Hepatitis B Virus-associated Acute-on-chronic Liver Failure Research Articles

Ultrasound-based Radiomics Predicts Short-term Outcomes in Hepatitis B Virus-related Acute-on-chronic Liver Failure.

The prognosis in hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is challenging due to heterogeneity. Radiomics may enable noninvasive outcome prediction. This study aimed to evaluate ultrasound-based radiomics for predicting outcomes in HBV-ACLF. We enrolled 264 HBV-ACLF patients, dividing them into a training cohort (n=184) and a validation cohort (n=80). From hepatic ultrasound images, 455 radiomic features were extracted. Radiomics-based phenotypes were identified through unsupervised hierarchical clustering. A radiomic signature was developed using a Cox-LASSO algorithm to predict 30-day mortality. Furthermore, we integrated the signature with independent clinical predictors via multivariate Cox regression to construct a combined clinical-radiomic nomogram (CCR-nomogram). Integrated discrimination improvement (IDI) and net reclassification improvement (NRI) assessed performance improvements achieved by adding radiomic features to clinical data. Both clustering and radiomic signature identified two distinct subgroups with significant differences in clinical characteristics and 30-day prognosis. In the training cohort, the signature achieved a C-index of 0.746, replicated in validation with a C-index of 0.747. The CCR-nomogram achieved C-indices of 0.834 and 0.819 for the training and validation cohorts. Incorporating radiomic features significantly improved the CCRnomogram over the signature and clinical-only models, evidenced by IDI of 0.108-0.264 and NRI of 0.292-0.540 in both cohorts (all p0.05). Ultrasound-based radiomics offered prognostic information complementary to clinical data and demonstrated potential to enhance outcome prediction in HBV-ACLF.

Single-Cell RNA Sequencing Shows T-Cell Exhaustion Landscape in the Peripheral Blood of Patients with Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure.

The occurrence and development of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is closely related to the immune pathway. We explored the heterogeneity of peripheral blood T cell subsets and the characteristics of exhausted T lymphocytes, in an attempt to identify potential therapeutic target molecules for immune dysfunction in ACLF patients. A total of 83,577 T cells from HBV-ACLF patients and healthy controls were screened for heterogeneity by single-cell RNA sequencing. In addition, exhausted T-lymphocyte subsets were screened to analyze their gene expression profiles, and their developmental trajectories were investigated. Subsequently, the expression of exhausted T cells and their capacity in secreting cytokines (interleukin 2, interferon γ, and tumor necrosis factor α) were validated by flow cytometry. A total of eight stable clusters were identified, among which CD4+ TIGIT+ subset and CD8+ LAG-3+ subset, with high expression of exhaust genes, were significantly higher in the HBV-ACLF patients than in normal controls. As shown by pseudotime analysis, T cells experienced a transition from naïve T cells to effector T cells and then exhausted T cells. Flow cytometry confirmed that the CD4+TIGIT+ subset and CD8+LAG-3+ subset in the peripheral blood of the ACLF patients were significantly higher than those in the healthy controls. Moreover, in vitro cultured CD8+LAG-3+ T cells were significantly fewer capable of secreting cytokines than CD8+LAG-3- subset. Peripheral blood T cells are heterogeneous in HBV-ACLF. The exhausted T cells markedly increase during the pathogenesis of ACLF, suggesting that T-cell exhaustion is involved in the immune dysfunction of HBV-ACLF patients.

Superoxide dismutase 2 as a predictor in patients with hepatitis B virus-associated acute-on-chronic liver failure.

The prognosis of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is critical in clinical management. We aimed to assess the prognostic efficacy of superoxide dismutase 2 (SOD2) for 90-day mortality in HBV-ACLF patients. The expression patterns of SOD2 in peripheral blood mononuclear cells (PBMCs) were examined in a derivation set (n = 82) by quantitative real-time polymerase chain reaction (RT-qPCR). The results were further validated in a validation set (n = 35). The expression levels of SOD2 were significantly decreased in the derivation set compared to those with chronic hepatitis B (CHB) or the healthy controls (HCs) (P < 0.001). In HBV-ACLF patients, SOD2 levels were negatively correlated with serum total bilirubin (TBIL) (rs = - 0.43, P < 0.001) and model for end-stage liver disease (MELD) scores (rs = - 0.22, P = 0.047), but positively correlated with alkaline phosphatase (AKP) (rs = 0.23, P = 0.034). SOD2 was identified as an independent risk factor for 90-day mortality in HBV-ACLF patients (hazard ratio: 0.124, 95% confidence interval: 0.059-0.261, P < 0.001). SOD2 yielded a larger area under the receiver operating characteristic curve (AUROC) than the MELD score in predicting 90-day mortality (0.914 vs. 0.712, P < 0.001). Kaplan-Meier analysis revealed a favorable overall survival (OS) for the SOD2 high expression group compared with the SOD2 low expression group in both the derivation and validation sets (P < 0.001). SOD2 has promising potential as a predictor of 90-day mortality in patients with HBV-ACLF.

