Development and validation of a new prognostic model for patients with acute-on-chronic liver failure in intensive care unit

BACKGROUND Cirrhotic patients with acute-on-chronic liver failure(ACLF)in the intensive care unit(ICU)have a poor but variable prognoses.Accurate prognosis evaluation can guide the rational management of patients with ACLF.However,existing prognostic scores for ACLF in the ICU environment lack sufficient accuracy.AIM To develop a new prognostic model for patients with ACLF in ICU.METHODS Data from 938 ACLF patients in the Medical Information Mart for Intensive Care(MIMIC)database were used to develop a new prognostic model(MIMIC ACLF)for ACLF.Discrimination,calibration and clinical utility of MIMIC ACLF were assessed by area under receiver operating characteristic curve(AUROC),calibration curve and decision curve analysis(DCA),respectively.MIMIC ACLF was then externally validated in a multiple-center cohort,the Electronic Intensive Care Collaborative Research Database and a single-center cohort from the Second Hospital of Hebei Medical University in China.RESULTS The MIMIC ACLF score was determined using nine variables:ln(age)×2.2+ln(white blood cell count)×0.22-ln(mean arterial pressure)×2.7+respiratory failure×0.6+renal failure×0.51+cerebral failure×0.31+ln(total bilirubin)×0.44+ln(internationalized normal ratio)×0.59+ln(serum potassium)×0.59.In MIMIC cohort,the AUROC(0.81/0.79)for MIMIC ACLF for 28/90-day ACLF mortality were significantly greater than those of Chronic Liver Failure Consortium ACLF(0.76/0.74),Model for End-stage Liver Disease(MELD;0.73/0.71)and MELD-Na(0.72/0.70)(all P<0.001).The consistency between actual and predicted 28/90-day survival rates of patients according to MIMIC ACLF score was excellent and superior to that of existing scores.The net benefit of MIMIC ACLF was greater than that achieved using existing scores within the 50%threshold probability.The superior predictive accuracy and clinical utility of MIMIC ACLF were validated in the external cohorts.CONCLUSION We developed and validated a new prognostic model with satisfactory accuracy for cirrhotic patients with ACLF hospitalized in the ICU.The model-based risk stratification and online calculator might facilitate the rational management of patients with ACLF.

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.

Prognostic role of the stromal cell derived factor-1 in patients with hepatitis B virus-related acute-on-chronic liver failure

BACKGROUND Stromal cell derived factor-1(SDF-1)plays a pivotal role in the recruitment of stem cells to injured livers.However,the changes of SDF-l in patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF)have yet to be elucidated.AIM To study the SDF-1 changes in patients with HBV-related ACLF.METHODS 30 patients with HBV-related ACLF,27 patients with chronic hepatitis B and 20 healthy individuals are involved in our study.The SDF-l mRNA expression in liver tissue was detected by quantitative real-time polymerase chain reaction.Immunohistochemical staining was performed to illustrate the expression of SDFl,CXC receptor 4(CXCR4)and Ki67.The serum SDF-l concentrations were also detected by enzyme-linked immunosorbent assays.RESULTS The expression of SDF-1 mRNA from ACLF patients was remarkably higher than that from other patients(both P<0.05).The expression of SDF-l,CXCR4 and Ki67 from ACLF were the highest among the three groups(all P<0.01).The serum SDF-l levels in ACLF patients were significantly lower than that in other patients(both P<0.01).Moreover,in ACLF patients,the serum SDF-1 Levels were positively correlated with serum total bilirubin and international normalized ratio.In addition,the serum SDF-l levels in survival were significantly lower compared with the non-survivals(P<0.05).The area under the curve for the serum SDF-1 level in predicting 28-d mortality was 0.722(P<0.05).CONCLUSION This study provides the SDF-1 changes in patients with HBV-related ACLF.The SDF-1 Level at admission may serve as a promising prognostic marker for predicting short-term prognosis.

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.

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.

Changes in circulating Foxp3^+ regulatory T cells and interleukin-17-producing T helper cells during HBV-related acute-on-chronic liver failure

AIM: To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACHBLF) and to analyze changes in Th17 and Treg phenotypes during disease progression.

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.

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.

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.

