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Background Hepatitis B virus–related acute-on-chronic liver failure (HBV-ACLF) has a high short-term mortality. This study aimed to determine the diagnostic and prognostic role of MER tyrosine kinase (MERTK) in patients with HBV-ACLF. Methods Transcriptomics analysis evaluated MERTK expression and function during disease progression. The diagnostic and prognostic significance of MERTK for patients with HBV-ACLF were verified by enzyme-linked immunosorbent assay, area under the receiver operating characteristic curve (AUROC) analysis, and immunohistochemistry (IHC) of liver tissues. Results MERTK mRNA was highly expressed in patients with HBV-ACLF compared to those with liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NC). Elevated MERTK mRNA predicted poor prognosis for HBV-ACLF at 28 and 90 days (AUROC = 0.814 and 0.731, respectively). Functional analysis showed MERTK was significantly associated with toll-like receptor and inflammatory signaling and several key biological processes. External validation with 285 plasma subjects confirmed the high diagnostic accuracy of plasma MERTK for HBV-ACLF (AUROC = 0.859) and potential prognostic value for 28- and 90-day mortality rates (AUROC = 0.673 and 0.644, respectively). Risk stratification analysis indicated higher mortality risk for patients with plasma MERTK level above the cutoff value. Moreover, IHC staining showed increasing MERTK expression from NC, CHB, and LC to HBV-ACLF. Conclusions MERTK shows promise as a candidate biomarker for early diagnosis and prognosis of HBV-ACLF. [ABSTRACT FROM AUTHOR]

Xingping Zhou,1,* Jinjin Luo,1,* Xi Liang,1,2 Peng Li,1 Keke Ren,1 Dongyan Shi,1,2 Jiaojiao Xin,1,2 Jing Jiang,1,2 Jiaxian Chen,1 Lulu He,1 Hui Yang,1 Shiwen Ma,1 Bingqi Li,1 Jun Li1,2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 2Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel/Fax +86-571-87236425, Email lijun2009@zju.edu.cnBackground and Aim: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with high short-term mortality. Effective biomarkers are required for its early diagnosis and prognosis. This study aimed to determine the diagnostic and prognostic value of thrombomodulin (TM) in patients with HBV-ACLF.Methods: The expression of TM during disease progression was evaluated through transcriptomics analysis. The plasma TM concentrations of 393 subjects with HBV-ACLF (n=213), acute-on-chronic hepatic dysfunction (ACHD, n=50), liver cirrhosis (LC, n=50) or chronic hepatitis B (CHB, n=50), and normal controls (NC, n=30) from a prospective multicenter cohort, were measured to verify the diagnostic and prognostic significance of plasma TM for HBV-ACLF patients by enzyme-linked immunosorbent assay (ELISA).Results: TM mRNA was highly expressed in the HBV-ACLF group compared with the ACHD group (AUROC=0.710). High expression of TM predicted poor prognosis for HBV-ACLF patients at 28/90 days (AUROCs=0.823/0.788). Functional analysis showed that TM was significantly associated with complement activation and the inflammatory signaling pathway. External validation confirmed its high diagnostic accuracy for HBV-ACLF patients (AUROC=0.796). Plasma TM concentrations were correlated with organ failure, including coagulation and kidney failure. Plasma TM concentrations showed a potential prognostic value for 28-day mortality rates (AUROC=0.702). Risk stratification specifically identified HBV-ACLF patients with a high risk of death as having a plasma TM concentration of ≥ 8.4 ng/mL.Conclusion: This study reveals that the plasma TM can be a candidate biomarker for early diagnosis and prognosis of HBV-ACLF, and might play a vital role in coagulation and inflammation.Keywords: thrombomodulin, HBV-ACLF, biomarker, organ failure

