HBV-ACLF Patients Research Articles

Development and validation of a novel prognostic nomogram for hepatitis B virus-related acute-on-chronic liver failure patients receiving artificial liver therapy

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV–ACLF) is frequently accompanied by short-term morbidity and mortality. However, there have been no studies on the associations between baseline clinicopathologic characteristics at hospital admission and clinical prognosis after receiving artificial liver therapy. Therefore, the current study aimed to develop a prognostic nomogram for predicting the outcomes of patients with HBV–ACLF following artificial liver support.MethodsA retrospective study of 110 consecutive patients who were diagnosed with HBV–ACLF between January 2018 and August 2022 was conducted. First, univariate and multivariate logistic regression analyses were performed to determine the independent prognostic factors significantly associated with patient outcomes. Moreover, a predictive nomogram model underlying the prognostic factors was established and further evaluated. The area under the curve (AUC) was used to gauge the predictive accuracy. The calibration curve and decision curve analysis (DCA) were employed to assess the discriminability and clinical effectiveness, respectively.ResultsIn patients with HBV–ACLF, multivariate logistic analysis revealed that age ≥ 40 years (OR 6.76, p = 0.025), middle-stage liver failure (OR 49.96, p < 0.001), end-stage liver failure (OR 19.27, p = 0.002), hepatic encephalopathy (OR 7.06, p = 0.032), upper gastrointestinal hemorrhage (OR 47.24, p = 0.047), and artificial liver therapy consisting of plasma exchange (PE) + plasma exchange double plasma molecular adsorption system (DPMAS) (OR 0.26, p = 0.04) were identified as prognostic factors. Then, we established and evaluated a predictive nomogram with an AUC of 0.885, which showed better predictive accuracy than the model for end-stage liver disease (MELD) score (AUC of 0.634) and the Child–Pugh score (AUC of 0.611). Moreover, the calibration curve showed good agreement between the ideal and bias-corrected curves. Decision curve analysis confirmed the better clinical utility of this approach.ConclusionsWe developed and evaluated a unique nomogram that was more accurate than conventional prognostic models for predicting the clinical prognosis of HBV–ACLF patients receiving artificial liver therapy. As a result, the nomogram may be a helpful tool in clinical decision-making to predict the outcomes of patients with HBV–ACLF.

Hepatic and extrahepatic metabolic modulation in hbv-related decompensated cirrhosis and acute-on-chronic liver failure

ABSTRACT Acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) are life-threatening syndromes that can develop at the end-stage of chronic hepatitis B virus (HBV) infection. Both ACLF and DC are complicated by hepatic and extrahepatic pathogeneses. To better understand the compartment-specific metabolic modulations related to their pathogenesis, HBV-DC, HBV-ACLF patients, and controls (30 each) were analyzed by metabolomics using portal (Port), hepatic vein (Hep), and peripheral (Peri) serum. Compartment ratios of metabolites (RatioHep/Port, RatioPeri/Hep, and RatioPort/Peri) were calculated. The liver tissues (10 per group) were analyzed using transcriptomics and metabolomics. An additional 75 patients with ACLF, 20 with DC, and 20 with liver cirrhosis (LC) were used to confirm oxlipid dysregulation. Both multi-omics datasets suggest suppressed energy, amino acid, and pyrimidine metabolism in the ACLF/DC liver. The serum metabolomic variations were contributed primarily by disease rather than sampling compartments, as both HBV-ACLF and HBV-DC patients demonstrated abnormal profiles of amino acids and peptides, indoles, purines, steroids, and benzimidazoles. In ACLF/DC patients, impaired hepatic metabolism resulted in a highly correlated hepatic and portal vein serum metabolome and release of inflammatory lipids and heme metabolites from the liver. HBV-ACLF showed higher RatioPeri/Hep of extrahepatic inflammatory oxlipids, while HBV-DC patients showed higher RatioPort/Peri of gut microbial metabolites. An inflammatory oxlipid outburst was confirmed in the early stages of HBV-ACLF. The inflammatory effects of the selected oxlipids were confirmed in monocytes. These findings support a synergy between liver-specific mechanisms and systemic inflammation in ACLF/DC development, and that pro-inflammatory oxlipids are metabolic signatures of early HBV-ACLF.

