Noninvasive evaluation of significant liver fibrosis in chronic hepatitis B patients.

Background & Aims: Chronic hepatitis B is still a major cause of morbidity and mortality worldwide. In recent years, there has been increasing research on inexpensive, noninvasive, reproducible methods for detecting fibrosis in the liver. In this study, we examined the efficacy of 15 different noninvasive fibrosis markers for predicting significant liver fibrosis in chronic hepatitis B patients. Methods: Patients who underwent liver biopsy for chronic hepatitis B between 01.01.2010 and 01.01.2022 were retrospectively analysed. The study population was divided into two groups according to significant fibrosis (F≥3). Receiver operating characteristic analysis was performed to examine the diagnostic performance of these noninvasive fibrosis markers for the prediction of significant fibrosis. Multiple logistic regression analysis was used create a model which predicts significant fibrosis better than the individual markers. Results: In total, 234 chronic hepatitis B patients were enrolled in this study. Among the 15 noninvasive fibrosis markers, King's score was found to have the biggest AUC in predicting significant fibrosis (F≥3). Furthermore, a model containing King's score, GUCI and GPR has the ability of prediction of significant fibrosis better than every individual marker (cut-off of the model >0,3356, p<0.0001). Conclusion: According to our study results, the model containing King's score, GUCI and GPR can be used to predict significant liver fibrosis in chronic hepatitis B patients followed-up in countries with limited sources.

Retrospective cohort evaluation study in terms of cardiovascular and metabolic diseases in chronic hepatitis B patients.

Background: Chronic hepatitis B (CHB) and nucleotide analogues [entecavir (ETV) and tenofovir disoproxil fumarate (TDF)] used in its treatment have been shown to affect metabolic parameters in many studies. In this study, we aimed to investigate the effects of metabolic events associated with CHB and nucleotide analogues (NAs) used in CHB treatment on ischemic heart diseases (IHD) and cardiovascular diseases (CVD). Methods: This retrospective study was conducted between June 2022 and January 2024 with a total of 241 patients diagnosed with non-cirrhotic CHB in the gastroenterology outpatient clinic, 96 of whom did not receive hepatitis B treatment, 110 of whom received TDF, and 35 of whom received ETV treatment. Patients were evaluated in terms of metabolic, CVD, and hepatology depending on whether they received antiviral treatment or not. In our study, the triglyceride-glucose (TyG) index and triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C) were calculated in patients to evaluate potential risk factors for CVD. Again, while the total cholesterol-to-HDL-C ratio (TC/HDL-C), which is associated with CVD\IHD, was evaluated, the '4-factor fibrosis index' (FIB-4) score, which is a non-invasive indicator of liver fibrosis, was also evaluated. Results: Diabetes mellitus (DM), fasting blood sugar (FBS), oral antidiabetic drug (OAD) usage rate, and insulin usage rate were high in patients receiving ETV treatment. The TyG index of patients receiving ETV was higher than patients in the other group (p = 0.035; p<0.05). It was determined that the probability of detecting ETV treatment in patients with a TG/HDL-C ratio of ≥1.82 cut-off value was 4.250 times higher. The odds ratio for TG/HDL-C measurements was 4.250 (95% CI: 1.384-13.054). FIB-4 score, which is a non-invasive indicator of liver fibrosis, was found to be higher in patients receiving ETV than in other groups. Conclusion: In patients with CHB, a relationship was observed between markers used to predict CVD risk, such as the TyG index and TG/HDL-C ratio. The group with high levels of these two markers and a high potential for developing CVD was patients receiving ETV treatment. In this first study in the literature showing the relationship between CHB and CVD, we found that the relative risk of CVD was increased in patients using ETV.

Performance of GPR score for non-invasive assessment of liver fibrosis in chronic hepatitis B Tunisian patients.

