scores.Presence of fecal cytolysin was not associated with other liver disease markers,including Fibrosis-4(FIB-4)index,‘Age,serum Bilirubin,INR,and serum Creatinine(ABIC)’score,Child-Pugh score,model for end-stage liver disease(MELD)nor MELD-Na scores in AD or ACLF patients.Conclusions:Fecal cytolysin does not predict disease severity in AD and ACLF patients.The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.

Application of extended criteria donor grafts in liver transplantation for acute-on-chronic liver failure:A retrospective cohort study

BACKGROUND There is no consensus on the usage of extended criteria donor(ECD)grafts in liver transplantation(LT)for acute-on-chronic liver failure(ACLF)patients.AIM To summarize the experience of using ECD livers in ACLF-LT.METHODS A retrospective cohort study was conducted,enrolling patients who underwent LT at the First Affiliated Hospital of Sun Yat-Sen University from January 2015 to November 2021.The patients were divided into ECD and non-ECD groups for analysis.RESULTS A total of 145 recipients were enrolled in this study,of which ECD and non-ECD recipients accounted for 53.8%and 46.2%,respectively.Donation after cardiac death(DCD)recipients accounted for the minority compared with donation after brain death(DBD)recipients(16.6%vs 83.4%).Neither overall survival nor graft survival significantly differed between ECD and non-ECD and DCD and DBD recipients.ECD grafts were associated with a significantly higher incidence of early allograft dysfunction(EAD)than non-ECD grafts(67.9%vs 41.8%,P=0.002).Postoperative outcomes between DCD and DBD recipients were comparable(P>0.05).ECD graft(P=0.009),anhepatic phase(P=0.034)and recipient gamma glutamyltransferase(P=0.016)were independent risk factors for EAD.Recipient preoperative number of extrahepatic organ failures>2(P=0.015)and intraoperative blood loss(P=0.000)were independent predictors of poor post-LT survival.CONCLUSION Although related to a higher risk of EAD,ECD grafts can be safely used in ACLF-LT.The main factors affecting post-LT survival in ACLF patients are their own severe preoperative disease and intraoperative blood loss.

Hypermethylation of thymosinβ4 predicts a poor prognosis for patients with acute-on-chronic hepatitis B liver failure

Background:It has been demonstrated that thymosinβ4(Tβ4)could inflect the severity of acute-on-chronic hepatitis B liver failure(ACHBLF),but the relationship between its methylation status and the prognosis of liver failure is not clear.This study aimed to determine Tβ4 promoter methylation status in patients with ACHBLF and to evaluate its prognostic value.Methods:The study recruited 115 patients with ACHBLF,80 with acute-on-chronic hepatitis B pre-liver failure(pre-ACHBLF),and 86 with chronic hepatitis B(CHB).In addition,there were 36 healthy controls(HCs)from the Department of Hepatology,Qilu Hospital of Shandong University.The 115 patients with ACHBLF were divided into three subgroups:33 with early stage ACHBLF(E-ACHBLF),42 with mid-stage ACHBLF(M-ACHBLF),and 40 with advanced stage ACHBLF(A-ACHBLF).Tβ4 promoter methylation status in peripheral blood mononuclear cells(PBMCs)was measured by methylation-specific polymerase chain reaction,and mRNA was detected by quantitative real-time polymerase chain reaction.Results:Methylation frequency of Tβ4 was significantly higher in patients with ACHBLF than in those with pre-ACHBLF,CHB or HCs.However,expression of Tβ4 mRNA showed the opposite trend.In patients with ACHBLF,Tβ4 promoter methylation status correlated negatively with mRNA levels.The 3-month mortality of ACHBLF in the methylated group was significantly higher than that in the unmethylated group.Also,Tβ4 promoter methylation frequency was lower in survivors than in non-survivors.When used to predict the 1-,2-,and 3-month incidence of ACHBLF,Tβ4 methylation status was better than the model for end-stage liver disease(MELD)score.The predictive value of Tβ4 methylation was higher than that of MELD score for the mortality of patients with E-ACHBLF and M-ACHBLF,but not for A-ACHBLF.Conclusions:Tβ4 methylation might be an important early marker for predicting disease incidence and prognosis in patients with ACHBLF.