Efficacy and Economic Evaluation of Nonbiological Artificial Liver Therapy in Acute-on-chronic Hepatitis B Liver Failure.

Nonbiological artificial liver (NBAL) is frequently used as a first-line treatment for hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). This study aimed to compare the therapeutic efficacy and cost-effectiveness ratio (CER) of comprehensive medical treatment, plasma exchange (PE), and double plasma molecular adsorption system (DPMAS) plus half-dose PE (DPMAS+PE) in patients with HBV-ACLF. A total of 186 patients with HBV-ACLF randomly received comprehensive medical treatment, PE, or DPMAS+PE and were prospectively evaluated. Patients were divided into four subgroups based on the pretreatment prothrombin activity (PTA): Group I (PTA>40%), group II (PTA 30-40%), group III (PTA 20-30%), and group IV (PTA<20%). The main outcome measures were 28 day effectiveness; 90 day liver transplantation-free survival; change of biochemical parameters; and CER. DPMAS+PE treatment was associated with significantly higher 28 day effectiveness and 90 day liver transplantation-free survival compared with PE treatment in patients with group I liver failure. Clearance of serum total bilirubin (TBIL), AST, and creatinine (Cr) were significantly higher in the DPMAS+PE group than in the PE group. For subjects with group I liver failure, DPMAS+PE treatment had advantages of lower CER values and better cost-effectiveness. Compared with comprehensive medical treatment and PE alone, DPMAS with half-dose sequential PE treatment more effectively improved TBIL, AST, and Cr in HBV-ACLF patients, improved 28 day effectiveness and 90 day survival rates in patients with group I liver failure, and was more cost effective. DPMAS+PE is a viable NBAL approach for treatment of HBV-ACLF.

Plasma Exchange-Based Non-bioartificial Liver Support System Improves the Short-Term Outcomes of Patients With Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure: A Multicenter Prospective Cohort Study

Background and aims: Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with extremely high short-term mortality. Whether plasma exchange (PE) improves HBV-ACLF outcomes remains controversial. Here, PE-based non-bioartificial liver support system (NB-ALSS) effects on short-term HBV-ACLF patient outcomes were investigated.Materials and methods: HBV-ACLF patients from Chinese Acute-on-chronic Liver Failure (CATCH-LIFE) cohort receiving standard medical therapy (SMT) alone or PE-based NB-ALSS in addition to SMT were allocated to SMT and SMT+PE groups, respectively; propensity score matching (PSM) was used to eliminate confounding bias. Short-term (28/90-day and 1-year) survival rates were calculated (Kaplan-Meier).Results: In total, 524 patients with HBV-ACLF were enrolled in this study; 358 received SMT alone (SMT group), and the remaining 166 received PE-based NB-ALSS in addition to SMT (SMT+PE group). PSM generated 166 pairs of cases. In the SMT+PE group, 28-day, 90-day, and 1-year survival rates were 11.90, 8.00, and 10.90%, respectively, higher than those in the SMT group. Subgroup analysis revealed that PE-based NB-ALSS had the best efficacy in patients with ACLF grade 2 or MELD scores of 30–40 (MELD grade 3). In MELD grade 3 patients who received SMT+PE, 28-day, 90-day, and 1-year survival rates were improved by 18.60, 14.20, and 20.10%, respectively. According to multivariate Cox regression analysis, PE-based NB-ALSS was the only independent protective factor for HBV-ACLF patient prognosis at 28 days, 90 days, and 1 year (28 days, HR = 0.516, p = 0.001; 90 days, HR = 0.663, p = 0.010; 1 year, HR = 0.610, p = 0.051). For those who received SMT+PE therapy, PE-based NB-ALSS therapy frequency was the only independent protective factor for short-term prognosis (28-day, HR = 0.597, p = 0.001; 90-day, HR = 0.772, p = 0.018).Conclusions: This multicenter prospective study showed that the addition of PE-based NB-ALSS to SMT improves short-term (28/90 days and 1-year) outcomes in patients with HBV-ACLF, especially in MELD grade 3 patients. Optimization of PE-based NB-ALSS may improve prognosis or even save lives among HBV-ACLF patients.

Plasma Interleukin-6 Level: A Potential Prognostic Indicator of Emergent HBV-Associated ACLF.