Ethyl pyruvate protects against experimental acute-on-chronic liver failure in rats

AIM： To investigate the protective effects of ethyl py- ruvate （EP） on acute-on-chronic liver failure （ACLF） in rats. METHODS： An ACLF model was established in rats, and animals were randomly divided into normal, mod- el and EP treatment groups. The rats in EP treatment group received EP （40 mg/kg） at 3 h, 6 h, 12 h and 24 h after induction of ACLF. Serum endotoxin, high mobility group box-1 （HMGB1）, alanine transaminase （ALT）, tumor necrosis factor-α （TNF-α）, interferon-α （IFN-γ）, interleukin （IL）-10 and IL-18 levels, changes of liver histology and HMGB1 expressions in liver tis- sues were detected at 48 h after induction of ACLF. The effects of EP on the survival of ACLF rats were also observed.RESULTS： Serum levels of endotoxin （0.394 ± 0.066 EU/mL vs 0.086±0.017 EU/mL, P 〈 0.001）, HMGB1 （35.42±10,86 μg/L vs 2.14 ± 0.27 μg/L, P 〈 0.001）, ALT （8415.87 ± 3567.54 IU/L vs 38.64 ± 8.82 IU/L, P 〈 0.001）, TNF-α （190.77 ± 12.34 ng/L vs 124.40 ± 4.12 ng/L, P 〈 0.001）, IFN-γ （715.38 ± 86.03 ng/L vs 398.66 ± 32.91 ng/L, P 〈 0.001）, IL-10 （6.85 ± 0.64 ng/L vs 3.49 ± 0.24 ng/L, P 〈 0.001） and IL-18 （85.19 ±3.49 ng/L vs 55.38 ±1.25 ng/L, P 〈 0.001） were significantly increased, and liver tissues presented se- vere pathological injury in the model group compared with the normal group, Howeverr EP administration significantly improved hepatic histopathology and re- duced the serum levels of endotoxin （0.155±0.045 EU/mL vs 0.394 ± 0.066 EU/mL vs P 〈 0.001） and in- flammatory cytokines （11.13 ± 2.58 μg/L vs 35.42 ± 10.86 μg/L for HMGB1, 3512.86 ± 972.67 IU/L vs 8415.87 ± 3567.54 IU/L for ALT, 128.55 ± 5.76 ng/L vs 190.77 ± 12.34 ng/L for TNF-α 438.16 ± 38.10 ng/L vs 715.38 ± 86.03 ng/L for IFN-γ 3.55 ± 0.36 ng/L vs 6.85 ± 0.64 ng/L for IL-10, and 60.35 ± 1.63 ng/L vs 85.19 ± 3.49 ng/L for IL-18, respectively, P 〈 0.001）, and the levels of HMGB1 in liver tissues re- gardless of treatment time after induction of ACLF. EP treatment at the four time points prolonged the me- dian survival time of ACLF rats （60 h） to 162 h, 120 h, 102 h and 78 h, respectively （χ2 = 41.17, P 〈 0.0001）. CONCLUSION： EP administration can protect against ACLF in rats, and is a potential and novel therapeutic agent for severe liver injury.

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. M65 and 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/M65 ratio 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. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Serum levels of mi RNA in patients with hepatitis B virus-associated acute-on-chronic liver failure

Background: Hepatitis B virus(HBV)-associated acute-on-chronic liver failure(HBV-ACLF) is a lifethreatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum mi RNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF.Methods: Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to30 chronic asymptomatic HBV carriers as controls. The mi RNAs expressions were measured by real-time quantitative PCR(q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed mi RNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model.Results: Real-time q-PCR indicated that serum miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and mi R-122-3 p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+-1.72 × INR-4.963 × gastrointestinal bleeding(Yes = 0; No = 1)-0.278 ×(mi R-122-3 p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve(AUROC) was 0.847.Conclusions: Expression levels of these mi RNAs(miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.

Serum soluble ST2 is a promising prognostic biomarker in HBV-related acute-on-chronic liver failure