Low platelet to high-density lipoprotein ratio predicts poor short-term prognosis in hepatitis B-related acute-on-chronic liver failure

BackgroundAcute-on-chronic liver failure (ACLF) is characterized by a systemic inflammatory response, predominantly associated with hepatitis B virus in the Asia-Pacific region, with a high short-term mortality rate. The platelet to high-density lipoprotein ratio (PHR) has been used to predict the prognosis of patients with various inflammatory diseases. We aim to is to use the PHR to predict the short-term prognosis of patients with HBV-ACLF.MethodIn this study, we retrospectively analyzed clinical data from 270 HBV-ACLF patients. Using logistic regression, we identified independent risk factors for short-term mortality and developed a prognostic model. This model was then validated, compared, and its clinical utility assessed via decision curve analysis (DCA).ResultsAmong the 270 HBV-ACLF patients, 98 patients died within 28 days. The deceased group exhibited a higher proportion of severe hepatic encephalopathy and ascites. Additionally, there was a statistically significant difference (P = 0.046) in the novel inflammation scoring system, PHR, between the two groups. Following stringent variable selection, PHR was identified as a predictive factor for short-term mortality in HBV-ACLF patients using logistic regression analysis (OR: 0.835 (0.756–0.999), P = 0.009), and it exhibited a synergistic effect with certain traditional scores. The prognostic model constructed based on PHR demonstrated a superior ability to predict short-term mortality compared to traditional scores such as Child-Turcotte-Pugh (AUC: 0.889). Evaluation using calibration curves and decision curve analysis (DCA) suggested its practical utility.ConclusionPHR can predict short-term mortality in patients, with a low PHR upon admission being associated with an increased risk of death.

Alpha-fetoprotein and APRI as predictive markers for patients with Type C hepatitis B-related acute-on-chronic liver failure: a retrospective study

BackgroundType C hepatitis B-related acute-on-chronic liver failure (HBV-ACLF), which is based on decompensated cirrhosis, has different laboratory tests, precipitating events, organ failure and clinical outcomes. The predictors of prognosis for type C HBV-ACLF patients are different from those for other subgroups. This study aimed to construct a novel, short-term prognostic score that applied serological indicators of hepatic regeneration and noninvasive assessment of liver fibrosis to predict outcomes in patients with type C HBV-ACLF.MethodPatients with type C HBV-ACLF were observed for 90 days. Demographic information, clinical examination, and laboratory test results of the enrolled patients were collected. Univariate and multivariate logistic regression were performed to identify independent prognostic factors and develop a novel prognostic scoring system. A receiver operating characteristic (ROC) curve was used to analyse the performance of the model.ResultsA total of 224 patients with type C HBV-ACLF were finally included. The overall survival rate within 90 days was 47.77%. Age, total bilirubin (TBil), international normalized ratio (INR), alpha-fetoprotein (AFP), white blood cell (WBC), serum sodium (Na), and aspartate aminotransferase/platelet ratio index (APRI) were found to be independent prognostic factors. According to the results of the logistic regression analysis, a new prognostic model (named the A3Twin score) was established. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was 0.851 [95% CI (0.801-0.901)], the sensitivity was 78.8%, and the specificity was 71.8%, which were significantly higher than those of the MELD, IMELD, MELD-Na, TACIA and COSSH‐ACLF II scores (all P < 0.001). Patients with lower A3Twin scores (<-9.07) survived longer.ConclusionsA new prognostic scoring system for patients with type C HBV-ACLF based on seven routine indices was established in our study and can accurately predict short-term mortality and might be used to guide clinical management.

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

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

Short-Term Efficacy of Tenofovir Alafenamide in Acute-On-Chronic Liver Failure: A Single Center Experience.