Acute-on-chronic liver failure in patients with severe acute respiratory syndrome coronavirus 2 infection

The coronavirus disease 2019(COVID-19)pandemic caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has had a significant impact on the lives of millions of people,especially those with other concomitant diseases,such as chronic liver diseases.To date,seven coronaviruses have been identified to infect humans.The main site of pathological action of these viruses is lung tissue.However,a substantial number of studies have proven that SARSCoV-2 shows affinity towards several organs,including the gastrointestinal tract and the liver.The current state of evidence points to several proposed mechanisms of liver injury in patients with COVID-19 and their combination.Liver impairment is considered to be the result of the direct effect of the virus on the hepatic tissue cells,a systemic reaction consisting of inflammation,hypoxia and cytokine storm,drug-induced liver injury,with the possible contribution of a perturbed gut-liver axis.Reactivation of chronic hepatic disease could be another factor for liver impairment in patients with SARS-CoV-2 infection.Acute-onchronic liver failure(ACLF)is a relatively new syndrome that occurs in 10%–30%of all hospitalized patients with chronic liver disease.It is crucial to recognize high-risk patients due to the increased morbidity and mortality in these cases.Several published studies have reported virus infection as a trigger factor for ACLF.However,to date,there are few relevant studies describing the presence of ACLF in patients with acute SARS-CoV-2 infection.In this minireview we summarize the current state of knowledge regarding the relation between ACLF and acute SARS-CoV-2 infection.

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.

Acute-on-chronic liver failure induced by antiviral therapy for chronic hepatitis C: A case report

BACKGROUND There have been no reports of acute-on-chronic liver failure(ACLF)during treatment of chronic hepatitis C(CHC)with direct-acting antivirals(DAAs).CASE SUMMARY We report a 50-year-old male patient with CHC.The patient sought medical attention from the Department of Infectious Diseases at our hospital due to severe yellowing of the skin and sclera,which developed 3 mo previously and attended two consecutive hospitals without finding the cause of liver damage.It was not until 1 mo ago that he was diagnosed with CHC at our hospital.After discharge,he was treated with DAAs.During treatment,ACLF occurred,and timely measures such as liver protection,enzyme lowering,anti-infective treatment,and suppression of inflammatory storms were implemented to control the condition.CONCLUSION DAA drugs significantly improve the cure rate of CHC.However,when patients have factors such as autoimmune attack,coinfection,or unclear hepatitis C virus genotype,close monitoring is required during DAA treatment.

Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.

Entecavir vs lamivudine therapy for na?ve patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure

AIM:To investigate the short-term and long-term efficacy of entecavir versus lamivudine in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure(ACLF).METHODS:This was a single center,prospective cohort study.Eligible,consecutive hospitalized patients received either entecavir 0.5 mg/d or lamivudine 100mg/d.All patients were given standard comprehensive internal medicine.The primary endpoint was survival rate at day 60,and secondary endpoints were reduction in hepatitis B virus(HBV)DNA and alanine aminotransferase(ALT)levels,and improvement in Child-Turcotte-Pugh(CTP)and model for end-stage liver disease(MELD)scores at day 60 and survival rate at week 52.RESULTS:One hundred and nineteen eligible subjects were recruited from 176 patients with severe acute exacerbation of chronic hepatitis B:65 were included in the entecavir group and 54 in the lamivudine group(full analysis set).No significant differences were found in patient baseline clinical parameters.At day 60,entecavir did not improve the probability of survival(P=0.066),despite resulting in faster virological suppression(P<0.001),higher rates of virological response(P<0.05)and greater reductions in the CTP and MELD scores(all P<0.05)than lamivudine.Intriguingly,at week 52,the probability of survival was higher in the entecavir group than in the lamivudine group[42/65(64.6%)vs 26/54(48.1%),respectively;P=0.038].The pretreatment MELD score(B,1.357;95%Cl:2.138-7.062;P=0.000)and virological response at day30(B,1.556;95%Cl:1.811-12.411;P=0.002),were found to be good predictors for 52-wk survival.CONCLUSION:Entecavir significantly reduced HBV DNA levels,decreased the CTP and MELD scores,and thereby improved the long-term survival rate in patients with spontaneous reactivation of hepatitis B presenting as ACLF.