Gang Qin,1 Bo Wang,2 Geng Zhang,2 Lili Wu,1 Peng Zhu,1 Qian Zhang2 1Department of Gastroenterology, Suining First People’s Hospital, Suining, People’s Republic of China; 2Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of ChinaCorrespondence: Qian Zhang, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Email zhangqian105@swmu.edu.cnPurpose: To screen out potential prognostic biomarkers for HBV-related acute-on-chronic liver failure (HBV-ACLF).Patients and Methods: Peripheral blood samples of HBV-ACLF patients (n=56) and normal controls (n=15) from the Affiliated Hospital of Southwest Medical University from January 2021 to April 2022 were collected, 5 normal patients and 10 patients with ACLF were randomly selected for Data independent acquisition (DIA) mass spectrometry analysis, and the potential core proteins were screened out via bioinformatics. All samples were validated by Enzyme linked immunosorbent assays (ELISA) technology, and the survival curve was constructed based on the patient’s 90-day survival time.Results: A total of 247 differentially expressed proteins (DEPs) were screened, of which 148 were upregulated and 99 were down-regulated. The DEPs were mainly enriched in high-density lipoprotein particle remodeling, coagulation, and hemostasis and participated in signaling pathways such as cholesterol metabolism, coagulation cascades, and PPAR signaling pathway. Finally, bikunin was selected for further study and validated via the ELISA, compared with the normal group, bikunin was poorly expressed in the HBV-ACLF group, the difference was statistically significant (P < 0.0001), the area under the curve (AUC) for Receiver operating characteristic (ROC) analysis was 0.917. Furthermore, compared with the non-survival group, bikunin was highly expressed in the HBV-ACLF survival group, the difference was statistically significant (P=0.0015), and the survival curve showed a positive correlation with patient survival (P=0.0063).Conclusion: The level of plasma bikunin in HBV-ACLF is down-regulated, which is positively correlated with the survival of the patients with HBV-ACLF, and is expected to become a new prognostic biomarker.Keywords: HBV-ACLF, AMBP, bikunin, DIA

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. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) has significant morbidity and mortality and is associated with the induction of cytokines/chemokines, which might contribute to the pathogenesis of liver injury. This study aimed to explore the cytokine/chemokine profiles of patients with HBV-ACLF and develop a composite clinical prognostic model. Methods: We prospectively collected blood samples and the clinical data of 107 patients with HBV-ACLF admitted to the Beijing Ditan Hospital. The concentrations of 40-plex cytokines/chemokines were measured in 86 survivors and 21 non-survivors using the Luminex assay. Discrimination between the cytokine/chemokine profiles in different prognosis groups was analyzed using the multivariate statistical techniques of principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). An immune-clinical prognostic model was obtained using multivariate logistic regression analysis. Results: The PCA and PLS-DA indicated that cytokine/chemokine profiling could clearly distinguish patients with different prognoses. A total of 14 cytokines, namely, IL-1b, IL-6, IL-8, IL-10, TNF-a, IFN-g, CXCL1, CXCL2, CXCL9, CXCL13, CX3CL1, GM-SCF, CCL21, and CCL23, were significantly correlated with disease prognosis. Multivariate analysis identified CXCL2, IL-8, total bilirubin, and age as independent risk factors that constituted the immune-clinical prognostic model, which showed the strongest predictive value of 0.938 compared with those of the Chronic Liver Failure Consortium (CLIF-C) ACLF (0.785), Model for End-Stage Liver Disease (MELD) (0.669), and MELD-Na (0.723) scores (p < 0.05 for all). Conclusion: The serum cytokine/chemokine profiles correlated with the 90-day prognosis of patients with HBV-ACLF. The proposed composite immune-clinical prognostic model resulted in more accurate prognostic estimates than those of the CLIF-C ACLF, MELD, and MELD-Na scores. [ABSTRACT FROM AUTHOR]

Background and Objectives: The platelet (PLT) value in hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is not sufficiently understood. The present study aimed to evaluate the prognostic effect of PLT on the prediction of HBV-ACLF outcomes after plasma exchange (PE). Methods: HBV-ACLF patients treated with PE between January 2017 and August 2021 were followed up for at least 6 months. Cox regression was performed to develop the predictive model, and the model's performance was analyzed using the receiver operating characteristic curve (ROC). Results: A total of 170 patients were included. The overall survival rate within 180 days was 75.88%. Age, PLT, total bilirubin (TBil), and the iMELD scores were independent risk factors affecting the prognosis of HBV-ACLF patients after PE. According to the Cox regression results, the new model was calculated: R = 0.142 × iMELD-0.009 × PLT. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was 0.758 (95% CI 0.678–0.838), and patients with lower PLT-iMELD scores (<4.50) had a better prognosis (p < 0.001). Conclusion: PLT is a valuable prognostic biomarker for HBV-ACLF patients after PE. The modified iMELD model incorporating PLT has a better sensitivity and efficacy in predicting the prognosis of patients. [ABSTRACT FROM AUTHOR]