Objective To identify markers that predict the progression to hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). Methods We recruited 125 patients with chronic hepatitis B (CHB) between September 2013 and March 2017. During hospitalization, 25 patients progressed to LF and were classified as the LF group, while the remaining 100 patients were classified as the non-LF (NLF) group. We compared the kinetic changes in clinical and immune indicators including age, total bilirubin level, prothrombin time, model for end-stage liver disease score, interleukin (IL)-6, IL-8, and IL-10 cytokine levels, and number of T helper 17 and regulatory T cells between groups to determine their association with progression to HBV-ACLF. The prognostic value of clinical and immune indicators was determined using the area under the receiver operating characteristic curve (AUC) value. Results Cox regression analysis suggested that the plasma IL-6 level could predict CHB progression to HBV-ACLF (relative risk = 1.082, 95% confidence interval: 1.006–1.164; P=0.034). The AUC value, sensitivity, and specificity of baseline IL-6 level for predicting HBV-ACLF were 82.63%, 83.3%, and 82.9%, respectively (P=0.001). Conclusion A high plasma IL-6 level in CHB patients could be an early biomarker for HBV-ACLF.

Computed Tomography Image Features under Convolutional Neural Network Algorithm in Analysis of Inflammatory Factor Level and Prognosis of Patients with Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure.

This study aimed to explore the application value of three-dimensional (3D) convolutional neural networks (3D-CNN)-based computed tomography (CT) image intelligent segmentation model in the identification of lesions of patients with hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). A total of 30 patients with HBV-ACLF, 30 patients with chronic HBV hospitalized in hospital, and 30 healthy volunteers were selected as subjects. Liver function and serum inflammatory factors were measured in each group, and the 3D-CNN algorithm model was applied to CT imaging. The results showed that the levels of interleukin (IL)-6, IL-26, and IL-37 in the HBV-ACLF group were the highest, which were 128.43 ± 45.16 pg/mL, 1237.47 ± 536.22 pg/mL, and 50.83 ± 7.62 pg/mL, respectively. Total bilirubin (TBIL) (P=0.035) and IL-26 (P=0.013) were independent predictors that affected the prognosis of HBV-ACLF patients. The results of lesion segmentation showed that the Dice coefficient of 3D-CNN low-density focus and enhanced focus segmentation was the highest (0.821 ± 0.07 and 0.773 ± 0.071), and the marked area was close to the area manually drawn by the doctor. 3D CNN was superior to other algorithms in the number of nodular lesions detected (533), sensitivity (97.5%), and missed detection rate (0.52%) (P < 0.05). In short, IL-26 may become a useful biomarker in the treatment of HBV-ACLF. The 3D-CNN model improved the segmentation performance of lesions in CT images of HBV-ACLF patients, which provided a reference for the diagnosis and prognosis of HBV-ACLF.

The NLRP3 inflammasome mediates liver failure by activating procaspase-1 and pro-IL-1 β and regulating downstream CD40-CD40L signaling.

ObjectivesIn this prospective case–control study, we explored the regulatory roles of the NLRP3 inflammasome in hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF).MethodsThirty patients with HBV-ACLF, 30 patients with chronic hepatitis B, and 30 healthy individuals were enrolled. Real-time reverse transcription polymerase chain reaction was used to assess mRNA levels in peripheral blood mononuclear cells and serum protein levels were assessed by enzyme-linked immunosorbent assay.ResultsSerum levels of alanine aminotransferase, asparagine aminotransferase, total bilirubin, and direct bilirubin in patients with HBV-ACLF were increased. Transcript levels of NLRP3 and ASC and protein levels of interleukin (IL)-1β, IL-18, and sCD40L were elevated in patients with HBV-ACLF. Expression of the NLRP3 inflammasome signaling pathway components procaspase-1 and pro-IL-1β was elevated in patients with HBV-ACLF.ConclusionsThis prospective case-control study demonstrated that significant activation of the NLRP3 inflammasome occurs in patients with HBV-ACLF. The activated NLRP3 inflammasome mediated liver failure by stimulating procaspase-1 and pro-IL-1 β and regulating downstream CD40-CD40L signaling.