INTRODUCTION: Several non-invasive tests (NIT) have been reported for predicting liver fibrosis to avoid percutaneous liver biopsy (PLB). AIM: To evaluate the performance of NIT in Tunisian patients with chronic hepatitis B (CHB). METHODS: We calculated the ASAT/platelet ratio index (APRI), GGT-to-platelet ratio (GPR), Fibrosis-4 score (FIB-4), and RDW/platelet ratio (RPR). The accuracy of NIT was compared with the Metavir score for the detection of liver fibrosis stage using the area under the ROC curves (AUROC). RESULTS: Seventy-seven CHB patients were included. For predicting significant fibrosis, the AUROC of GPR (0.81; CI95% [0.68-0.93]; P < 0.001) was significantly higher than that of RPR (0.67; CI95% [0.52-0.82]; P = 0.03) and FIB-4 (0.746; CI95% [0.61-0.88]; P = 0.002), but was similar to APRI (0.88; CI95% [0.79-0.97]; P < 0.001). For advanced fibrosis, the AUROC of GPR (0.93; CI95% [0.84-1]; P < 0.001) was higher than that of RPR (0.83; CI95% [0.69-0.97]; P < 0.001) and FIB-4 (0.88; CI95% [0.76-0.99]; P < 0.001), but similar to APRI (0.93; CI95% [0.87-0.99]; P < 0.001). For predicting cirrhosis, the AUROC of GPR (0.98; CI95% [0.95-1]; P < 0.001) was higher than that of APRI (0.95; CI95% [0.90-1]; P = 0.02), similar to RPR (0.99; CI95% [0.98-1]; P < 0.001) but lower than that of FIB-4 (1; CI95% [1-1]; P < 0.001). In multivariate analysis, APRI (OR = 3.78; P = 0.002) and FIB-4 (OR = 2.65; P = 0.01) were independent predictors of significant fibrosis. GPR was the only independent predictor of advanced fibrosis (OR = 4.64; P = 0.001) and FIB-4 was the independent predictor of cirrhosis (OR = 2.85; P < 0.001). CONCLUSION: GPR does not demonstrate significant advantages over APRI, FIB-4, and RPR in identifying liver fibrosis in patients with chronic hepatitis B (CHB).

Association of IL-6 G-174C (rs1800795) variant with the susceptibility to hepatocellular carcinoma in patients with chronic hepatitis.

AIM: An ineffective immune response resulting from dysregulation of cytokine production might encourage viral persistence and cause chronic viral hepatitis to worsen. This study examined the relationship between alterations in interleukin-6 (IL-6) levels and the IL-6 - 174 G > C (rs1800795) polymorphism, as well as how this polymorphism affects the development and progression of chronic hepatitis brought on by hepatitis B (HBV) and hepatitis C (HCV) into hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Whole blood samples from 126 Egyptian patients with HCC (111 with HCV and 15 with HBV), as well as 126 age- and sex-matched healthy individuals, were used to extract DNA. Using PCR-based allele-specific amplification (ASA), the existence of the IL-6 G-174C polymorphism was investigated. Additionally, each participant's serum IL-6 levels were determined using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The primary observations revealed that HCC patients had greater serum levels of IL-6 compared to the control groups (p < 0.001). Patients with the variant (CG and GG) genotype in the HCC group were found to have more disease severity indicated by higher levels of alpha-fetoprotein (AFP) and a higher ascites grade, as well as increased inflammatory activity as defined by higher levels of IL-6 and C-reactive protein (CRP) (p < 0.001 for both) in comparison to patients with the wild-type (CC) genotype (p < 0.001 and p = 0.002, respectively). CONCLUSION: The rs1800795 SNP in the IL-6 gene was associated with increased inflammatory activity and high levels of IL-6, indicating that this SNP may play a role in the development of HCC in Egyptian patients with chronic viral hepatitis.

Updating AFP Level in Chronic Hepatitis B to Evaluate the Risk of Hepatocellular Carcinoma Occurrence.