Patients with acute-on-chronic liver failure (ACLF) who take entecavir (ETV) and tenofovir disoproxil fumarate (TDF) experience a reduction in hepatic events and mortality. The effectiveness of tenofovir alafenamide (TAF) was not well investigated. This study was aim to compare the antiviral efficacy and mortality between TAF and ETV in patients with ACLF caused by the hepatitis B virus (HBV). One hundred and six patients with HBV-ACLF who received TAF (25 mg/day) and ETV (0.5 mg/day) for 12 weeks were analyzed. The primary endpoints were overall mortality and liver transplantation (LT) at week 12. Biochemical responses, virologic responses, mortality, drug safety, and side effects were evaluated. At 4 and 12 weeks of TAF treatment, patients showed significantly higher HBV-DNA reduction (P < .001), higher HBV-DNA undetectability rates (P < .001), and lower HBV DNA levels (P < .001) in serum. Lower Child-Turcotte-Pugh (CTP) scores (P = .003) were observed at 4 weeks in the TAF group, although the CTP scores showed no difference between TAF group and ETV group at 12 weeks (P = 1.143). Lower alanine aminotransferase (ALT) levels of patients in the TAF group at week 4 and 12 were observed (P = .023 and P < .0001, separately). The mortality of TAF group was lower after 4 weeks of treatment (P = .038); however, the 2 groups had similar mortality rates at week 8 and 12. Among the causes of death in HBV-ACLF patients, we found the same incidence of liver-related problems in both groups (P > .05). This study showed that ACLF patients with chronic HBV infection treated with TAF had a rapid decline in HBV DNA, a higher rate of ALT reduction and improved CTP scores compared to the ETV group, thereby improving patient survival.

A nomogram based on psoas muscle index predicting long-term cirrhosis incidence in non-cirrhotic patients with HBV-related acute‑on‑chronic liver failure

There is a lack of scoring system to predict the occurrence of cirrhosis in individuals with acute-on-chronic liver failure (ACLF) in the absence of cirrhosis. The goal of this study was to develop a psoas muscle index (PMI)-based nomogram for cirrhosis risk in non-cirrhotic patients with HBV-related ACLF. We included 274 non-cirrhotic HBV-ACLF patients who were randomly assigned to training and validation groups. Logistic analyses were performed to identify risk factors for cirrhosis. A nomogram was then constructed. The predictive performance of the nomogram was assessed using the area under the receiver operating characteristic curve (AUROC), calibration curve, and decision curve analysis (DCA). During the 360-day follow-up, 44.5% (122/274) of non-cirrhotic HBV-ACLF patients developed cirrhosis. A higher PMI at the L3 level was correlated with a decreased risk of long-term cirrhosis occurrence (OR 0.677, 95% CI 0.518–0.885, P = 0.004). The nomogram incorporating PMI, age, neutrophil-to-lymphocyte ratio (NLR), and international normalized ratio (INR), indicated satisfactory predictive performance for cirrhosis risk stratification in ACLF population. The nomograms had an AUROC of 0.812 (95% CI 0.747–0.866) and 0.824 (95% CI 0.730–0.896) in the training and validation cohorts, respectively. The calibration curves displayed excellent predictive accuracy of the nomogram in both sets. In both cohorts, the DCA verified the nomogram's clinical efficacy. In non-cirrhotic HBV-ACLF patients, a greater PMI appears to protect against long-term cirrhosis occurrence. Strong predictive performance has been demonstrated by PMI-based nomograms in assessing the likelihood of 1-year cirrhosis in those with HBV-ACLF.

A novel imaging index for predicting adverse progression in acute-on-chronic liver failure related to hepatitis B virus: the low erector spine index

BackgroundIt is widely known that muscle mass influences the outcomes of many chronic diseases. Erector spine mass is a convenient parameter obtained from routine abdominal computed tomography (CT). The clinical application value of erector spine mass, and whether erector spine mass could predict the outcome of disease has not been studied.AimTo evaluate the role of the erector spine index (ESI) calculated based on abdominal CT imaging in the progression of acute-on-chronic liver failure related to the hepatitis B virus (HBV-ACLF).MethodsWe performed a retrospective study of 118 HBV-ACLF patients and calculated the ESI (the total erector spine area normalized for height2 in meters) for each patient through abdominal CT. The findings were analyzed regarding the progression of HBV-ACLF and the ESI at baseline, including mortality and the development of complications.ResultsThe ESI level was associated with mortality and the development of complications. During the 90-day follow-up period, patients with a low ESI (<12.05 cm2/m2) had higher mortality than those with a high ESI (≥ 12.05 cm2/m2) (51.7% vs. 26.7%), and the cumulative survival rates were 71.0%±4.6 and 85.8%±3.9, respectively (log-rank P = 0.003). The hazard ratios (HRs) calculated using univariable and multivariable analyses were 2.23(95% confidence interval (CI): 1.25–4.21, P = 0.005) and 2.52 (95% CI: 1.34–9.24, P = 0.011), respectively. Patients with a low ESI (<12.05 cm2/m2) had higher incidences of kidney dysfunction (43.5% vs. 23.2%, P = 0.029; log-rank P = 0.017) and hepatic encephalopathy (39.6% vs. 14.0%, P = 0.003; log-rank P = 0.010) than those with a high ESI. A low ESI was an independent risk factor for kidney dysfunction (adjusted HR = 1.36, 95% CI: 1.05–2.93, P = 0.043) and the development of hepatic encephalopathy (adjusted HR = 2.26; 95% CI: 2.05–3.13, P = 0.036). In addition, the presence of hepatic encephalopathy (the odds ratio (OR) = 2.26, 95% CI: 2.05–3.18, P = 0.006), spontaneous bacterial peritonitis (OR = 3.95, 95% CI: 1.01–5.46, P = 0.037), and kidney dysfunction (OR = 4.47, 95% CI: 1.02–9.64, P = 0.032) was independently associated with a low ESI in patients.ConclusionA low ESI is an independent risk factor for mortality in patients with HBV-ACLF, as well as the development of kidney dysfunction and hepatic encephalopathy.