Early diagnosis and prediction of hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) is important to reduce mortality. This study aimed to assess the diagnostic and predictive value of serum ferritin (SF) in HBV‐ACLF patients. Clinical data from 1905 hospitalized patients with acute deterioration of HBV‐related chronic liver diseases were analyzed to explore the association between SF and ACLF. A co‐expression network based on transcriptomics data for 20 HBV‐ACLF patients was constructed to investigate biological processes related to ferritin. Of 1270 patients in the derivation group, 440 and 830 were diagnosed with and without ACLF, respectively, based on Chinese Group on the Study of Severe Hepatitis B‐ACLF criteria. SF levels showed high diagnostic accuracy (area under the receiver operating characteristic [AUROC]: 0.820) for ACLF at admission. In patients with ACLF, SF was associated with liver and coagulation failure. In patients without ACLF, SF predicted risk for 28‐day progression to ACLF (AUROC: 0.808). A validation group of 635 patients confirmed the above results. Moreover, SF was significantly associated with the immune response based on transcriptomics analysis. SF is a potential diagnostic and predictive marker for HBV‐ACLF and might play a crucial role in immune disorders in HBV‐ACLF. [ABSTRACT FROM AUTHOR]

Acute-on-chronic liver failure (ACLF) is a major cause of liver-related death worldwide, but its key pathological features remain incompletely defined. This study aimed to reveal the molecular basis of hepatitis B virus-related ACLF (HBV-ACLF) by transcriptome sequencing of human liver tissue. A total of 18 human liver tissues from patients with different stages of HBV-related disease were collected for RNA sequencing, and liver tissues from patients and mouse models with ACLF were used for subsequent validation. Specifically, 6,853 differentially expressed genes (DEGs) and 5,038 differentially expressed transcripts were identified in patients with ACLF compared to patients with chronic hepatitis B (CHB) and normal controls (NCs). Investigation of functional by KEGG pathway enrichment analysis revealed prominent immune and metabolic dysregulation at the ACLF stage. We found that the key genes FGF19, ADCY8 and KRT17, which are related to immunometabolic disturbances, were significantly upregulated in the progression of ACLF. The three key genes were validated in human and mouse samples, indicating their prognostic and therapeutic potential in ACLF. In summary, our work reveals that immunometabolic disorder is involved in HBV-ACLF pathogenesis and indicates that FGF19, ADCY8 and KRT17 may be sensitive biomarkers for HBV-related ACLF. [ABSTRACT FROM AUTHOR]

Abstract Background Host genetic factors such as single nucleotide variations may play a crucial role in the onset and progression of HBV-related acute-on-chronic liver failure (ACLF). However, the underlying genomic copy number variations (CNVs) involved in the pathology are currently unclear. Methods We genotyped two cohorts with 389 HBV-related ACLF patients and 391 asymptomatic HBV carriers (AsCs), and then carried out CNV-based global burden analysis and a genome-wide association study (GWAS). Results For 1874 rare CNVs, HBV-related ACLF patients exhibited a high burden of deletion segments with a size of 100–200 kb (P value = 0.04), and the related genes were significantly enriched in leukocyte transendothelial migration pathway (P value = 4.68 × 10–3). For 352 common CNVs, GWAS predicted 17 significant association signals, and the peak one was a duplication segment located on 1p36.13 (~ 38 Kb, P value = 1.99 × 10–4, OR = 2.66). The associated CNVs resulted in more copy number of pro-inflammatory genes (MST1L, DEFB, and HCG4B) in HBV-related ACLF patients than in AsC controls. Conclusions Our results suggested that the impact of host CNV on HBV-related ACLF may be through decreasing natural immunity and enhancing host inflammatory response during HBV infection. The findings highlighted the potential importance of gene dosage on excessive hepatic inflammation of this disease.