BACKGROUND: Hepatocellular carcinoma (HCC) is a cancer with poor prognosis. Indonesia is a country with high prevalence of chronic hepatitis B infection. The performance of alpha fetoprotein (AFP) as a tumor marker in HCC surveillance is primarily influenced by the etiology of the underlying liver disease. We aimed to determine the best cut-off value of AFP biomarker examination for HCC surveillance in patients with chronic hepatitis B infection. METHODS: The study collected medical record data of the Hepatobiliary Division of Dr. Cipto Mangunkusumo Hospital from the period of 2017 to 2023. A total of 506 subjects with chronic hepatitis B of all spectrums (hepatitis B without cirrhosis, liver cirrhosis, and early-stage HCC, BCLC 0 and A) were included by total sampling that was performed from 26 July 2023 to 31 August 2023. Determination of the AFP cut-off value was carried out using the receiver operating characteristics (ROC) method.  Results: For HCC surveillance caused by hepatitis B virus, ROC curve analysis resulted in an area under the curve (AUC) of 0.792 (95% CI, 0.719-0.866), and the cut-off value with the highest Youden index was 8.7 ng/ml, with 58% sensitivity, 94% specificity, positive predictive value (PPV)  56.14%, negative predictive value (NPV) 94.43%, positive likelihood ratio (LR+) 10.08, and negative likelihood ratio (LR-) 0.46. CONCLUSION: The cut-off value of AFP in HCC surveillance on hepatitis B specific etiology is lower than the cut-off value of AFP in previous HCC surveillance which was not etiologically specific. The cut-off value of 8.7 ng/ml produces the best sensitivity and specificity for the cut-off value for HCC surveillance with hepatitis B etiology.

The expression of sICAM-1 influenced by Clonorchis sinensis co-infection in CHB patients.

Soluble Intercellular Adhesion Molecule-1 (sICAM-1) has emerged as an inflammatory biomarker of many essential functions. We investigated the level of sICAM-1 influenced by Clonorchis sinensis (C. sinensis) co-infection in chronic hepatitis B (CHB) patients to explore the degree of liver tissue inflammation and liver function damage after co-infection. The study included data from patients with C. sinensis mono-infection (n=27), hepatitis B virus (HBV) mono-infection (n=32), C. sinensis and HBV co-infection (n=24), post-hepatitis B liver cirrhosis (n=18), post-hepatitis B liver cirrhosis co-infected with C. sinensis (n=16), and healthy controls (n=39). The level of sICAM-1 was measured with specific enzyme-linked immunosorbent assay method. Compared to the healthy control group, all the experimental groups had significantly higher serum sICAM-1 levels. The levels of sICAM-1 in co-infected groups were significantly higher compared to the mono-infection groups and were positively correlated with the levels of glutamate aminotransferase (ALT) and aspartate aminotransferase (AST). Our research findings confirmed that co-infection could exacerbate liver tissue inflammation and liver function damage in patients, could raise the sICAM-1 level, and may lead to the chronicity of HBV infection. These results provide clues for pathological mechanism study and formulating treatment plans.

Review of the Effects of Antiviral Therapy on Hepatitis B/C-Related Mortality and the Regression of Fibrosis.

Hepatitis B and Hepatitis C are viral causes of Hepatitis that lead to significant worldwide mortality and morbidity through the sequelae of fibrosis and hepatocellular carcinoma. In this review, we have summarized recent studies that have examined the effects of antiviral therapy on the regression of fibrosis and the reduction in mortalities associated with the viruses. Antiviral therapy significantly decreases mortality and induces the regression of fibrosis.

Circulating thrombospondin 2 as a predictor of hepatocellular carcinoma in hepatitis B patients undergoing nucleos(t)ide analog therapy.

Thrombospondin 2 (TSP2) plays a vital role in collagen/fibrin formation, bone growth, vascular density regulation, hemostasis, and cell adhesion. Close associations of serum TSP2 with histological severity in non-alcoholic fatty liver disease and chronic hepatitis C were reported. The present study investigated the significance of circulating TSP2 in chronic hepatitis B patients. Eighty-seven biopsy-proven chronic hepatitis B patients were analyzed in cross-sectional Study 1 to search for correlations between serum TSP2 levels prior to liver biopsy and clinicopathological parameters. In longitudinal Study 2, 51 chronic hepatitis B patients with long-term follow-up (mean: 7.5 years) were examined for changes in serum TSP2 levels during nucleos(t)ide analog (NA) therapy along with trends in hepatocarciongenesis. In Study 1, serum TSP2 levels were not significantly associated with portal inflammation or fibrosis. Study 2 revealed that serum TSP2 was significantly decreased after 48 weeks of NA therapy (P < 0.001). Notably, TSP2 levels at 48 weeks of NA administration (TSP2-48W) were significantly higher in the hepatocellular carcinoma (HCC) (+) group than in the HCC (-) group (P = 0.043). Kaplan-Meier analysis showed that higher TSP2-48W (≥ 24 ng/mL) was associated with future HCC development (P = 0.030). Serum TSP2 levels may be a potential predictor of HCC development in hepatitis B patients receiving NA therapy. Longitudinal prospective studies are necessary to validate our findings.