The value of NLR versus MLR in the short-term prognostic assessment of HBV-related acute-on-chronic liver failure.

Systemic inflammation is associated with the development and progression of hepatitis B-associated acute-on-chronic liver failure (HBV-ACLF). The neutrophil-to-lymphocyte ratio (NLR) has been reported to be a prognostic biomarker in patients with HBV-ACLF. However, the role of the monocyte-to-lymphocyte ratio (MLR) as a prognostic inflammatory biomarker in multiple diseases is rarely mentioned in HBV-ACLF. We included a total of 347 patients with HBV-ACLF who met the definition of the Chinese Guidelines for the Diagnosis and Treatment of Liver Failure (2018 edition). Among them, 275 cases were included retrospectively, and 72 cases were collected prospectively. Clinical characteristics and laboratory examination data were collected from medical records within 24h after diagnosis to calculate MLR and NLR levels, and lymphocyte subpopulation counts were collected in prospectively included patients. Of the 347 patients with HBV-ACLF, 128 patients in the non-surviving group had a mean age of 48.87±12.89years; 219 patients in the survival group had a mean age of 44.80±11.80years and a combined 90-day mortality rate of 36.9%. The median MLR was higher in the non-survivors than in the survivors (0.690 vs 0.497, P<0.001). MLR values were significantly associated with 90-day mortality in HBV-ACLF (OR 6.738; 95% CI 3.188-14.240, P<0.001). The AUC for the predictive power of the combined MLR and NLR analysis for HBV-ACLF was 0.694, and the calculated MLR threshold was 4.495. In addition, in the analysis of peripheral blood lymphocyte subsets in HBV-ACLF, a significant decrease in the number of circulating lymphocytes was found in HBV-ACLF patients in the non-surviving group (P<0.001), with a predominant decrease in the number of CD8+T cells and no significant difference in the number of CD4+T cells, B cells or NK cells. Increased MLR values are associated with 90-day mortality in patients with HBV-ACLF, and the MLR may serve as a potential prognostic indicator for patients with HBV-ACLF. Decreased CD8+T-cell counts may be associated with poor survival in patients with HBV-ACLF.

Metabolic biomarkers significantly enhance the prediction of HBV-related ACLF occurrence and outcomes