Cystatin C is a biomarker for predicting acute kidney injury in patients with acute-on-chronic liver failure

AIM:To investigate serum cystatin C level as an early biomarker for predicting acute kidney injury(AKI)in patients with acute-on-chronic liver failure(ACLF).METHODS:Fifty-six consecutive patients with hepatitis B virus-related ACLF who had normal serum creatinine(Cr)level(<1.2 mg/dL in men,or<1.1 mg/dL in women)were enrolled in the Liver Failure Treatment and Research Center of Beijing 302 Hospital between August 2011 and October 2012.Thirty patients with chronic hepatitis B(CHB)and 30 healthy controls in the same study period were also included.Measurement of serum cystatin C(CysC)was performed by a particle-enhanced immunonephelometry assay using the BN Prospec nephelometer system.The ACLF patients were followed during their hospitalization period.RESULTS:In the ACLF group,serum level of CysC was 1.1±0.4 mg/L,which was significantly higher(P<0.01)than those in the healthy controls(0.6±0.3mg/L)and CHB patients(0.7±0.2 mg/L).During the hospitalization period,eight ACLF patients developed AKI.Logistic regression analysis indicated that CysC level was an independent risk factor for AKI development(odds ratio=1.8;95%CI:1.4-2.3,P=0.021).The cutoff value of serum CysC for prediction of AKI in ACLF patients was 1.21 mg/L.The baseline CysC-based estimated glomerular filtration rate(eGFR CysC)was significantly lower than the creatinine-based eGFR(eGFR CG and eGFR MDRD)in ACLF patients with AKI,suggesting that baseline eGFR CysC represented early renal function in ACLF patients while the Cr levels were still within the normal ranges.CONCLUSION:Serum CysC provides early prediction of renal dysfunction in ACLF patients with a normal serum Cr level.

Acute kidney injury in acute-on-chronic liver failure is different from in decompensated cirrhosis

AIM To evaluate the differences in acute kidney injury(AKI) between acute-on-chronic liver failure(ACLF) and decompensated cirrhosis(DC) patients. METHODS During the period from December 2015 to July 2017, 280 patients with hepatitis B virus(HBV)-related ACLF(HBV-ACLF) and 132 patients with HBV-related DC(HBV-DC) who were admitted to our center were recruited consecutively into an observational study. Urine specimens were collected from all subjects and the levels of five urinary tubular injury biomarkers were detected,including neutrophil gelatinase-associated lipocalin(NGAL), interleukin-18(IL-18), liver-type fatty acid binding protein(L-FABP), cystatin C(CysC), and kidney injury molecule-1(KIM-1). Simultaneously, the patient demographics, occurrence and progression of AKI, and response to terlipressin therapy were recorded. All patients were followed up for 3 mo or until death after enrollment. RESULTS AKI occurred in 71 and 28 of HBV-ACLF and HBV-DC patients, respectively(25.4% vs 21.2%, P = 0.358). Among all patients, the levels of four urinary biomarkers(NGAL, CysC, L-FABP, IL-18) were significantly elevated in patients with HBV-ACLF and AKI(ACLF-AKI), compared with that in patients with HBV-DC and AKI(DC-AKI) or those without AKI. There was a higher proportion of patients with AKI progression in ACLF-AKI patients than in DC-AKI patients(49.3% vs 17.9%, P = 0.013). Fortythree patients with ACLF-AKI and 19 patients with DC-AKI were treated with terlipressin. The response rate of ACLFAKI patients was significantly lower than that of patients with DC-AKI(32.6% vs 57.9%, P = 0.018). Furthermore, patients with ACLF-AKI had the lowest 90 d survival rates among all groups(P < 0.001).CONCLUSION AKI in ACLF patients is more likely associated with structural kidney injury, and is more progressive, with a poorer response to terlipressin treatment and a worse prognosis than that in DC patients.

Prognosis of acute-on-chronic liver failure patients treated with artificial liver support system

AIM: To establish a new model for predicting survival in acute-on-chronic liver failure(ACLF) patients treated with an artificial liver support system. METHODS: One hundred and eighty-one ACLF patients who were admitted to the hospital from January 1, 2012 to December 31, 2014 and were treated with an artificial liver support system were enrolled in this retrospective study, including a derivation cohort(n = 113) and a validation cohort(n = 68). Laboratory parameters at baseline were analyzed and correlatedwith clinical outcome. In addition to standard medical therapy, ACLF patients underwent plasma exchange(PE) or plasma bilirubin adsorption(PBA) combined with plasma exchange. For the derivation cohort, KaplanMeier methods were used to estimate survival curves, and Cox regression was used in survival analysis to generate a prognostic model. The performance of the new model was tested in the validation cohort using a receiver-operator curve.RESULTS: The mean overall survival for the derivation cohort was 441 d(95%CI: 379-504 d), and the 90- and 270-d survival probabilities were 70.3% and 58.3%, respectively. The mean survival times of patients treated with PBA plus PE and patients treated with PE were 531 d(95%CI: 455-605 d) and 343 d(95%CI: 254-432 d), respectively, which were significantly different(P = 0.012). When variables with bivariate significance were selected for inclusion into the multivariate Cox regression model, number of complications, age, scores of the model for end-stage liver disease(MELD) and type of artificial liver support system were defined as independent risk factors for survival in ACLF patients. This new prognostic model could accurately discriminate the outcome of patients with different scores in this cohort(P < 0.001). The model also had the ability to assign a predicted survival probability for individual patients. In the validation cohort, the new model remained better than the MELD.CONCLUSION: A novel model was constructed to predict prognosis and accurately discriminate survival in ACLF patients treated with an artificial liver support system.