Serum laminin γ2 monomer as a predictive biomarker for hepatocellular carcinoma in patients with chronic hepatitis B virus infection: a retrospective cohort study.

This retrospective study evaluated the use of laminin γ2 monomer (LG2m) as a predictive biomarker for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Serum LG2m levels were measured in two cohorts of patients: cohort 1 comprised 56 patients with chronic liver disease for assessing LG2m stability, whereas cohort 2 included 89 patients with chronic HBV infection who did not have HCC for evaluating the usefulness of LG2m measurement in HCC prediction. LG2m was highly stable in cryopreserved serum, and an increased LG2m level was significantly associated with a higher risk of HCC in chronically HBV-infected patients (P = 0.012). Multivariable Cox regression analysis revealed that high LG2m was an independent significant risk factor for HCC (hazard ratio, 7.16; 95% confidence interval, 1.31-39.2; P = 0.023). These findings suggest that LG2m may serve as a useful biomarker for the prediction of future HCC in patients with chronic HBV infection.

The potential value of fatty acid binding protein 1 in Chronic HBV-related liver disease progression assessment.

BACKGROUND: Fatty acid binding protein 1 (FABP1), a low molecular weight intracellular protein, has been proposed as a potential useful serum biomarker for liver injury. However, limited investigations have been conducted in chronic hepatitis B virus (HBV)-related liver disease. OBJECTIVE: To investigate the diagnostic potential of FABP1 in disease progression among patients with chronic HBV-related liver disease. METHODS: A prospective study was conducted on 293 patients with chronic HBV-related liver diseases, including chronic asymptomatic carrier (ASC), chronic hepatitis B (CHB). FABP1 was measured in serum samples collected at admission and some selected liver biopsies. RESULTS: Immunohistochemical analysis revealed abundant cytoplasmic expression of FABP1 in hepatocytes. A significant negative correlation was observed between FABP1 expression and inflammation grades in liver tissue (Spearman's r = -0.355, P = 0.017). However, no statistically significant correlation was found with fibrosis (P > 0.05). Serum FABP1 levels in the case group were significantly higher than in the healthy control (HC) group [median: 804.2 (687.8, 939.2) vs. 709.1 (626.2, 807.8) ng/ml, Z = -5.505, P < 0.001] and showed correlations with alanine aminotransferase (ALT), aspartate aminotransferase (AST); total bilirubin (TBIL); direct bilirubin (DBIL); albumin (ALB), etc. Its levels progressively increased with the advancement from ASC to CHB, with significant differences compared to the HC group (P < 0.001), especially in ASC patients with high HBV DNA (exceeding 106 IU/ml, P = 0.019), HBeAg positive (P = 0.013) and ALT higher than 0.5 times upper limit of normal (ULN)(P = 0.035). Meanwhile, serum FABP1 in CHB patients with higher TBIL(P = 0.005) or the severe CHB were higher (P = 0.002). CONCLUSION: Our study demonstrated a significant inverse correlation between FABP1 levels and the severity of inflammation grades in patients with HBV-related liver diseases. Furthermore, elevated serum FABP1 levels were observed in these patients, suggesting its potential as a biomarker for assessing HBV-related liver damage to initiate antiviral therapy. Additionally, further evaluation is required to determine its potential as a biomarker for assessing disease severity.

The rate of change in clinical indicators can predict the progression of hepatitis B virus-related acute-on-chronic preliver failure.