BACKGROUND： The IL-33/ST2 axis is involved in the pathogenesis of many diseases such as autoimmune diseases, cancer,and heart failure. However, studies of the IL-33/ST2 pathway in HBV-related acute-on-chronic liver failure（HBV-ACLF） are lacking. The present study aimed to determine the prognostic role of serum IL-33/soluble ST2（s ST2） in HBV-ACLF.METHODS： Serum levels of IL-33 and sS T2 in healthy controls（HC, n=18）, chronic hepatitis B（CHB, n=27） and HBV-ACLF（n=51） patients at the 1st and 4th week after enrollment were detected using ELISA, and clinical data were collected. The follow-up of HBV-ACLF patients lasted for 6 months at least.RESULTS： There was no significant difference of serum IL-33 level among HC, CHB and HBV-ACLF patients at week 1.However, serum s ST2 level differed significantly among the three groups： highest in the HBV-ACLF group, moderate in the CHB group and lowest in the HC group. There was a reverse correlation between serum s ST2 level and the survival of HBV-ACLF patients. The level of serum s ST2 in HBV-ACLF survivors was significantly declined from week 1 to week 4 following the treatment, whereas that in HBV-ACLF nonsurvivors remained at a high level during the same period. Furthermore, serum sS T2 level was significantly correlated with laboratory parameters and the most updated prognostic scores（CLIF-C OF score, CLIF-C ACLF score and ACLF grades）. Thereceiver operating characteristics curves demonstrated that serum sS T2 level was a good diagnostic marker for predicting the 6-month mortality in HBV-ACLF patients, comparable to the most updated prognostic scores. Serum sS T2 cut-off points for predicting prognosis in HBV-ACLF patients were 76 ng/mL at week 1 or 53 ng/mL at week 4, respectively. HBV-ACLF patients with serum sS T2 level above the cut-off point often had a worse prognosis than those below the cut-off point.CONCLUSION： Serum s ST2 may act as a promising biomarker to assess severity and predict prognosis of patients with HBV-ACLF and help for the early identification and optimal treatment of HBV-ACLF patients at high risk of mortality.

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.

Acute-on-chronic liver failure in a multi-ethnic Asian city:A comparison of patients identified by Asia-Pacific Association for the Study of the Liver and European Association for the Study of the Liver definitions

AIM To explore the applicability of the Asia-Pacific Association for the Study of the Liver(APASL) and European Association for the Study of the Liver(EASL) guidelines for acute-on-chronic liver failure(ACLF) in profiling patients and determining the outcome.METHODS Patients admitted to a tertiary hospital in Singapore with acute decompensation of liver disease from January 2004to July 2014 are screened for ACLF according to the APASL and EASL criteria. The patients' data(including basic demographics, information about existing chronic liver disease, information about the acute decompensation, relevant laboratory values during admission, treatment, and outcome) are retrospectively analyzed to determine the background, precipitating factors and outcome.RESULTS A total of 458 liver patients is analyzed, and 78 patients with ACLF are identified. Sixty-three patients(80.8%) meet the APASL criteria, 64 patients(82.1%) meet the EASL criteria, and 49 patients(62.8%) fulfilled both criteria. The most common causes of acute liver injury are bacterial infections(59.0%), hepatitis B flare(29.5%), and variceal bleeding(24.4%). The common aetiologies of the underlying chronic disease included hepatitis B(43.6%), alcoholic(20.5%) and cryptogenic(11.5%) liver disease. The overall mortality rate is 61.5%. Increased age, the number of organ failures(as per CLIF-SOFA score), peak creatinine, INR, and amylase levels are associated with increased mortality or the need for liver transplantation. 14.3% of patients undergo liver transplantation with a 100% 1-year survival rate. CONCLUSION Both APASL and EASL criteria have identified ACLF patients with high three-month mortality, but those who fulfill APASL criteria alone have a better survival.

Elevated serum prostaglandin E2 predicts the risk of infection in hepatitis B virus-related acute-on-chronic liver failure patients

Objective: To evaluate the serum Prostaglandin E2(PGE2) level in Acute-on-chronic liver failure(ACLF) and determine its predicative value for infection.Methods: From April 2014 to April 2015, ninety-one patients with hepatitis B virus and ACLF but without infection were enrolled into this prospective study that was carried out at our Hospital. Twenty patients with stable chronic hepatitis B were enrolled from the outpatient department and twenty healthy control subjects without any disease were enrolled from hospital staff. Serum PGE2 levels were determined using ELISA at enrollment. Clinical and laboratory parameters were collected. Receiver operating characteristic(ROC) curves were used to determine optimal cut-off values to predict infection.Results: Significantly higher PGE2 levels were found in patients with ACLF in comparison with healthy controls and patients with stable CHB(P < 0.000 1). In ACLF patients, PGE2 levels were significantly higher in patients that eventually developed infection than those without this complication(P < 0.000 1). ROC analysis showed that serum PGE2(area under the ROC curve, 0.83) could predict infection in patients with ACLF with sensitivity of 78.4% and specificity of 81.5% using a threshold of 141 pg/m L.Conclusions: Serum PGE2 is associated with the susceptibility to secondary infections for patients with ACLF. Increased PGE2 serum levels may serve as a potential biomarker for developing infections in ACLF patients.