Plasma exchange in patients with acute and acute-on-chronic liver failure: A systematic review

BACKGROUND Acute liver failure(ALF)and acute-on-chronic liver(ACLF)carry high short-term mortality rate,and may result from a wide variety of causes.Plasma exchange has been shown in a randomized control trial to improve survival in ALF especially in patients who did not receive a liver transplant.Other cohort studies demonstrated potential improvement in survival in patients with ACLF.AIM To assess utility of plasma exchange in liver failure and its effect on mortality in patients who do not undergo liver transplantation.METHODS Databases MEDLINE via PubMed,and EMBASE were searched and relevant publications up to 30 March,2019 were assessed.Studies were included if they involved human participants diagnosed with liver failure who underwent plasma exchange,with or without another alternative non-bioartificial liver assist device.RESULTS Three hundred twenty four records were reviewed,of which 62 studies were found to be duplicates.Of the 262 records screened,211 studies were excluded.Fifty-one articles were assessed for eligibility,for which 7 were excluded.Twenty-nine studies were included for ALF only,and 9 studies for ACLF only.Six studies included both ALF and ACLF patients.A total of 44 publications were included.Of the included publications,2 were randomized controlled trials,14 cohort studies,12 case series,16 case reports.All of three ALF studies which looked at survival rate or survival days reported improvement in outcome with plasma exchange.In two out of four studies where plasma exchange-based liver support systems were compared to standard medical treatment(SMT)for ACLF,a biochemical improvement was seen.Survival in the non-transplanted patients was improved in all four studies in patients with ACLF comparing plasma exchange vs SMT.Using the aforementioned studies,plasma exchange based therapy in ACLF compared to SMT improved survival in non-transplanted patients at 30 and 90-d with a pooled OR of 0.60(95%CI 0.46-0.77,P<0.01).CONCLUSION The level of evidence for use of high volume plasma exchange in selected ALF cases is high.Plasma exchange in ACLF improves survival at 30-and 90-d in nontransplanted patients.Further well-designed randomized control trials will need to be carried out to ascertain the optimal duration and amount of plasma exchange required and assess if the use of high volume plasma exchange can be extrapolated to patients with ACLF.

Restoring the Treg cell to Th17 cell ratio may alleviate HBV-related acute-on-chronic liver failure

AIM: To investigate the role of T helper 17 cells (Th17) and regulatory T cells (Treg) in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF).METHODS: We enrolled 79 patients with HBV infection into the study, 50 patients with HBV-related ACLF and 29 patients with chronic hepatitis B (CHB), from the First Affiliated Hospital of Medical College from January 2009 to June 2012. The ACLF patients were diagnosed according to the criteria recommended by The 19th Conference of the Asian Pacific Association for the Study of the Liver in 2009. Twenty healthy individuals with a similar gender and age structures to the two patient groups were also included as the normal controls (NC). Of the 50 ACLF patients, 28 were subsequently classified as non-survivors: 19 patients died from multiorgan failure, 3 underwent liver transplantation, and 6 discontinued therapy during follow-up because of financial reasons. The remaining 22 ACLF patients whose liver and anticoagulation function recovered to nearly normal levels within the next 6 mo were classified as survivors. The number of circulating Treg and Th17 cells was determined upon diagnosis and during the 8th week of follow-up through flow cytometry. RESULTS: The percentage of circulating Treg cells in the ACLF group was significantly higher than that in the CHB group (5.50% ± 1.15% vs 3.30% ± 1.13%, P < 0.01). The percentages of circulating Th17 cells in the ACLF and the CHB groups were significantly higher than that in the NC group (6.32% ± 2.22% vs 1.56% ± 0.44%, P < 0.01; 3.53% ± 1.65% vs 1.56% ± 0.44%, P < 0.01). No significant difference in Treg cell to Th17 cell ratio was observed between the ACLF group and the CHB group (0.98 ± 0.44 vs 1.12 ± 0.64, P = 0.991), whereas those in the two HBV infection groups were significantly lower than that in the NC group (1.85 ± 1.22; both P < 0.01). The percentage of Treg cells in the survivors during the 8th week of follow-up was significantly lower than that during peak ACLF severity [total bilirubin (TBIL) peak] (3.45% ± 0.97% vs 5.18% ± 1.02%, P < 0.01). The percentage of Th17 cells in survivors during the 8th week of follow-up was significantly lower than that during the peak TBIL (2.89% ±0.60% vs 5.24% ± 1.46%; P < 0.01). The Treg cell to Th17 cell ratio during the 8 th week of follow-up was significantly higher than that during the TBIL peak (1.22 ± 0.36 vs 1.10 ± 0.54; P < 0.05). CONCLUSION: Restoring the Treg cell to Th17 cell ratio during the follow-up phase of ACLF could maintain the immune system at a steady state, which favours good prognosis.