The objective of this study was to investigate the predictors and predictive model construction of the progression of HBV-Pre.Acute-on-chronic liver failure (ACLF), a total of 133 patients with HBV-Pre.ACLF was divided into the progressive group (52 patients) and the recovery group (81 patients) according to whether they progressed to ACLF or not. The clinical parameters N%, L%, PLT, ALT, TBiL, ALB, Cre, Na, NH3, CRP, AFP, prothrombin time (PT), international normalized ratio (INR), FIB, and their rate of change at baseline were analyzed in the 2 groups. The independent risk factors for HBV-Pre.ACLF progression was found by univariate and multivariate analyses, and a predictive model was constructed. The clinical parameters ALB, FIB, Na, combined alprostadil treatment and MELD, and MELD-Na scores at baseline were significantly different between the 2 groups (P <.05), while ALT, TBiL, Cre, CHE, NH3, N%, L%, PLT, INR, and PT were not significantly different (P >.05). The change rates of Na, CHE, PT, FIB, CRP, Cre, PLT, and the ratio after to before of N% were significantly different between the 2 groups (P <.05), while the change rates of ALT, TBIL, NH3, AFP, L%, and the ratio after to before of INR were not significantly different between the 2 groups (P >.05). Univariate and multivariate analyses showed that baseline ALB, Na, FIB, combined alprostadil therapy and the rate of change of Na and PLT were protective factors for disease progression, and the rate of change of PT, CRP, and the ratio after to before of N% were independent risk factors for disease progression. The novel model was LogitP = -6.051 + 4.049×ΔPT + 0.626×ΔCRP + 4.527×the ratio after to before N% and its area under the curve was 0.944 (95% confidence interval: 0.900-0.988) predicting progression of HBV-Pre.ACLF, and the best cutoff value was -0.22. The patients with a higher logitP score (> -0.22) had an increased risk for progression to ACLF (P <.05). The novel model logitP shows good predictive value for the disease progression of HBV-Pre.ACLF.

Diagnostic accuracy of FibroScan-AST (FAST) score, non-alcoholic fatty liver fibrosis score (NFS), FibroScan, and liver fibrosis index (FIB-4) for identifying fibrotic non-alcoholic steatohepatitis in patients with chronic hepatitis B with metabolic dysfunction-associated fatty liver disease.

OBJECTIVE: To evaluate the diagnostic value of the FibroScan-AST (FAST) score, non-alcoholic fatty liver fibrosis score (NFS), FibroScan, and liver fibrosis index (FIB-4) for identifying fibrotic non-alcoholic steatohepatitis (NASH) in patients with chronic hepatitis B (CHB) with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: All patients with CHB and MAFLD who underwent liver biopsy at the Zhenjiang Third Hospital affiliated with Jiangsu University between August 2010 and December 2022 were included in the analysis. The diagnostic accuracy of FAST, NFS, FibroScan, and FIB-4 for diagnosing NASH and liver fibrosis were evaluated based on the area under the receiver-operating characteristic curve (AUC). RESULTS: A total of 156 patients with CHB combined with MAFLD were included, including 69 with NASH and fibrosis stage 2 or higher (NASH+F ≥ 2), and 16 with NASH and cirrhosis (NASH+F4). The AUC of FAST, NFS, liver stiffness measurement (LSM), and FIB-4 for diagnosing NASH+F ≥ 2 was 0.739 (p < 0.001), 0.643 (p = 0.006), 0.754 (p < 0.001), and 0.665 (p = 0.003), respectively. The specificity of FAST, NFS, LSM, and FIB-4 was 67%, 51.8%, 78.6% and 76.8%, respectively, and the sensitivity was 75%, 78.6%, 67.9%, and 53.6%, respectively. No significant differences were found between groups. The AUC of FAST, NFS, LSM, and FIB-4 for diagnosing NASH+F4 was 0.650 (p = 0.038), 0.725 (p = 0.001), 0.851 (p < 0.001), and 0.560 (p = 0.533), respectively. The specificity of the FAST, NFS, LSM, and FIB-4 was 55.9%, 50.0%, 71.6%, and 75.5%, respectively and the sensitivity was 80.0%, 100%, 100%, and 50.0%, respectively. The differences between AUCs of FIB-4 and FAST compared with LSM were 0.291 and 0.201, respectively (p < 0.05). CONCLUSION: In patients with CHB combined with MAFLD, FAST did not have better accuracy than NFS and FIB-4 for predicting fibrotic NASH, whereas LSM had better accuracy than FAST and FIB-4.

[Risk prediction model of hepatitis B associated hepatocellular carcinoma].