Clinical Value of Cystatin C-Based Estimated Glomerular Filtration Rate in Assessing Short-Term Mortality in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure Treated with Artificial Liver Support System

To evaluate the predictive value of using cystatin c-based estimated glomerular filtration rate (eGFR-CysC) in assessing the prognosis of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) patients treated with artificial liver support system (ALSS). A total of 364 HBV-ACLF inpatients treated with ALSS at our hospital were enrolled retrospectively in the study. The patients were divided into the survival group ( n=269) and non-survival group ( n=95) according to mortality within 28 d, and their clinical information and laboratory data were analyzed for assessing short-term prognostic values. Multivariate Cox regression analysis identified eGFR-CysC as one of the independent risk factors associated with mortality within 28 days in HBV-ACLF patients (the hazard ratio=0.987; 95% confidence interval, 0.979-0.996, P=0.003). In addition, baseline eGFR-CysC was negatively correlated with the model for end-stage liver disease (MELD) score ( r=-0.439, P<0.001), MELD plus sodium (MELD-Na) score ( r=-0.481, P<0.001) and Chronic Liver Failure Consortium ACLF (CLIF-C ACLF) score ( r=-0.340, P<0.001). Receiver operating characteristic (ROC) curve analysis showed area under the curve ( AUC) of eGFR-CysC were 0.639, 0.697, 0.716, 0.749 and the best cut-off value were 70.620, 67.525, 61.725, 64.685 mL/(min·1.73 m 2), respectively, for baseline value and the first, second, and third treatment with ALSS. eGFR-CysC could be used to assist clinical assessment of short-term mortality in HBV-ACLF patients treated with ALSS, and has better clinical application value for dynamic monitoring.

Value of high-density lipoprotein cholesterol in evaluating the severity and prognosis of hepatitis B virus-associated acute-on-chronic liver failure

Objective To investigate the association of high-density lipoprotein cholesterol (HDL-C) with the prognosis of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) and its predictive value. Methods The patients with liver disease who were admitted to Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, from January 2015 to January 2019 were enrolled, and according to the stage of disease progression, they were divided into HBV-ACLF group with 42 patients, liver cirrhosis group with 30 patients, and chronic hepatitis group with 25 patients. A total of 24 healthy individuals were enrolled as healthy control group. General clinical data were collected, including sex, age, prothrombin time (PT), albumin (Alb), total bilirubin (TBil), serum creatinine, blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), and Model for End-Stage Liver Disease (MELD) score. The HBV-ACLF group was further divided into improvement group with 17 patients and non-improvement group with 25 patients, and the patients were followed up for 3 months. The Mann-Whitney U test was used for comparison of non-normally distributed continuous variables between two groups; the Kruskal-Wallis H test was used for comparison between multiple groups, and the Wilcoxon rank-sum test was used for comparison within each group. A binary logistic regression analysis was used to investigate independent risk factors for prognosis, and the receiver operating characteristic (ROC) curve was used to evaluate the accuracy of the variables in prediction. Results There were significant differences in PT, Alb, BUN, TBil, TC, TG, HDL-C, LDL-C, and MELD scores between the liver cirrhosis group, the HBV-ACLF group, the chronic hepatitis group, and the healthy control group (χ2=75.134, 44.638, 10.253, 80.357, 55.067, 19.858, 68.174, 52.492, and 64.359, all P Conclusion HDL-C is an independent risk factor for the prognosis of patients with HBV-ACLF and has a good value in predicting the prognosis of HBV-ACLF.

High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure.

BACKGROUNDPatients with hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) present a complex and poor prognosis. Systemic inflammation plays an important role in its pathogenesis, and interleukin-6 (IL-6) as a pro-inflammatory cytokine is related with severe liver impairment and also plays a role in promoting liver regeneration. Whether serum IL-6 influences HBV-ACLF prognosis has not been studied.AIMTo determine the impact of serum IL-6 on outcome of patients with HBV-ACLF.METHODSWe performed a retrospective study of 412 HBV-ACLF patients. The findings were analyzed with regard to mortality and the serum IL-6 level at baseline, as well as dynamic changes of serum IL-6 within 4 wk.RESULTSThe serum IL-6 level was associated with mortality. Within 4 wk, deceased patients had significantly higher levels of IL-6 at baseline than surviving patients [17.9 (7.3-57.6) vs 10.4 (4.7-22.3), P = 0.011]. Patients with high IL-6 levels (> 11.8 pg/mL) had a higher mortality within 4 wk than those with low IL-6 levels (≤ 11.8 pg/mL) (24.2% vs 13.2%, P = 0.004). The odds ratios calculated using univariate and multivariate logistic regression were 2.10 (95% confidence interval [CI]: 1.26-3.51, P = 0.005) and 2.11 (95%CI: 1.15-3.90, P = 0.017), respectively. The mortality between weeks 5 and 8 in patients with high IL-6 levels at 4 wk was 15.0%, which was significantly higher than the 6.6% mortality rate in patients with low IL-6 levels at 4 wk (hazard ratio = 2.39, 95%CI: 1.05-5.41, P = 0.037). The mortality was 5.0% in patients with high IL-6 levels at baseline and low IL-6 levels at 4 wk, 7.5% in patients with low IL-6 levels both at baseline and at 4 wk, 11.5% in patients with low IL-6 levels at baseline and high IL-6 levels at 4 wk, and 16.7% in patients with high IL-6 levels both at baseline and at 4 wk. The increasing trend of the mortality rate with the dynamic changes of IL-6 was significant (P for trend = 0.023).CONCLUSIONA high level of serum IL-6 is an independent risk factor for mortality in patients with HBV-ACLF. Furthermore, a sustained high level or dynamic elevated level of serum IL-6 indicates a higher mortality.