Acute-on-chronic liver failure (ACLF) is a clinical syndrome of high short-term mortality in patients with chronic liver disease. Chronic hepatitis B is the main cause of ACLF (HBV-ACLF) in China and other Asian countries. To improve disease management and survival for ACLF patients, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognosis. We performed a metabolomics profiling of 1,024 plasma samples collected from HBV-related chronic liver disease patients with acute exacerbation at hospital admission in a multi-year and multi-center prospective study (367 ACLF and 657 non-ACLF). The samples were randomly separated into equal halves as a discovery set and a validation set. We identified metabolites associated with 90-day mortality in the ACLF group and the progression to ACLF within 28 days in the non-ACLF group (pre-ACLF) using statistical analysis and machine learning. We developed diagnostic algorithms in the discovery set and used these to assess the findings in the validation set. ACLF significantly altered the serum metabolome, particularly in membrane lipid metabolism, steroid hormones, oxidative stress pathways, and energy metabolism. Numerous metabolites were significantly associated with 90-day mortality in the ACLF group and/or pre-ACLF in the non-ACLF group. We developed algorithms for the prediction of ACLF 90-day mortality (area under curve, AUC: 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (AUC: 0.94 and 0.88 for the discovery set and validation set, respectively). To translate our discoveries into practical clinical tests, we developed targeted assays using liquid chromatography mass spectrometry (LCMS). Based on novel metabolite biomarkers, we established HBV-ACLF tests with higher accuracy than existing methods. Acute-on-chronic liver failure (ACLF) is a clinical syndrome of high short-term mortality affecting 25% of hospitalized cirrhosis patients. Chronic hepatitis B (HBV) is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognosis for disease management are critical for improving clinical outcomes for ACLF patients. Based on novel metabolite biomarkers, we developed liquid chromatography mass spectrometry (LCMS) tests with improved accuracy for the early diagnosis and prognosis of HBV-ACLF. The LCMS tests can be implemented in clinical labs and used by physicians to triage HBV-ACLF patients for treatment options and proactive disease management. NCT02457637 and NCT03641872.

M6A Regulator-mediated RNA Methylation Modulates Immune Microenvironment of Hepatitis B Virus-related Acute Liver Failure.

Acute liver failure (ALF) is a rare and complicated disease with a high mortality rate. Emergency liver transplantation is the only treatment method that can improve the ALF prognosis. However, its clinical application remains limited owing to the aggressive nature of liver transplantation, limited donors, and high postoperative mortality. The study investigated the effect of m6A on the immune microenvironment of hepatitis B virus-related ALF (HBV-ALF). In this study, the gene expression data of 47 normal people and 42 HBV-ALF patients were downloaded from the Gene Expression Omnibu (GEO) database. The known 23 m6A regulators which mediated RNA modification patterns were compared and analyzed in these two groups, and the gene diagnosis model of HBV-ALF patients was established based on the analysis results. In addition, we used unsupervised clustering to identify different m6A RNA methylation modification patterns in HBV-ALF based on m6A regulators, and evaluated the immune infiltration and biological differences in these subtypes. In addition, the relationship between m6A genes and immune cell activation in HBV-ACLF patients was explored by immune infiltration analysis. Nineteen m6A regulators mediated RNA methylation (m6A regulators for short) were differentially expressed in HBV-ALF and control groups. m6A regulators could well distinguish control samples from HBV-ALF samples, and m6A regulators might be used as a basis for diagnosing HBV-ALF patients. Immune cells such as activated CD8 T cells, activated B cells, and activated CD4 T cells might play important roles in HBV-ALF, and m6A regulators were closely associated with immune cell infiltration. ALKBH15, CBLL1, IGF2BP2, IGF2BP3, and ZC3H13 were significantly associated with immune cells. Considering 23 m6A regulators, HBV-ALF patients could be classified into two subtypes (cluster 1 and cluster 2) based on different immune cell infiltration. m6A regulators of the IGFBP and YHDF families have extremely different levels in these two subtypes. Differential immune cell infiltration among these subtypes was observed, a total of 913 differentially expressed genes among different m6A modification patterns was identified, and their biological functions were explored. m6A modification might play a crucial role in the diverse and complex immune microenvironment of HBV-ALF patients.

Evaluation of peripheral blood T-lymphocyte subpopulations features in patients with hepatitis B virus-related acute-on-chronic liver failure based on single-cell sequencing technology

Objective: T lymphocyte exhaustion is an important component of immune dysfunction. Therefore, exploring peripheral blood-exhausted T lymphocyte features in patients with hepatitis B virus-related acute-on-chronic liver failure may provide potential therapeutic target molecules for ACLF immune dysfunction. Methods: Six cases with HBV-ACLF and three healthy controls were selected for T-cell heterogeneity detection using the single-cell RNA sequencing method. In addition, exhausted T lymphocyte subpopulations were screened to analyze their gene expression features, and their developmental trajectories quasi-timing. An independent sample t-test was used to compare the samples between the two groups. Results: Peripheral blood T lymphocytes in HBV-ACLF patients had different differentiation trajectories with different features distinct into eight subpopulations. Among them, the CD4(+)TIGIT(+) subsets (P = 0.007) and CD8(+)LAG3(+) (P = 0.010) subsets with highly exhausted genes were significantly higher than those in healthy controls. Quasi-time analysis showed that CD4(+)TIGIT(+) and CD8(+)LAG3(+) subsets appeared in the late stage of T lymphocyte differentiation, suggesting the transition of T lymphocyte from naïve-effector-exhausted during ACLF pathogenesis. Conclusion: There is heterogeneity in peripheral blood T lymphocyte differentiation in patients with HBV-ACLF, and the number of exhausted T cells featured by CD4(+)TIGIT(+)T cell and CD8(+)LAG3(+) T cell subsets increases significantly, suggesting that T lymphocyte immune exhaustion is involved in the immune dysfunction of HBV-ACLF, thereby identifying potential effective target molecules for improving ACLF patients' immune function.