Hepatocellular carcinoma is one of the most common malignant tumors in the world, which is a serious threat to human health. HBV infection is one of the most common causes of hepatocellular carcinoma.The diagnosis of most hepatocellular carcinoma has progressed to the middle and late stage, and the prognosis is poor. Early detection, diagnosis and treatment are important supports to improve the clinical outcome of hepatocellular carcinoma. In recent years, scholars at home and abroad have established various hepatocellular carcinoma risk prediction models, which are conducive to improving the early diagnosis rate of hepatocellular carcinoma and reducing the mortality rate. This article reviews the risk factors and risk prediction models of chronic hepatitis B associated hepatocellular carcinoma, in order to provide reference for HBV-associated liver cancer risk monitoring and management decision.

Associations between single nucleotide polymorphisms of cytokines and hepatitis B virus-related liver cirrhosis: A case-control study.

BACKGROUND AND AIMS: Various inflammatory and immune cytokines play key roles in the progression of hepatitis B virus (HBV)-related liver cirrhosis (LC). This study explored the relationship between single nucleotide polymorphisms (SNPs) in cytokines with the combined effect of polymorphisms and gender-polymorphisms interaction and LC risk. METHODS: In this study, a case-control design was used, samples were selected from 45 patients with hepatitis B-related cirrhosis and 45 age-gender-matched chronic HBV-infected patients without cirrhosis attending the tumor hospital of Wuwei Academy of Medical Sciences. Fifteen SNPs were examined using a real-time polymerase chain reaction allelic discrimination system. Logistic regression was utilized to assess cytokine-associated SNPs and the association between SNPs and LC progression in HBV-infected patients. RESULTS: The multivariate-adjusted logistic model revealed that the GG/AG dominant model (OR, 16.38; 95% CI, 1.13-236.70) and G allele (OR, 5.93; 95% CI, 0.98-36.01) of rs1800896 were associated with an increased risk of cirrhosis in CHB patients. Instead, rs2227306 CT presented a reduced cirrhosis risk (OR, 0.22; 95% CI, 0.04-1.38). Rs2055979 AA/AC was negatively associated with the risk of cirrhosis, potentially reversed in males (p = 0.021). Rs1799964 CC/CT was positively related to the risk of cirrhosis but reduced the risk of cirrhosis in males (OR, 0.13; 95% CI, 0.022-0.808; p = 0.028). Both rs1799964 TT and rs1799724 CT/TT genotype showed a synergistic effect in reducing the risk of cirrhosis with rs1800896 AA (OR, 0.08; 95% CI, 0.01-1.43 and OR, 0.12; 95% CI, 0.01-2.21). CONCLUSION: Polymorphisms rs1800896 and rs2227306 are potentially associated with the risk of cirrhosis. For the first time, the study highlights that the rs2055979 AA/AC and rs1799964 CC/CT polymorphism interact with gender and its potential reversal of cirrhosis risk in males. Furthermore, rs1800896 AA showed a synergistic effect with rs1799964 TT and rs1799724 CT/TT to prevent the progression of HBV infection to cirrhosis.

Galectin-9 as a new biomarker of acute-on-chronic liver failure.

Galectin-9 (Gal-9) expression in patients with acute-on-chronic liver failure and its correlation with prognosis remain unclear. This study investigated the relationship between liver failure prognosis and Gal-9 expression analysis in patients with acute-on-chronic liver failure. Patients with acute-on-chronic liver failure attributable to hepatitis B and those with chronic hepatitis B were included in this single-center prospective cohort study. The Gal-9 levels in the acute-on-chronic liver failure group were significantly higher than those in the chronic hepatitis B group, and there was an upregulation of Gal-9 and T-cell immunoglobulin domain and mucin domain-3 expressions in peripheral blood T cells. Gal-9 was localized in the regenerative areas of liver tissues in patients with acute-on-chronic liver failure, co-localizing with Kupffer cells. Kaplan-Meier survival curves showed that patients with Gal-9 levels < 9.6 ng/ml had a worse prognosis, with the area under the receiver operating characteristic curve (AUC-ROC) being similar to that of the Model for End-Stage Liver Disease score. The combined ROC curve of the two had better predictive performance, with an AUC of 0.945. High Gal-9 levels in liver regenerative areas can serve as a prognostic marker, indicating a better prognosis for patients with hepatitis B virus-acute-on-chronic liver failure.

SEMA6B induces macrophage-mediated inflammation and hepatocyte apoptosis in hepatitis B virus-related acute-on-chronic liver failure.