Artificial neural network-based models used for predicting 28- and 90-day mortality of patients with hepatitis B-associated acute-on-chronic liver failure

BackgroundThis study aimed to develop prognostic models for predicting 28- and 90-day mortality rates of hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) through artificial neural network (ANN) systems.MethodsSix hundred and eight-four cases of consecutive HBV-ACLF patients were retrospectively reviewed. Four hundred and twenty-three cases were used for training and constructing ANN models, and the remaining 261 cases were for validating the established models. Predictors associated with mortality were determined by univariate analysis and were then included in ANN models for predicting prognosis of mortality. The receiver operating characteristic curve analysis was used to evaluate the predictive performance of the ANN models in comparison with various current prognostic models.ResultsVariables with statistically significant difference or important clinical characteristics were input in the ANN training process, and eight independent risk factors, including age, hepatic encephalopathy, serum sodium, prothrombin activity, γ-glutamyltransferase, hepatitis B e antigen, alkaline phosphatase and total bilirubin, were eventually used to establish ANN models. For 28-day mortality in the training cohort, the model’s predictive accuracy (AUR 0.948, 95% CI 0.925–0.970) was significantly higher than that of the Model for End-stage Liver Disease (MELD), MELD-sodium (MELD-Na), Chronic Liver Failure-ACLF (CLIF-ACLF), and Child-Turcotte-Pugh (CTP) (all p < 0.001). In the validation cohorts the predictive accuracy of ANN model (AUR 0.748, 95% CI: 0.673–0.822) was significantly higher than that of MELD (p = 0.0099) and insignificantly higher than that of MELD-Na, CTP and CLIF-ACLF (p > 0.05). For 90-day mortality in the training cohort, the model’s predictive accuracy (AUR 0.913, 95% CI 0.887–0.938) was significantly higher than that of MELD, MELD-Na, CTP and CLIF-ACLF (all p < 0.001). In the validation cohorts, the prediction accuracy of the ANN model (AUR 0.754, 95% CI: 0.697–0.812 was significantly higher than that of MELD (p = 0.019) and insignificantly higher than MELD-Na, CTP and CLIF-ACLF (p > 0.05).ConclusionsThe established ANN models can more accurately predict short-term mortality risk in patients with HBV- ACLF.The main content has been postered as an abstract at the AASLD Hepatology Conference (https://doi.org/10.1002/hep.30257).

Correlation between interleukin-6 single nucleotide polymorphism and the occurrence and prognosis of hepatitis B virus-associated acute-on-chronic liver failure

Objective: To investigate the correlation between interleukin-6 (IL-6) single nucleotide polymorphism (SNP) and the occurrence and prognosis of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). Methods: Patients with chronic hepatic diseases diagnosed as HBV infection in the Hepatology Center of the First Affiliated Hospital of Fujian Medical University from July 2012 to March 2018 were divided into HBV-ACLF and non-ACLF group. SNP genotyping of eight loci in IL-6 gene (rs1524107, rs1800795, rs1800797, rs2069827, rs2069830, rs2069837, rs2069840 and rs2069845) was determined by the improved multi-temperature ligase detection reaction (imLDRTM) technique. Simultaneously, case data were reviewed with the 3-months followed up survival condition of the ACLF group. Normally distributed data were expressed as arithmetic means and SDs, and t-test was adopted. Data with skewed distribution were expressed as medians with interquartile range, and were measured by non-parametric test. Multivariate logistic regression analysis was used to analyze the relative risk of genetic polymorphism and HBV-ACLF as well as the relationship between IL-6 SNPs with the occurrence and prognosis of HBV-ACLF. Results: Four hundred patients were included in the study, with 122 (30.5%) in the HBV-ACLF and 278 (69.5%) in the non-ACLF group. There were significant differences in total bilirubin, albumin, and white blood cell count, percentage of neutrophils, platelet count, alanine aminotransferase, aspartate aminotransferase, prothrombin time and international standardized ratio, creatinine and the model for end-stage liver disease score between the two groups (P < 0.001). The genotype of IL-6 genes (rs1800795, rs1800797, rs2069827, and rs2069830) of all subjects showed no mutation or the mutation rate under 1%. There was no significant difference in the genotype of IL-6 (rs1524107, rs2069837, rs2069840 and rs2069845) between the two groups (P > 0.05). Multivariate logistic regression analysis showed that the SNPs in the above four loci of IL-6 gene was not associated with HBV-ACLF risk, nor had significant correlation with the 3-months prognosis. Conclusion: The SNP genotyping of eight loci in IL-6 gene (rs1524107, rs1800795, rs1800797, rs2069827, rs2069830, rs2069837, rs2069840 and rs2069845) is unrelated to the occurrence and short-term prognosis of HBV-ACLF.