Background: Acute-on-chronic liver failure (ACLF) is characterized by rapid onset, rapid development and a high short-term mortality rate. Systemic inflammation exerts an effect on the disease progression of ACLF., Objectives: The purposes of this study were to explore the clinical significance that the inflammatory response has on the disease process of hepatitis B virus acute-on-chronic liver failure (HBV-ACLF) patients, to further compare the values of different inflammation-related biomarkers in the prognosis evaluation of HBV-ACLF patients, and to combine inflammatory-related markers to establish a new prediction model., Material and Methods: Baseline admission data and 90-day outcomes were collected from 247 patients who met the inclusion criteria. According to the 90-day survival situation, they were divided into a survival group and a death group. The differences in baseline data and inflammation levels between the 2 groups were compared. A regression model was used to analyze the risk factors for 90-day mortality and establish a new model., Results: The study found that the differences between the survival group and the death group were statistically significant in terms of age, total bilirubin (Tbil), prothrombin time (PT), international standardized ratio (INR), inflammation level, and model for end-stage liver disease (MELD) series scores (p < 0.05). The monocyte-to-lymphocyte ratio (MLR)-integrated iMELD model (MLR-iMELD) can effectively predict the 90-day survival rate of HBV-ACLF patients. The area under the receiver operating characteristic (ROC) curve (AUROC) of the new model was 0.792, and the best cutoff for predicting the prognosis of 90 days for patients was -0.33 (sensitivity 0.577 and specificity 0.898)., Conclusions: The higher the level of inflammation in patients with HBV-ACLF, the greater the risk of 90-day death. Compared with other inflammation-related markers, the MLR-iMELD model can better predict the 90-day survival rate of HBV-ACLF patients.

Purpose: Neutrophils and cytokines play a major role in the pathogenesis of acute-on-chronic liver failure (ACLF). We aimed to determine whether chemokine (CXC) ligand 1 (CXCL1), a key marker of neutrophil recruitment and activation, could predict the severity and prognosis of hepatitis B virus–related ACLF (HBV-ACLF).Methods: Hospitalized patients with HBV-ACLF were enrolled in a prospective study and stratified as survivors (alive at 28 days) and nonsurvivors (deceased at 28 days). Serum CXCL1 levels were measured in healthy controls, patients with chronic HBV, patients with HBV-related compensated cirrhosis, and patients with HBV-ACLF. Univariate and multivariable logistic analyses, Pearson correlation analysis, area under the receiver operating characteristic curve (AUROC), and Z tests were used to evaluate the performance of CXCL1 as a marker in HBV-ACLF.Results: Patients with HBV-ACLF had significantly higher serum levels of CXCL1 and neutrophil count than healthy controls and patients with chronic HBV or HBV-related compensated cirrhosis (P < 0.01, respectively). Among patients with HBV-ACLF, survivors had lower serum CXCL1 levels and neutrophil count than those of nonsurvivors (P < 0.001, P < 0.05, respectively). Serum CXCL1 level was positively correlated with neutrophil count (r = 0.256, P = 0.001), ACLF grade (r = 0.295, P < 0.001) and organ failure, including coagulation (r = 0.21, P = 0.005) and brain failure (r = 0.198, P = 0.008). Multivariable logistic analyses showed serum CXCL1 [OR (95% CI) = 1.017 (1.009–1.025), P < 0.001] was an independent risk factor for 28-day mortality in HBV-ACLF. Meanwhile, the AUROC analysis demonstrated that serum CXCL1 [0.741 (0.669–0.804)] might be a reliable prognostic biomarker for patients with HBV-ACLF.Conclusions: Overall, serum CXCL1 can serve as a biomarker indicating the severity of disease and prognosis for patients with HBV-ACLF. CXCL1 might also be a therapeutic target in this disease.