Rationale: Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) have a high short-term mortality rate. Semaphorin-6B (SEMA6B) plays a crucial role in the pathogenesis of HBV-ACLF, but its molecular basis remains unclear. This study aimed to elucidate the mechanisms of SEMA6B in HBV-ACLF progression. Methods: A total of 321 subjects with HBV-ACLF, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NC) from a prospective multicenter cohort were studied. 84 subjects (HBV-ACLF, n = 50; LC, n = 10; CHB, n = 10; NC, n = 14) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs) to clarify the mechanisms of SEMA6B in HBV-ACLF. These mechanisms were validated through in vitro studies with hepatocytes and macrophages, as well as in vivo using SEMA6B knockout mice and mice treated with synthetic SEMA6B siRNA. Results: Transcriptome analysis of PBMCs showed that SEMA6B was among the most differentially expressed genes when comparing patients with HBV-ACLF to those with LC, CHB, or NC. ROC analysis demonstrated the reliable diagnostic value of SEMA6B for HBV-ACLF in both the sequencing cohort and an external validation cohort (AUROC = 0.9788 and 0.9026, respectively). SEMA6B levels were significantly higher in the HBV-ACLF patients, especially in non-survivors, with high expression mainly observed in macrophages and hepatocytes in liver tissue. Genes significantly associated with highly expressed SEMA6B were enriched in inflammation and apoptosis pathways in HBV-ACLF non-survivors. Overexpression of SEMA6B in macrophages activated systemic inflammatory responses, while its overexpression in hepatocytes inhibited proliferation through G0/G1 cell cycle arrest and induced apoptosis. Knocking out SEMA6B rescued mice with liver failure by improving liver functions, reducing inflammatory responses, and decreasing hepatocyte apoptosis. Transcriptome analysis of liver tissue showed that SEMA6B knockout significantly ameliorated the liver failure signature, significantly downregulating inflammation-related pathways. Importantly, therapeutic delivery of synthetic SEMA6B siRNA also improved liver function, and reduced both inflammation and hepatocyte apoptosis in mice with liver failure. Conclusion: SEMA6B, a potential diagnostic biomarker for HBV-ACLF, exacerbates liver failure through macrophage-mediated systemic inflammation and hepatocyte apoptosis. These findings highlight SEMA6B as a promising early treatment target for HBV-ACLF patients.

Hepatitis B Viral Protein HBx: Roles in Viral Replication and Hepatocarcinogenesis.

Hepatitis B virus (HBV) infection remains a major public health concern worldwide, with approximately 296 million individuals chronically infected. The HBV-encoded X protein (HBx) is a regulatory protein of 17 kDa, reportedly responsible for a broad range of functions, including viral replication and oncogenic processes. In this review, we summarize the state of knowledge on the mechanisms underlying HBx functions in viral replication, the antiviral effect of therapeutics directed against HBx, and the role of HBx in liver cancer development (including a hypothetical model of hepatocarcinogenesis). We conclude by highlighting major unanswered questions in the field and the implications of their answers.

Liver biopsy-proven non-alcoholic fatty liver disease predicts no impact on antiviral response in patients with chronic hepatitis B.

OBJECTIVE: The role of Non-Alcoholic Fatty Liver Disease (NAFLD) on antiviral response in Chronic Hepatitis B (CHB) remains unclear. Previous studies mainly focus on the impact of the Non-Alcoholic Fatty Liver (NAFL) on antiviral efficacy, whereas the role of Non-Alcoholic Steatohepatitis (NASH) has not been highlighted. The authors aimed to investigate the association of NAFLD (NAFL and NASH), viral and histological characteristics with antiviral response. METHODS: The authors collected data of treatment-naïve CHB patients who underwent liver biopsy. All these patients received antiviral monotherapy and 48-week follow-up. The antiviral response was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the variables associated with antiviral response. RESULTS: Overall, 120 treatment-naïve CHB patients were enrolled, with 49.2 % (59/120) of them were complicated by NAFLD. Male (Odd Ratio [OR = 4.222], 95 % Confidence Interval [95 % CI 1.620-11.003]) and overweight (OR = 8.709, 95 % CI 3.355-22.606) were independent predictors for concurrent NAFLD. After 48-week follow-up, the authors found that the overall antiviral response did not differ between CHB patients with and without concomitant NAFL/NASH (p > 0.05). High viral load (Hazard Ratio [HR = 0.522], 95 % CI 0.286-0.952), advanced fibrosis (HR = 2.426, 95 % CI 1.256-4.686), and moderate-to-severe interface hepatitis (HR = 2.541, 95 % CI 1.406-4.592) were significantly correlated with antiviral response after 8-week follow-up. CONCLUSION: Neither NAFL nor NASH had an impact on antiviral therapy for CHB. It was low hepatitis B load, advanced fibrosis, and moderate-to-severe interface hepatitis that contributed to the virological response.