Model for end-stage liver disease combined with arterial blood lactate to assess the prognosis of hepatitis B virus-associated acute-on-chronic liver failure: a retrospective analysis of 97 cases

Objective: To explore the prognostic value of model for end-stage liver disease (MELD) combined with arterial blood lactate (Lac) in admitted patients with hepatitis B virus-associated acute- on-chronic liver failure (HBV-ACLF). Methods: Clinical data of 97 cases with hepatitis B virus-associated acute- on-chronic liver failure (HBV-ACLF) admitted to the First Affiliated Hospital of Suzhou University between March 2016 and March 2018 was retrospectively analyzed. Age, gender, complications, MELD score, lactic acid (Lac), total bilirubin (TBil), creatinine (Cr), serum albumin (Alb), high-sensitivity C-reactive protein (CRP), white blood cell count (WBC), platelet count (PLT), hematocrit (Hct), quantification of HBV DNA and HBsAg, and organ support treatment (artificial liver support system, renal replacement therapy and mechanical ventilation ) were documented after admission. The primary endpoint of treatment was death due to ineffective medical treatment during hospitalization, abandonment of medical treatment due to deterioration of the health condition, and switch to liver transplantation for patients with poor medical treatment. The risk factors for primary endpoint of treatment were analyzed by binary logistic regression. Hosmer-Lemeshow test was used to evaluate the goodness of fit for the scoring system, and the ROC to predict the prognosis of MELD-Lac. Results: Ninety-seven cases with HBV-ACLF were included, 56 cases had good prognosis, and 41 cases had bad prognosis (including two cases with poor medical treatment and liver transplantation). The overall improvement rate was 57.7%. MELD score and Lac value in treated group was significantly lower than non-treated group. Bivariable and multivariable logistic regression analysis showed that the MELD score [odds ratio (OR = 1.806)], and Lac score [odds ratio (OR = 1.820)] was the risk factor for hospitalization and mortality in patients with liver failure (P < 0.05). The area under the ROC curve (AUC) and the 95% confidence interval (95% CI) of prognostic patients with MELD-Lac were significantly better than Lac and MELD scores [0.923 (0.84 to 1.00) vs. 0.804 (0.067 to 0.942) and 0.864 (0.75). 0.977)], P < 0.05. When the MELD-Lac Youden index was set at 0.746, the optimal threshold was 18.36, and the sensitivity and specificity were 91.3% and 83.3%, respectively. Conclusion: MELD-Lac score has a high prognostic value in HBV-ACLF patients.

Therapeutic effect of double plasma molecular adsorption system and sequential half-dose plasma exchange in patients with HBV-related acute-on-chronic liver failure.

ObjectiveThe artificial liver support system (ALSS) is used frequently as a first‐line treatment for hepatitis B virus‐associated acute‐on‐chronic liver failure (HBV‐ACLF). This study aims to compare the therapeutic efficacy of double plasma molecular adsorption system (DPMAS) with sequential half‐dose plasma exchange (PE) (DPMAS+PE) and full‐dose PE in patients with HBV‐ACLF.MethodsA total of 131 hospitalized patients who were diagnosed with HBV‐ACLF and underwent DPMAS+PE or PE were retrospectively analyzed. According to the treatment methods used, they were divided into PE group (n = 77) and DPMAS+PE group (n = 54). The main evaluation indexes included the change of liver function and the 28‐days liver transplant‐free survival rates after the different treatments.ResultsThere were no significant differences on severity of illness between PE group and DPMAS+PE group (P > 0.05). The total bilirubin (TBIL) levels immediately after treatment, and at 24 and 72 hours after treatment were markedly decreased in DPMAS+PE group than that in PE group (52.3 ± 9.4% vs 42.3 ± 7.2%, P < 0.05; 24.2 ± 10.0% vs 13.5 ± 13.0%, P < 0.05; 24.8 ± 13.1% vs 14.9 ± 14.9%, P < 0.05; respectively). The 28‐days survival rates was 62.3% and 72.2% in PE and DPMAS+PE groups (P = 0.146). Furthermore, the 28‐days survival rates were significantly higher in DPMAS+PE group than that in PE group (57.4% vs 41.7%, P = 0.043) in the intermediate‐advanced stage patients.ConclusionCompared with PE alone, DPMAS+PE might more effectively improve temporary TBIL in ACLF patients, and improve the 28‐days survival rates in HBV‐ACLF patients with intermediate‐advanced stage. Therefore, DPMAS+PE may be an available ALSS treatment for HBV‐ACLF patients.