Upregulation of Toll-like Receptor 4 on T Cells in PBMCs Is Associated with Disease Aggravation of HBV-related Acute-on-chronic Liver Failure

Summary： Immune-mediated inflammatory injury is an important feature of the disease aggravation of hepatitis B virus-related acute-on-chronic liver failure （ACLF）. Toll-like receptors （TLRs） have been shown previously to play a pivotal role in the activation of innate immunity. The purpose of this study was.to characterize the TLR4 expression in peripheral blood mononuclear cells （PBMCs） of ACLF pa- tients and its possible role in the disease aggravation. Twelve healthy subjects, 15 chronic HBV-infected （CHB） patients and 15 ACLF patients were enrolled in this study. The TLR4 expression in PBMCs and T cells of all subjects was examined by real-time PCR and flow cytometry. The correlation of TLR4 ex- pression on T cells with the markers of disease aggravation was evaluated in ACLF patients. The ability of TLR4 ligands stimulation to induce inflammatory cytokine production in ACLF patients was ana- lyzed by flow cytometry. The results showed that TLR4 mRNA level was upregulated in PBMCs of ACLF patients compared to that in the healthy subjects and the CHB patients. Specifically, the expres- sion of TLR4 on CD4＋ and CD8＋ T cells of PBMCs was significantly increased in ACLF patients. The TLR4 levels on CD4＋ and CD8＋T cells were positively correlated with serum total bilirubin （TBIL）, direct bilirubin （DBIL）, international normalized ratio （INR） levels and white blood cells （WBCs）, and negatively correlated with serum albumin （ALB） levels in the HBV-infected patients, indicating TLR4 pathway may play a role in the disease aggravation of ACLF. In vitro TLR4 ligand stimulation on PBMCs of ACLF patients induced a strong TNF-α production by CD4＋ T cells, which was also posi- tively correlated with the serum markers for liver injury severity. It was concluded that TLR4 expression is upregulated on T cells in PBMCs, which is associated with the aggravation of ACLF.

High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid

BACKGROUND： Linezolid is an effective antibiotic reagent for Gram-positive bacterial infection; its most common side effect is thrombocytopenia. However, the incidence of throm- bocytopenia in patients with acute-on-chronic liver failure （ACLF） who underwent linezolid therapy was unclear. The present study was to evaluate the incidence of thrombocyto- penia in ACLF and non-ACLF patients treated with linezolid and the risk factors of thrombocytopenia in these patients.

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

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

Assessment of scoring systems for acute-on-chronic liver failure at predicting short-term mortality in patients with alcoholic hepatitis

AIM To assess the performance of proposed scores specific for acute-on-chronic liver failure in predicting shortterm mortality among patients with alcoholic hepatitis.METHODS We retrospectively collected data from 264 patients with clinically diagnosed alcoholic hepatitis from January to December 2013 at 21 academic hospitals in Korea. The performance for predicting short-term mortality was calculated for Chronic Liver FailureSequential Organ Failure Assessment(CLIF-SOFA), CLIF Consortium Organ Failure score(CLIF-C OFs), Maddrey'sdiscriminant function(DF), age, bilirubin, international normalized ratio and creatinine score(ABIC), Glasgow Alcoholic Hepatitis Score(GAHS), model for end-stage liver disease(MELD), and MELD-Na.RESULTS Of 264 patients, 32(12%) patients died within 28 d. The area under receiver operating characteristic curve of CLIF-SOFA, CLIF-C OFs, DF, ABIC, GAHS, MELD, and MELD-Na was 0.86(0.81-0.90), 0.89(0.84-0.92), 0.79(0.74-0.84), 0.78(0.72-0.83), 0.81(0.76-0.86), 0.83(0.78-0.88), and 0.83(0.78-0.88), respectively, for 28-d mortality. The performance of CLIF-SOFA had no statistically significant differences for 28-d mortality. The performance of CLIF-C OFs was superior to that of DF, ABIC, and GAHS, while comparable to that of MELD and MELD-Na in predicting 28-d mortality. A CLIF-SOFA score of 8 had 78.1% sensitivity and 79.7% specificity, and CLIF-C OFs of 10 had 68.8% sensitivity and 91.4% specificity for predicting 28-d mortality.CONCLUSION CLIF-SOFA and CLIF-C OF scores performed well, with comparable predictive ability for short-term mortality compared to the commonly used scoring systems in patients with alcoholic hepatitis.