PLT Counts as a Predictive Marker after Plasma Exchange in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

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). 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). 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). 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.

Predictive Values of Programmed Death-1, CC Chemokine Ligand 20, and Treg/T Helper 17 Cytokines for Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure

Background: This study aimed to explore the correlations of programmed death-1 (PD-1) and CC chemokine ligand 20 (CCL20) with Treg/T helper 17 (Th17) balance in patients with HBV-ACLF. Methods: In this cross-sectional study, 50 patients with HBV-ACLF and 50 cases with chronic hepatitis B (CHB) diagnosed from February 2021 to February 2022 were selected, and another 50 healthy volunteers who received physical examinations in the same period were selected as a control group. The expression levels of PD-1, CCL20, and Treg/Th17 cytokines were detected by Western blotting, immunoturbidimetry, and enzyme-linked immunosorbent assay (ELISA), respectively. The correlations of PD-1 and CCL20 with Treg/Th17 cytokines were explored by Pearson analysis. The predictive values of PD-1, CCL20, and Treg/Th17 cytokines for the prognosis of HBV-ACLF patients were analyzed. Results: The expression levels of PD-1 and CCL20 were higher in the HBV-ACLF group than in the CHB and control groups (P &lt; 0.05). Severe HBV-ACLF patients had higher levels of PD-1 and CCL20 compared with mild and moderate HBV-ACLF patients (P &lt; 0.05). Hepatitis B virus-related acute-on-chronic liver failure patients with poor prognosis had higher levels of PD-1 and CCL20 than those with good prognosis (P &lt; 0.05). The levels of transforming growth factor β (TGF-β), interleukin 10 (IL-10), IL-23, and tumor necrosis factor α (TNF-α) were higher in the HBV-ACLF group than in the CHB and control groups (P &lt; 0.05). The levels of PD-1 and CCL20 in the HBV-ACLF group were positively correlated with those of Treg/Th17 cytokines (TGF-β, IL-10, IL-23, and TNF-α; P &lt; 0.05). The combined detection of PD-1, CCL20, and Treg/Th17 cytokines had higher sensitivity and lower specificity than single detection in predicting the prognosis of HBV-ACLF patients (P &lt; 0.05). Conclusions: The expression levels of PD-1 and CCL20 are higher in HBV-ACLF patients, being correlated with Treg/Th17 balance. The combined detection of PD-1, CCL20, and Treg/Th17 cytokines has a higher value for predicting the prognosis of HBV-ACLF patients.

Efficacy and predictive factors of glucocorticoid therapy for patients with hepatitis B virus-related acute-on-chronic liver failure.

Glucocorticoid (GC) treatment for liver failure is controversial. This study sought to evaluate the efficacy and predictive factors of glucocorticoid therapy for hepatitis B virus-related acute-on-chronic liver failure (HBV- ACLF). A total of 302 patients with HBV- ACLF were enrolled and categorized by treatment modality (GC vs. Control). Baseline characteristics, liver function, disease complications, and mortality were recorded. Univariate and multivariate analysis were used to identify predictive factors for HBV-ACLF-related mortality. GC therapy significantly improved the 30- and 60-day mortality of HBV-ACLF patients (4.64% vs. 11.92%, P=0.022 and 16.56% vs. 25.83%, P=0.049 for the Control and GC groups, respectively) and GC was an independent prognostic factor for 30-day mortality (OR = 0.177, 95% CI 0.051-0.616, P = 0.007). However, enhanced survival was not associated with improved liver function. There were no significant differences in the incidence of complications (i.e., ascites, bacterial infection, encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding) between the GC and Control groups (P >0.05), except that fungal infection occurred with higher frequency in the GC group (P = 0.037). A significant improvement in the 30-day survival associated with GC therapy was observed among patients <40 years of age, a Model for End-stage Liver Disease (MELD) score of 25-35 or a CLIF- Consortium ACLF (CLIF-C ACLF) grade 0-1 (all P <0.05). GC therapy improved the short-term (30- and 60- day) mortality of patients with HBV-ACLF. This treatment may be of particular benefit to patients who are <40 years of age, have a MELD score of 25-35, or have a CLIF-C ACLF grade of 0-1. (Acta gastroenterol. belg., 2022, 85, 593-600).

