Search Results (1,332)

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain a world health problem leading to fibrosis and cirrhosis. Liver damage is primarily mediated by the innate and adaptive immune responses since HBV and HCV are not directly cytotoxic. Kupffer cells and liver-recruited macrophages are heavily implicated in both viral elimination and progression of the disease. HBV and HCV proteins polarize macrophages into either an M1 pro-inflammatory phenotype, promoting hepatocyte damage or into an M2 immunosuppressive phenotype, leading to viral persistence and fibrogenesis via cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). In this review a brief overview of the heterogeneity of liver macrophages in health and during chronic viral infection is presented. Recognition of viruses by macrophages and the modulation of macrophages by viral proteins in the pathogenesis of liver inflammation and injury are discussed in detail. Most importantly, the mechanisms that HBV and HCV are using to manipulate macrophages and escape elimination are also presented. The role of macrophages in the evolution of acute-on-chronic liver failure is analyzed. Finally, a concise presentation of the emerging, but not yet clinically used, therapeutic strategies targeting macrophages to control chronic HBV infection and restore the dysregulated immune response is discussed. In conclusion, this integrated review of liver macrophage implication summarizes the pathophysiology and pathogenesis of HBV and HCV including acute-on-chronic- liver failure and viral cirrhosis. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) arises through heterogeneous pathways involving chronic hepatitis B virus infection, hepatitis C virus infection, alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease, fibrosis, cirrhosis, and environmental exposures. Genome-wide association studies (GWASs) have identified host germline loci associated with HCC susceptibility, but interpretation is complicated by aetiology, ancestry, liver disease stage, and the definition of controls. This narrative review examines current GWAS evidence for HCC, with emphasis on aetiology-specific susceptibility, functional interpretation, cross-disorder genetic effects, and clinical translation. Methods: Studies were identified through iterative searches of PubMed/PMC, publisher pages, academic search tools, and citation tracking, supplemented by targeted searches for major HCC-associated loci. Sources were chosen based on relevance to GWAS discovery, replication, meta-analysis, functional interpretation, polygenic risk modelling, or HCC risk stratification, rather than by a formal systematic review protocol. Results: Viral HCC studies most often implicate immune regulation and antigen presentation, including MICA, HLA-DQ, HLA-DQB1, HLA class I, HCP5, STAT4, DEPDC5, and FAM114A1. Alcohol-related, metabolic, and non-viral HCC studies more often implicate hepatic lipid metabolism, telomere biology, iron metabolism, steatosis, and cirrhosis-related pathways, including PNPLA3, TM6SF2, TERT, HSD17B13, APOE, HFE, and MTARC1. Recent studies increasingly combine GWASs with fine-mapping, functional annotation, transcriptomic analyses, and risk modelling. Conclusions: HCC genetic susceptibility is highly aetiology-specific and overlaps with other liver and metabolic disorders, but discoveries from genetic studies have not yet been translated into routine clinical practice. Future work should prioritise multi-ancestry cohorts, disease-stage-aware controls, functional validation, and prospectively tested genetic risk models. Full article

Background: Hepatitis B and C viral infections remain a significant global health challenge, despite the implementation of an effective direct-acting antiviral (DAAs) and nucleos(t)ide analogues (NAs). Current HBV therapy is not curative as stopping therapy usually leads to active disease in most patients requiring long-term treatment. Although current HCV-DAAs are highly effective they fall short due to arising drug-resistance and have limited ability to avert re-infections. Furthermore, current HCV DAA treatments lead to the reactivation of occult HBV infection, compromising the effectiveness of current antiviral therapies, and increasing the risk of severe liver complications like cirrhosis and hepatocellular carcinoma. In addition, current treatments do not restore the immune dysfunction, a characteristic of chronic HBV infection. Given the global burden of disease, there is an urgent need for more effective therapy that can shorten the duration of treatment and achieve high rates of HBsAg reduction. Combining an antiviral to reduce viral antigen burden and an immunomodulator to boost the immune response could provide an effective treatment for HBV/HCV infections. Methods: In this study, we explored the potential of a novel bacterial therapeutic agent, heat-killed Caulobacter crescentus (HKCC), as an alternative and/or adjunct host-based therapy for HCV and HBV infections. Here, we have investigated the antiviral effects of the HKCC-stimulated human PBMCs using in vitro HCV and HBV infection models to assess viral replication, viral relapse responses, protein expression, and cytotoxicity. Results: Our findings reveal that HKCC induced a multi-functional cytokine response (IFN, TNF, IL-2, IL-10, IL-6, IL-17A, and IL-22) in PBMCs obtained from multiple healthy donors. Supernatants collected from these HKCC-stimulated human PBMCs, alone and in combination with antivirals, strikingly inhibited HCV replication and viral relapse responses without inducing any cytotoxic effects on HCV-1a replicon cells. In addition, these PBMC supernatants, with or without antivirals, led to the suppression of HBV DNA replication and inhibited HBsAg and HBeAg production in HepG 2.2.15 cells. Conclusions: In conclusion, HKCC is a promising candidate for eliminating HBV and HCV infections, and warrants further investigation to potentially contribute to the development of a novel host-based immunotherapy. Full article