Serum NGAL Is Superior to Cystatin C in Predicting the Prognosis of Acute-on-Chronic Liver Failure

Introduction and aim. Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality, and predicting the prognosis is challenging. This study aimed to compare the performance of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CysC) in predicting the 90-day mortality in patients with hepatitis B virus (HBV)-associated ACLF (HBV-ACLF). Materials and methods. This prospective, observational study enrolled 54 patients with HBV-ACLF. The serum NGAL and CysC levels were determined. A multivariate logistic regression analysis was used to analyze the independent risk factors of mortality. Results. Serum NGAL, but not CysC, was found to significantly correlate with the total bilirubin, international normalized ratio, and model for end-stage liver disease (MELD). Serum NGAL [odds ratio (OR), 1.008; 95% confidence interval (CI), 1.004-1.012; P < 0.01], but not CysC, was an independent risk factor for developing hepatorenal syndrome. Moreover, NGAL (OR, 1.005; 95% CI, 1.001-1.010; P < 0.01) along with the MELD score was independently associated with the overall survival in patients with HBV-ACLF. Patients with HBV-ACLF were stratified into two groups according to the serum NGAL level at baseline (low risk: <217.11 ng/mL and high risk: ≥ 217.11 ng/mL). The 90-day mortality rate was 22.73% (5/22) in the low-risk group and 71.88% (23/32) in the high-risk group. Moreover, NGAL, but not CysC, significantly improved the MELD score in predicting the prognosis of HBV-ACLF. Conclusion. The serum NGAL might be superior to CysC in predicting the prognosis of HBV-ACLF with the normal creatinine level.

Study on characteristics and prognosis of organ failure in patients with hepatitis B virus-associated acute-on-chronic liver failure

Objective: To evaluate the incidence, and the characteristics of organ failure in relationship to prognosis in hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) patients using chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score for judgments of clinical treatment and prognosis. Methods: Clinical data of 316 patients who were diagnosed as HBV-ACLF during hospitalization from February 2015 to February 2016 were retrospectively analyzed. Intrahepatic and extrahepatic organ failures were assessed according to CLIF-SOFA score, and the relationship between clinical characteristics and prognosis was analyzed. Continuity variables were analyzed by analysis of variance, or Kruskal-Wallis H test. Comparison of the categorical data were done using χ (2) or Fisher's exact test, and the predictive efficacy of various prognostic scores was compared using the area under the receiver operating characteristic curve (AUROC) and Z-test. Results: Of 316 cases (87.3% men) of HBV-ACLF, the mean age was (45 ± 11) years old. 78.8% of patients with underlying liver disease had hepatitis B virus induced cirrhosis. Mortality rates in patients without liver transplantation at 28 days, 90 days and 180 days were 20.5% (63/307), 36.7% (110/300) and 39.2% (116/296), respectively. According to the CLIF-SOFA score, 89.9% (284 patients) had organ failure at baseline, of which 97.5% had liver failure (Total bilirubin ≥ 12 mg/dl) and only 2.5% had coagulation, kidney, circulation or respiratory failure without liver failure. Besides liver failure, the incidence of extrahepatic organ failure was coagulation (23.1%), kidney (5.7%), brain (3.8%), circulation (1.3%) and respiratory failure (0.3%). With increasing number of organ failure, the mortality rate of two and three or more organ failures were 69.6% and 69.2%, respectively, which was significantly higher than that of single organ failure and non-organ failure patients (27% and 6.9%, respectively; P < 0.001). Liver failure with coagulation failure (International normalized ratio≥2.5 or platelet count≤20×10(9)/L) had worst prognosis with a mortality rate of up to 75% at 90 days. Conclusion: According to the CLIF-SOFA score, the main organ failure in patients with HBV-ACLF in China is liver failure. The mortality rate in patients with two or more organ failures is as high as 70% within 3 months. Therefore, timely manner liver transplantation should be considered.