Risk factors for progression to acute-on-chronic liver failure during severe acute exacerbation of chronic hepatitis B virus infection

BACKGROUND Acute exacerbation in patients with chronic hepatitis B virus(HBV) infection results in different severities of liver injury. The risk factors related to progression to hepatic decompensation(HD) and acute-on-chronic liver failure(ACLF) in patients with severe acute exacerbation(SAE) of chronic HBV infection remain unknown.AIM To identify risk factors related to progression to HD and ACLF in compensated patients with SAE of chronic HBV infection.METHODS The baseline characteristics of 164 patients with SAE of chronic HBV infection were retrospectively reviewed. Independent risk factors associated with progression to HD and ACLF were identified. The predictive values of our previously established prediction model in patients with acute exacerbation(AE model) and the model for end-stage liver disease(MELD) score in predicting the development of ACLF were evaluated.RESULTS Among 164 patients with SAE, 83(50.6%) had compensated liver cirrhosis(LC),43 had progression to HD without ACLF, and 29 had progression to ACLF within 28 d after admission. Independent risk factors associated with progression to HD were LC and low alanine aminotransferase. Independent risk factors for progression to ACLF were LC, high MELD score, high aspartate aminotransferase(AST) levels, and low prothrombin activity(PTA). The area under the receiver operating characteristic of the AE model [0.844, 95%confidence interval(CI): 0.779-0.896] was significantly higher than that of MELD score(0.690, 95%CI: 0.613-0.760, P < 0.05) in predicting the development of ACLF.CONCLUSION In patients with SAE of chronic HBV infection, LC is an independent risk factor for progression to both HD and ACLF. High MELD score, high AST, and low PTA are associated with progression to ACLF. The AE model is a better predictor of ACLF development in patients with SAE than MELD score.

The immunological roles in acute-on-chronic liver failure:An update

Background: Acute-on-chronic liver failure (ACLF) refers to the acute deterioration of liver function that occurs in patients with chronic liver disease. ACLF is characterized by acute decompensation, organ failure and high short-term mortality. Numerous studies have been conducted and remarkable progress has been made regarding the pathophysiology and pathogenesis of this disease in the last decade. The present review was to summarize the advances in this field. Data sources: A comprehensive search in PubMed and EMBASE was conducted using the medical subject words “acute-on-chronic liver failure”,“ACLF”,“pathogenesis”,“predictors”, and “immunotherapy” combined with free text terms such as “systemic inflammation” and “immune paralysis”. Relevant papers published before October 31, 2018, were included. Results: ACLF has two marked pathophysiological features, namely, excessive systemic inflammation and susceptibility to infection. The systemic inflammation is mainly manifested by a significant increase in the levels of plasma pro-inflammatory factors, leukocyte count and C-reactive protein. The underlying mechanisms are unclear and may be associated with decreased immune inhibitory cells, abnormal expression of cell surface molecules and intracellular regulatory pathways in immune cells and increased damageassociated molecular patterns in circulation. However, the main cause of susceptibility to infection is immune paralysis. Immunological paralysis is characterized by an attenuated activity of immune cells. The mechanisms are related to elevations of immune inhibitory cells and the concentration of plasma antiinflammatory molecules. Some immune biological indicators, such as soluble CD163, are used to explore the pathogenesis and prognosis of the disease, and some immunotherapies, such as glucocorticoids and granulocyte colony-stimulating factor, are effective on ACLF. Conclusions: Overwhelming systemic inflammation and susceptibility to infection are two key features of ACLF. A better understanding of the state of a patient’s immune system will help to guide immunotherapy for ACLF.

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.