Background and Aim: It has been reported that serum quantification of anti‐HBc (qAnti‐HBc) could predict antiviral response in chronic hepatitis B (CHB) patients, while its role in hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) remains unclear. Its implication in HBV‐ACLF was evaluated in this study. Methods: Baseline serum qAnti‐HBc levels were retrospectively detected in HBV‐ACLF and CHB patients using recently developed double‐sandwich immunoassay. The association of qAnti‐HBc level with clinical outcomes was evaluated by multiple logistic regression. Nomogram was adopted to formulate an algorithm incorporating qAnti‐HBc for the prediction of survival in HBV‐ACLF. The post‐hospitalization of HBV‐ACLF patients were followed‐up for 1 year. Results: Eighty‐eight HBV‐ACLF as training set, 80 HBV‐ACLF as validation set and 216 CHB cases were included. Serum qAnti‐HBc level was significantly higher in HBV‐ACLF (4.95 ± 0.54 log10 IU/mL) than CHB patients (4.47 ± 0.84 log10 IU/mL) (P < 0.01). Among HBV‐ACLF cases, both in training and validation set, patients with poor outcomes had lower qAnti‐HBc level. Area under receiver operating characteristic curve of the novel qAnti‐HBc inclusive model was 0.82, superior to 0.73 from model for end‐stage liver disease scores (P = 0.018), which was confirmed in validation set. During follow‐up, the qAnti‐HBc level declined at month 3 and month 6, then plateaued at 3.84 log10 IU/mL. Conclusions: Serum qAnti‐HBc level was associated with disease severity and might be served as a novel biomarker in the prediction of HBV‐ACLF clinical outcomes. The underlying immunological mechanism warrants further investigation. [ABSTRACT FROM AUTHOR]

Aim: To determine the prognostic risk factors of patients with hepatitis B virus related acute‐on‐chronic liver failure (HBV‐ACLF) treated with plasma exchange (PE)‐based artificial liver support system (ALSS), and create a prognostic predictive model. Methods: A total of 304 HBV‐ACLF patients who received PE‐based ALSS were retrospectively analyzed. Potential prognostic factors on admission associated with survival were investigated. Of note, 101 additional patients were analyzed to validate the performance of the prognostic models. Results: According to 28‐day survival, a total of 207 patients who survived and 97 non‐survivors were identified in the derivation group. Overall, 268 (88.2%) ACLF cases were caused by reactivation of HBV. Cox proportional hazards regression model revealed that age, total bilirubin, ln (alpha‐fetoprotein [AFP]), encephalopathy (HE) score, sodium level, and international normalized ratio (INR) were independent risk factors of short‐term prognosis. We built a model named ALSS‐prognosis model (APM) to predict the 28‐day survival of HBV‐ACLF patients with ALSS; the model APM showed potentially better predictive performance for both the derivation and validation groups than MELD, MELD‐Na, and CLIF‐C ACLF score. Conclusions: Low AFP was found to be an independent risk factor for high mortality in HBV‐ACLF patients treated with PE‐based ALSS. We generated a new model containing AFP, namely APM, which showed potentially better prediction performance than MELD, MELD‐Na, and CLIF‐C ACLF score for short‐term outcomes, and could aid physicians in making optimal therapeutic decisions. [ABSTRACT FROM AUTHOR]

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.

Background: The aim was to establish expression profiles of microRNAs (miRNAs) in Peripheral Blood Mononuclear Cells (PBMC) and of plasma cytokines from the patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) and high-risk of acute-on-chronic liver failure (ACLF) patients as well as healthy people and to examine the relationships between these profiles and clinical features. Methods: Herein, we collected PBMCs and plasma from peripheral blood of HBV-ACLF and ACLF patients as well as healthy people. Microarray, real-time qPCR, and ELISA assays were used. Results: In this study, we found 39 miRNAs including miR- 146a, miR-150, and miR-29 a downregulated and 5 miRNAs elevated in PBMCs from HBV-ACLF patients compared to healthy controls. However, elevated plasma levels of cytokines such as TNF-α, IFN-α, and TGF-β were found in PBMCs from HB V-ACLF patients compared with the controls, but no significant difference was found between the high-risk and control groups. MiR-146a, miR-150, miR-29a, PTA, and anti-HBc were positively correlated with the survival of ACLF patients, while TNF-α, IFN-α, INR, and TBiL were negatively correlated with the survival of these patients. Conclusions: Combined examination of miRNAs in PBMCs and cytokines in plasma together is a better method for monitoring and evaluating HBV-ACLF patients. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) has significant morbidity and mortality and is associated with the induction of cytokines/chemokines, which might contribute to the pathogenesis of liver injury. This study aimed to explore the cytokine/chemokine profiles of patients with HBV-ACLF and develop a composite clinical prognostic model., Methods: We prospectively collected blood samples and the clinical data of 107 patients with HBV-ACLF admitted to the Beijing Ditan Hospital. The concentrations of 40-plex cytokines/chemokines were measured in 86 survivors and 21 non-survivors using the Luminex assay. Discrimination between the cytokine/chemokine profiles in different prognosis groups was analyzed using the multivariate statistical techniques of principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). An immune-clinical prognostic model was obtained using multivariate logistic regression analysis., Results: The PCA and PLS-DA indicated that cytokine/chemokine profiling could clearly distinguish patients with different prognoses. A total of 14 cytokines, namely, IL-1β, IL-6, IL-8, IL-10, TNF-α, IFN-γ, CXCL1, CXCL2, CXCL9, CXCL13, CX3CL1, GM-SCF, CCL21, and CCL23, were significantly correlated with disease prognosis. Multivariate analysis identified CXCL2, IL-8, total bilirubin, and age as independent risk factors that constituted the immune-clinical prognostic model, which showed the strongest predictive value of 0.938 compared with those of the Chronic Liver Failure Consortium (CLIF-C) ACLF (0.785), Model for End-Stage Liver Disease (MELD) (0.669), and MELD-Na (0.723) scores ( p  < 0.05 for all)., Conclusion: The serum cytokine/chemokine profiles correlated with the 90-day prognosis of patients with HBV-ACLF. The proposed composite immune-clinical prognostic model resulted in more accurate prognostic estimates than those of the CLIF-C ACLF, MELD, and MELD-Na scores., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Gao, Li, Shi, Hou, Chen, Zhang and Wang.)