Reliability of Serum-Derived Connectome Indicators in Identifying Cirrhosis.

Patients with cirrhosis face a heightened risk of complications, underscoring the importance of identification. We have developed a Connectome strategy that combines metabolites with peptide spectral matching (PSM) in proteomics to integrate metabolomics and proteomics, identifying specific metabolites bound to blood proteins in cirrhosis using open search proteomics methods. Analysis methods including Partial Least Squares Discriminant Analysis (PLS-DA), Uniform Manifold Approximation and Projection (UMAP), and hierarchical clustering were used to distinguish significant differences among the Cirrhosis group, Chronic Hepatitis B (CHB) group, and Healthy group. In this study, we identified 81 cirrhosis-associated connectomes and established an effective model distinctly distinguishing cirrhosis from chronic hepatitis B and healthy samples, confirmed by PLS-DA, hierarchical clustering analysis, and UMAP analysis, and further validated using six new cirrhosis samples. We established a Unified Indicator for Identifying cirrhosis, including tyrosine, Unnamed_189.2, thiazolidine, etc., which not only enables accurate identification of cirrhosis groups but was also further validated using six new cirrhosis samples and extensively supported by other cirrhosis research data (PXD035024). Our study reveals that characteristic cirrhosis connectomes can reliably distinguish cirrhosis from CHB and healthy groups. The established unified cirrhotic indicator facilitates the identification of cirrhosis cases in both this study and additional research data.

Viral Load-Based Prediction of Hepatocellular Carcinoma Risk in Noncirrhotic Patients With Chronic Hepatitis B : A Multinational Study for the Development and External Validation of a New Prognostic Model.

BACKGROUND: A nonlinear association between serum hepatitis B virus (HBV) DNA levels and hepatocellular carcinoma (HCC) risk has been suggested in patients with chronic hepatitis B (CHB). OBJECTIVE: To develop and externally validate a prognostic model for HCC risk in noncirrhotic adult patients with CHB and no notable alanine aminotransferase (ALT) elevation. DESIGN: Multinational cohort study. SETTING: A community-based cohort in Taiwan (REVEAL-HBV [Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus]; REACH-B [Risk Estimation for HCC in CHB] model cohort) and 8 hospital-based cohorts from Korea and Hong Kong (GAG-HCC [Guide with Age, Gender, HBV DNA-HCC] and CU-HCC [Chinese University-HCC] cohorts). PARTICIPANTS: Model development: 6949 patients with CHB from a Korean hospital-based cohort. External validation: 7429 patients with CHB combined from the Taiwanese cohort and 7 cohorts from Korea and Hong Kong. MEASUREMENTS: Incidence of HCC. RESULTS: Over median follow-up periods of 10.0 and 12.2 years, the derivation and validation cohorts identified 435 and 467 incident HCC cases, respectively. Baseline HBV DNA level was one of the strongest predictors of HCC development, demonstrating a nonlinear parabolic association in both cohorts, with moderate viral loads (around 6 log10 IU/mL) showing the highest HCC risk. Additional predictors included in the new model (Revised REACH-B) were age, sex, platelet count, ALT levels, and positive hepatitis B e antigen result. The model exhibited satisfactory discrimination and calibration, with c-statistics of 0.844 and 0.813 in the derivation and validation cohorts with multiple imputation, respectively. The model yielded a greater positive net benefit compared with other strategies in the 0% to 18% threshold. LIMITATION: Validation in cohorts of other races and receiving antiviral treatment was lacking. CONCLUSION: Our new prognostic model, based on the nonlinear association between HBV viral loads and HCC risk, provides a valuable tool for predicting and stratifying HCC risk in noncirrhotic patients with CHB who are not currently indicated for antiviral treatment. PRIMARY FUNDING SOURCE: Korean government.