Serum NGAL Is Superior to Cystatin C in Predicting the Prognosis of Acute-on-Chronic Liver Failure

Introduction and aim. Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality, and predicting the prognosis is challenging. This study aimed to compare the performance of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CysC) in predicting the 90-day mortality in patients with hepatitis B virus (HBV)-associated ACLF (HBV-ACLF). Materials and methods. This prospective, observational study enrolled 54 patients with HBV-ACLF. The serum NGAL and CysC levels were determined. A multivariate logistic regression analysis was used to analyze the independent risk factors of mortality. Results. Serum NGAL, but not CysC, was found to significantly correlate with the total bilirubin, international normalized ratio, and model for end-stage liver disease (MELD). Serum NGAL [odds ratio (OR), 1.008; 95% confidence interval (CI), 1.004–1.012; P &lt; 0.01], but not CysC, was an independent risk factor for developing hepatorenal syndrome. Moreover, NGAL (OR, 1.005; 95% CI, 1.001–1.010; P &lt; 0.01) along with the MELD score was independently associated with the overall survival in patients with HBV-ACLF. Patients with HBV-ACLF were stratified into two groups according to the serum NGAL level at baseline (low risk: &lt;217.11 ng/mL and high risk: ≥217.11 ng/mL). The 90-day mortality rate was 22.73% (5/22) in the low-risk group and 71.88% (23/32) in the high-risk group. Moreover, NGAL, but not CysC, significantly improved the MELD score in predicting the prognosis of HBV-ACLF. Conclusion. The serum NGAL might be superior to CysC in predicting the prognosis of HBV-ACLF with the normal creatinine level.

Discovery of a Potential Plasma Protein Biomarker Panel for Acute-on-Chronic Liver Failure Induced by Hepatitis B Virus.

Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF), characterized by an acute deterioration of liver function in the patients with chronic hepatitis B (CHB), is lack of predicting biomarkers for prognosis. Plasma is an ideal sample for biomarker discovery due to inexpensive and minimally invasive sampling and good reproducibility. In this study, immuno-depletion of high-abundance plasma proteins followed by iTRAQ-based quantitative proteomic approach was employed to analyze plasma samples from 20 healthy control people, 20 CHB patients and 20 HBV-ACLF patients, respectively. As a result, a total of 427 proteins were identified from these samples, and 42 proteins were differentially expressed in HBV-ACLF patients as compared to both CHB patients and healthy controls. According to bioinformatics analysis results, 6 proteins related to immune response (MMR), inflammatory response (OPN, HPX), blood coagulation (ATIII) and lipid metabolism (APO-CII, GP73) were selected as biomarker candidates. Further ELISA analysis confirmed the significant up-regulation of GP73, MMR, OPN and down-regulation of ATIII, HPX, APO-CII in HBV-ACLF plasma samples (p < 0.01). Moreover, receiver operating characteristic (ROC) curve analysis revealed high diagnostic value of these candidates in assessing HBV-ACLF. In conclusion, present quantitative proteomic study identified 6 novel HBV-ACLF biomarker candidates and might provide fundamental information for development of HBV-ACLF biomarker.

GP73, a new marker for diagnosing HBV-ACLF in population with chronic HBV infections

Although Golgi protein 73 (GP73) has been widely evaluated for diagnosing hepatocellular carcinoma (HCC) and other liver diseases in recent decade, its serum profile of patients with hepatitis B virus (HBV)–associated acute-on-chronic liver failure (HBV-ACLF) is still unknown. This study was designed to evaluate the serum levels of GP73 in patients with HBV-ACLF. The participants included 200 apparently healthy controls; 200 patients with chronic hepatitis B (CHB); 200 patients with HCC; 210 patients with HBV-ACLF, in which 29 HBV-ACLF patients were followed up for 3 months. All patients were Hepatitis B virus surface antigen (HBsAg) positive. The concentrations of GP73 in patients with HBV-ACLF (285.3 ± 128.5 ng/mL) were markedly higher than those HCC patients (159.1 ± 105.8 ng/mL), CHB patients (64.65 ± 44.99 ng/mL), and healthy controls (35.37 ± 12.41 ng/mL). When the cut-off value was set at 182.1 ng/mL, the sensitivity and specificity of HBV-ACLF diagnosis were 77.62% (95% confidence interval [CI]: 71.37%–83.07%) and 95.50% (95% CI: 92.27%–98.26%), respectively. If serum GP73 concentration was still above 361.6 ng/mL after 14 days of follow-up, the patient's prognosis may be depressed. Serum GP73 may be used to diagnosis HBV-ACLF in population with chronic HBV infections.