Background: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a severe complication with a poor prognosis. Recently, mesenchymal stem cell (MSC)-based therapy for HBVACLF has shown considerable promise. Therefore, this systematic review and meta-analysis aimed to evaluate the efficacy and safety of MSC transplantation for patients with HBV-ACLF., Methods: The PubMed, Cochrane Library, CNKI, and Embase databases were searched from their inception to March 2021 for reports on MSC therapy for HBV-ACLF. We used RevMan 5.3 to perform the systematic review and meta-analysis., Results: Four studies were ultimately included. Compared with the control treatment, allogeneic MSC treatment resulted in a higher cumulative survival rate among ACLF patients (OR=2.27; 95% CI 1.35, 3.81; p=0.002). The umbilical cord-derived MSC (UC-MSC) group obtained a higher survival rate than the control group (OR = 2.33; 95% CI 1.17, 4.63; p=0.02). The group with multiple interval peripheral vein injections of MSCs obtained a higher survival rate than the control group (OR = 2.09; 95% CI 1.20, 3.67; p=0.01). None of the adverse events were MSC-related., Conclusion: Our study indicates that MSC transplantation can significantly increase survival rates by improving liver function without severe adverse events. UC-MSCs harvested for allogeneic infusion via peripheral veins appear to provide superior treatment for patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: This study aimed to evaluate the efficacy and safety of entecavir, lamivudine and telbivudine for treating patients with HBV-ACLF and to validate the Tongji prognostic predictor model (TPPM) in these patients. Methods: In this retrospective study, we enrolled 283 patients with HBV-ACLF (100 treated with entecavir, 98 treated with lamivudine and 85 treated with telbivudine). There were no significant differences in baseline clinical and virological characteristics among patients treated with entecavir, telbivudine or lamivudine. Results: There were no significant differences in the 4- and 12-week survival rates of entecavir-, telbivudine- and lamivudine-treated patients (79.00, 81.18 and 86.73 %, respectively, at 4 weeks; 67.00, 65.88 and 73.47 %, respectively, at 12 weeks). Patients in all three groups achieved an improvement in the model for end-stage liver disease (MELD) score. Using the Hosmer-Lemeshow test, the validation of the TPPM score for HBV-ACLF demonstrated a good degree of fit with disease prognosis. Based on this unique group of patients, the TPPM score with an AUC of 0.787 was superior to the MELD score, which had an AUC of 0.736 in the prediction of 12-week mortality. The TPPM had an AUC of 0.733, and the MELD score had an AUC of 0.672 in the prediction of 4-week mortality. Using a cutoff value of 0.22 for 12-week mortality prediction by the TPPM, the positive predictive value was 49.66 %, with a negative predictive value of 89.55 %. Conclusion: Treatment with nucleoside analogs including entecavir, lamivudine and telbivudine prevented disease progression and increased the survival of patients with HBV-ACLF. Validation of the established TPPM scoring system in this study confirmed its superior predictive value for HBV-ACLF patients when compared with the MELD system. [ABSTRACT FROM AUTHOR]