Artificial liver support systems for hepatitis B virus-associated acute-on-chronic liver failure: A meta-analysis of the clinical literature.

To evaluate the short-term and long-term survival efficacy of an artificial liver support system (ALSS) in patients with acute-on-chronic liver failure (ACLF). A systematic search was performed for relevant published data in PubMed, Web of Science and Cochrane Library databases. Studies that evaluated the efficacy of ALSS in patients with ACLF and provided the short-term or long-term survival rate were included. A total of 10 studies involving 3685 patients were included in this analysis. The pooled 28-day survival rate and 90-day survival rate were 68.7% (95% CI: 64.5%-72.9%) and 53.4% (95% CI: 45.5%-61.4%), respectively. The pooled estimates of the OR for the 28-day and 90-day survival rates between the ALSS group and the control group were 1.91 (95% CI: 1.21-3.04) and 1.41 (95% CI: 1.17-1.70), respectively. Subgroup analysis showed that patients treated with lower levels of TBIL and MELD scores had a higher 28-day survival rate (χ2 =15.75, p < 0.01; χ2 =13.80, p < 0.01). The present meta-analysis suggests that ALSS treatment could remarkably improve short-term survival rates in HBV-ACLF patients, which implies that treatment with ALSS may help to reduce high mortality. Further prospective randomized trials are needed to validate these findings.

Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study

Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n=4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p<0.001) and the propensity score matching cohort (77.2%/27.6%, p<0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p<0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortalityand survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).

A Lower HCC Incidence in Chronic HBV-Infected Patients Recovered from Acute-on-Chronic Liver Failure: A Prospective Cohort Study.

Activation of chronic hepatitis B virus (HBV) infection is an important cause of acute-on-chronic liver failure (ACLF). However, the effect of HBV-ACLF episode on hepatocellular carcinoma (HCC) occurrence remains largely unknown. A total of 769 HBV-ACLF patients and 2114 HBV-related chronic liver disease (HBV-CLD) patients diagnosed between August 1998 and December 2011 were enrolled in this prospective cohort study. Of the HBV-CLD patients, 380 received lifetime antiviral treatment with nucleos(t)ide analogues. Propensity score matching was applied to reduce baseline differences between HBV-ACLF and HBV-CLD cohorts. The survival rate of HBV-ACLF patients was 53.6%, 50.3%, 47.8%, and 46.2% at 90-day, 1-year, 5-year, and 10-year, respectively. The cumulative incidence of HCC was lower in HBV-ACLF cohort with 369 eligible patients survived for >90 days than in HBV-CLD cohort with the 380 patients (5.77/1,000 vs. 9.78/1,000 person-years, p = 0.0497). HBV-ACLF episode decreased HCC risk regardless of liver cirrhosis, and in patients without family history of HCC. Multivariate Cox analyses indicated that male, increasing age, liver cirrhosis, and platelet count (≤100 × 109/L) increased, whereas HBV-ACLF episode decreased, HCC risk independently. In the propensity score-matched cohorts, HBV-ACLF episode reduced HCC incidence (10.20/1,000 vs. 4.66/1,000 person-years, p = 0.0326). The area under curve of nomogram was 0.812 for 3-year HCC probability. HBV-ACLF episode decreases HCC occurrence in chronic HBV patients. Older age and liver cirrhosis independently increased HCC occurrence. A nomogram-enrolled episode of ACLF reliably predicts the occurrence of HCC.