Background: HBV-related acute-on-chronic liver failure (HBV-ACLF) is the most common type of liver failure with high mortality. Artificial liver support system (ALSS) is an important mean to reduce the mortality of HBV-ACLF but lacking index to assess its effectiveness. The cytokines are closely related to the prognosis of HBV-ACLF patients with ALSS treatment, however, which is not fully understood., Methods: One hundred forty-two patients with HBV-ACLF and 25 healthy donors were enrolled. The cytokine profile of peripheral blood was determined in the patients before and after ALSS treatment, and their relationship with effectiveness of ALSS treatment in HBV-ACLF was analyzed., Results: Serum IL-28A levels were markedly lower in ALSS-effective patients than those in non-effective patients pre-ALSS treatment. Similarly, serum IL-6 was significantly lower in ALSS-effective patients. Furthermore, for patients with effective treatment, serum IL-28A levels were positively related with IL-6 levels post-ALSS (r = 0.2413, p = 0.0383). The ROC curve analysis showed that serum levels of IL-28A (AUC = 0.6959 when alone or 0.8795 when combined with total bilirubin, platelet count and INR, both p < 0.0001) and IL-6 (AUC = 0.6704, p = 0.0005) were useful indices for separating effective from non-effective ALSS treatment of HBV-ACLF patients. Multivariate logistic regression analysis demonstrated that lower level of IL-28A was independently associated with higher effective rate of ALSS treatments., Conclusions: Lower level of IL-28A is a predictive biomarker for ALSS in effective treatment of HBV-ACLF patients and IL-28A may be potential target for the treatment of HBV-ACLF., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Objective: It has been demonstrated that signals from the inhibitory receptor B and T lymphocyte attenuator (BTLA) are involved in regulating the pathogenesis of infectious diseases. However, the expression and anatomical distribution of BTLA and its ligand, the herpes virus entry mediator (HVEM), have not yet been determined in cases of HBV-related acute-on-chronic liver failure (HBV-ACLF) patients. Methods: In this study, the expression of BTLA and HVEM in liver tissues from HBV-ACLF, chronic hepatitis B (CHB) patients and healthy individuals was analyzed by immunohistochemistry. Results: The results of this analysis demonstrated that both molecules were observed in the HBV-ACLF samples and that their expression was chiefly in the infiltrating inflammatory cells and the damaged bile ducts. However, they were absent in liver sections from CHB patients and healthy controls. Immunofluorescence double-staining indicated that BTLA was found on CK-18+ epithelial cells, CD31+ endothelial cells, CD68+ macrophages, CD56+ NK cells, CD16+ monocytes, CD3+ , CD8+ T cells, and Foxp3+ regulatory T cells (Treg). By contrast, HVEM expression was restricted to CK18+ epithelial cells and CD68+ macrophages. Moreover, the expression of several members of the B7 superfamily, including PD-L1, PD-L2, B7-H3 and B7-H4, was also detected in these liver tissues, and these proteins were co-expressed with HVEM. Interestingly, the expression of fibrinogen-like protein 2 (FGL2), a virus-induced procoagulant molecule, was also found in liver sections from HBV-ACLF, this molecule also co-expresses with BTLA and HVEM. Conclusions: These results suggest that BTLA-HVEM signaling is likely to affect the pathogenesis of HBV-ACLF, a clear understanding of the functional roles of these proteins should further elucidate the disease process. [ABSTRACT FROM AUTHOR]

Background: Host genetic factors such as single nucleotide variations may play a crucial role in the onset and progression of HBV-related acute-on-chronic liver failure (ACLF). However, the underlying genomic copy number variations (CNVs) involved in the pathology are currently unclear. Methods: We genotyped two cohorts with 389 HBV-related ACLF patients and 391 asymptomatic HBV carriers (AsCs), and then carried out CNV-based global burden analysis and a genome-wide association study (GWAS). Results: For 1874 rare CNVs, HBV-related ACLF patients exhibited a high burden of deletion segments with a size of 100–200 kb (P value = 0.04), and the related genes were significantly enriched in leukocyte transendothelial migration pathway (P value = 4.68 × 10–3). For 352 common CNVs, GWAS predicted 17 significant association signals, and the peak one was a duplication segment located on 1p36.13 (~ 38 Kb, P value = 1.99 × 10–4, OR = 2.66). The associated CNVs resulted in more copy number of pro-inflammatory genes (MST1L, DEFB, and HCG4B) in HBV-related ACLF patients than in AsC controls. Conclusions: Our results suggested that the impact of host CNV on HBV-related ACLF may be through decreasing natural immunity and enhancing host inflammatory response during HBV infection. The findings highlighted the potential importance of gene dosage on excessive hepatic inflammation of this disease. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate the value of hepatic T2 imaging for the evaluation of chronic hepatitis-B-related acute-on-chronic liver failure (HBV-ACLF)., Methods: Three groups of patients underwent liver MRI utilising m-GRASE sequence (multi-echo gradient and spin echo): HBV-ACLF patients (n = 28), chronic hepatitis B patients (n = 11), and healthy control patients (n = 14). A T 2 image was produced using post-processing software, and the mean T 2 (relaxation time) value was calculated. Blood biochemical indices for the HBV-ACLF and Chronic Hepatitis B were obtained within 2 days pre- or post-MR scanning. The patients' T 2 values, and the correlation between their biochemical indices and T 2 values were analysed. A receiver operating characteristic curve was employed to evaluate the efficiency of utilising T 2 values in the diagnosis of HBV-ACLF., Results: There were significant variations in the T 2 values (χ 2 = 19.074, P < 0.001) among the 3 groups. The AUC of T 2 values for diagnosing HBV-ACLF was 0.86 (P < 0.001), with a cut-off value of 57.73 ms. A moderately positive correlation was observed between the T2 value and the international normalised ratio, prothrombin time, and hyaluronic acid values (r s = 0.65, P < 0.001; r s = 0.67, P < 0.001; r s = 0.39, P = 0.025). A moderately negative correlation was observed between the T 2 value and the prothrombin activity, albumin, and prealbumin values (r s = -0.67, P < 0.001; r s = -0.48, P = 0.004; r s = -0.37, P = 0.030)., Conclusion: T 2 values could accurately reflect liver function state, as they correlated well with certain biochemical indices, illustrating good diagnostic efficiency for diagnosing HBV-ACLF., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chronic HBV infection (CHB) can lead to acute-on-chronic liver failure (HBV-ACLF) characterized by high mortality. This study aimed to reveal ACLF-related proteomic alterations, from which protein based diagnostic and prognostic scores for HBV-ACLF were developed. Methods : Ten healthy controls, 16 CHB, and 19 HBV-ACLF according to COSSH (Chinese group on the study of severe hepatitis B) criteria were enrolled to obtain the comprehensive proteomic portrait related to HBV-ACLF initiation and progression. Potential markers of HBV-ACLF were further selected based on organ specificity and functionality. An additional cohort included 77 healthy controls, 92 CHB and 71 HBV-ACLF was used to validate the proteomic signatures via targeted proteomic assays. Results : Significant losses of plasma proteins related to multiple functional clusters, including fatty acid metabolism/transport, immuno-response, complement and coagulation systems, were observed in ACLF patients. In the validation study, 28 proteins were confirmed able to separate ACLF, CHB patients. A diagnostic classifier P4 (APOC3, HRG, TF, KLKB1) was built to differentiate ACLF from CHB with high accuracy (auROC = 0.956). A prognostic model P8 (GC, HRG, HPR, SERPINA6, age, NEU, INR and total protein) was built to distinguish survivors from non-survivors in 28 and 90-days follow-up (auROC = 0.882, 0.871), and to stratify ACLF patients into risk subgroups showing significant difference in 28 and 90-days mortality (HR=7.77, 7.45, both P<0.0001). In addition, P8 score correlated with ACLF grades and numbers of extra-hepatic organ failures in ACLF patients, and was able to predict ACLF-associated coagulation and brain failure within 90 days (auROC = 0.815, 0.842). Conclusions : Proteomic signatures developed in this study reflected the deficiency of key hematological functions in HBV-ACLF patients, and show potential for HBV-ACLF diagnosis and risk prediction in complementary to current clinical based parameters., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.