Low Serum Soluble Transferrin Receptor Levels Are Associated with Poor Prognosis in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

Iron metabolism disorder is closely related to acute-on-chronic liver failure (ACLF). This study was conducted to analyze the serum levels of soluble transferrin receptor (sTfR) in hepatitis B virus (HBV)-related ACLF and to evaluate the predictive value of sTfR for the short-term prognosis of HBV-ACLF. A total of 359 patients, including 139 with HBV-ACLF, 103 with chronic hepatitis B (CHB), and 117 healthy controls (HCs), participated in this study. We measured serum levels of ferritin, transferrin, and sTfR using nephelometry and performed data analysis using SPSS software. Ferritin levels were significantly higher in HBV-ACLF patients (both P < 0.001), while transferrin and sTfR were significantly lower (all P < 0.001) than in patients with CHB and HCs. Spearman correlation analysis demonstrated that serum sTfR significantly correlated with the alanine aminotransferase (ALT) (r = -0.366, P<0.001), aspartate aminotransferase (AST) (r = -0.322, P < 0.001), total bilirubin (TBIL) (r = -0.222, P = 0.009), alpha fetoprotein (AFP) (r = 0.329, P < 0.001), prothrombin time-international normalization ratio (PT-INR) (r = -0.428, P < 0.001), and model for end-stage liver disease (MELD) (r = -0.459, P < 0.001). Nonsurviving HBV-ACLF patients who died within 30 days had much lower serum sTfR levels than surviving patients (P < 0.001). Logistic regression analysis showed that decreased serum sTfR levels were independently associated with 30-day mortality in patients with HBV-ACLF (P = 0.003). Receiver operating characteristic (ROC) curve analysis for predicting 30-day mortality showed that the area under the curve (AUC) for serum sTfR was 0.813 (95% CI: 0.738-0.874, P < 0.001). This was similar to that of the MELD score (AUC = 0.812, 95% CI: 0.737-0.873, P < 0.001). Serum sTfR combined with MELD score significantly improved the predictive capacity for 30-day mortality in patients with HBV-ACLF (AUC = 0.871, 95% CI: 0.803-0.922, P < 0.001). Kaplan-Meier analysis revealed that the overall cumulative 30-day mortality rate was significantly higher in patients with serum sTfR levels ≤ 0.55 mg/L compared to those with serum sTfR levels > 0.55 mg/L (P < 0.001).

Plasma-Derived Exosomal SncRNA as a Promising Diagnostic Biomarker for Early Detection of HBV-Related Acute-on-Chronic Liver Failure.

ObjectivesThe small noncoding RNAs (sncRNAs) including microRNAs and the noncanonical sncRNAs [i.e., tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs)] are a vital class of gene regulators in response to a variety of diseases. We focus on an sncRNA signature enriched in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) to develop a plasma exosome-based noninvasive biomarker for human ACLF.MethodsIn this work, sncRNAs related to HBV-ACLF were identified by small RNA sequencing (RNA-seq) in plasma exosomes collected from 3 normal subjects, 4 chronic hepatitis B (CHB) patients with flare, and 6 HBV-ACLF patients in the discovery cohort. Thereafter, the differentially expressed sncRNAs were further verified in a validation cohort (n = 313) using the newly developed molecular signature incorporating different mi/ts/rsRNAs (named as MTR-RNAs) through qRT-PCR assays. Subsequently, using the least absolute shrinkage and selection operator (LASSO) logistic regression (LR) model analysis, we developed an MTR-RNA classifier for early detection of ACLF.ResultsThe identified sncRNAs (hsa-miR-23b-3p, hsa-miR-223-3p, hsa-miR-339-5p, tsRNA-20, tsRNA-46, and rsRNA-249) were specifically differentially expressed in plasma exosomes of HBV-ACLF. The MTR-RNA signature (AUC = 0.787) containing the above sncRNAs distinguished HBV-ACLF cases among normal subjects with 71.67% specificity and 74.29% sensitivity, CHB patients with flare (AUC = 0.694, 85.71% sensitivity/59.5% specificity), and patients with CHB/cirrhosis (AUC = 0.785, 57.14% sensitivity/94.59% specificity). Notably, it revealed 100% specificity/94.80% sensitivity in detecting patients or normal people.ConclusionsOur as-constructed plasma-derived exosomal sncRNA signature can serve as a reliable biomarker for ACLF detection and also be adopted to be the pre−triage biomarker for selecting cases that can gain benefits from adjuvant treatment.