Chronic hepatitis B virus (HBV) infection remains one of the main causes of hepatocellular carcinoma (HCC), even though vaccination and long-term viral suppression have reduced new infections and circulating viral replication. This residual cancer risk suggests that serum HBV DNA alone does not capture the full biology of HBV-related carcinogenesis. Hepatitis B virus X protein (HBx) is a relevant entry point because it maintains the transcriptional competence of covalently closed circular DNA (cccDNA), engages host chromatin regulators, and may persist in tumors as cccDNA-derived, integration-derived, full-length, truncated, or fusion forms. This review focuses on a specific question: does the available literature support HBx-associated reactivation of the IGF2 locus in chronic HBV infection and HBV-related hepatocarcinogenesis, and, if so, at which regulatory layer is the claim defensible? The most direct evidence remains promoter-proximal. Classic mechanistic work shows acute HBx-dependent activation of IGF2 promoter P4 through Sp1- and PKC/ERK-dependent signaling. Human tissue and cell-based studies also support a broader fetal-promoter compartment, including P3/P4 transcript enrichment, local promoter hypomethylation, MBD2-HBx-CBP/p300 recruitment, and increased histone H3/H4 acetylation. These observations do not, however, establish HBV exclusivity, uniform loss of imprinting, or direct HBx-mediated rewiring of the human IGF2/H19 topological domain. Recent integration-aware and long-read studies further argue against treating tumor-stage HBx as a single biological variable. In the present evidence framework, HBx-associated IGF2 locus reactivation is therefore more appropriately viewed as a stage-aware, promoter-resolved, biomarker-oriented hypothesis than as a universal mechanism or a treatment algorithm for HBV-related HCC. Full article

Background: A complex interplay between viral activity and host immune responses drives the progression of liver fibrosis in chronic hepatitis B. The T helper 17 (Th17) immune pathway, which produces the pro-inflammatory cytokine interleukin-17A (IL-17A), has been implicated in hepatic fibrogenesis. However, the relationship between IL-17A levels, IL-17A G197A (rs2275913) gene SNP, and the degree of liver fibrosis across different phases of the natural history of chronic hepatitis B remains insufficiently explored. Methods: This study employed an analytical observational design with a cross-sectional approach in treatment-naïve patients with chronic hepatitis B. The degree of liver fibrosis was assessed using liver elastography. IL-17A (rs2275913) gene SNP was analysed using Real-Time PCR, while serum IL-17A levels were measured using enzyme-linked immunosorbent assay. Statistical analyses included Spearman’s correlation, the contingency coefficient, the Chi-square test, the Kruskal–Wallis test, and the Mann–Whitney test, with a significance level set at p < 0.05. Results: A total of 76 patients with chronic hepatitis B were included in this study. The phase of disease progression was significantly associated with the degree of liver fibrosis (p = 0.016). Median IL-17A levels increased in parallel with fibrosis severity (p = 0.003), with a particularly significant association observed during the R phase (p = 0.002). However, no significant association was found between the IL-17A G197A (rs2275913) gene SNP and either liver fibrosis severity or serum IL-17A levels. Conclusions: Elevated serum IL-17A levels were associated with greater liver fibrosis severity, particularly during the reactivation phase of chronic hepatitis B. These findings suggest a potential relationship between IL-17A-mediated immune responses and liver fibrosis in patients with chronic hepatitis B. Full article

While minimalist kinetic models effectively capture the acute inverse coupling between Hepatitis B (HBV) and Hepatitis Delta (HDV), they often fail to account for the asymptotic stability and long-term viral plateaus observed during clinical therapy. In this work, we present an expanded compartmental framework integrating the non-linear dynamics of susceptible (S) and infected (I) hepatocyte populations, explicitly incorporating the satellite nature of HDV. Using the next-generation matrix method and Lyapunov stability theory, we analytically derive R₀ and prove the global attractivity of the endemic equilibrium. We demonstrate that “Target Cell Limitation” serves as the fundamental homeostatic governor. A transcritical bifurcation at threshold drug efficacy ε ≈ 0.9 marks the mathematical boundary between chronic persistence and viral extinction. Full article

There have been reports of an association between the gut microbiota and the development of chronic liver disease, fibrosis, and carcinogenesis; however, it is not yet possible to reach a definite conclusion. In this cross-sectional study, we examined the association between the presence or absence of hepatocellular carcinoma (HCC) and the gut microbiota in patients with chronic hepatitis B virus (HBV) infection. The study subjects consisted of 62 consecutive HBV patients admitted to our hospital who provided informed consent to participate in the study. We performed 16S rRNA analysis using DNA extracted from fecal pellets. The sequencing depth per sample was 80,000 to 90,000 reads. We calculated the proportion of each bacterial genus so that the total for each sample added up to 100%. The male-to-female ratio was 49/13, the median age was 67 years, and 46 of the patients had HCC. Twenty microbial phyla spanning 41 classes, 79 orders, 163 families, and 431 genera were identified. Receiver operating characteristic (ROC) analysis was performed on the identified bacterial taxa, from the level of phylum down to genus, to assess their ability to distinguish between patients with and without HCC. Several bacteria with an area under the curve (AUC) > 0.65 were identified as follows: TM7 phylum TM7-3 class (AUC = 0.700); Firmicutes phylum Clostridiales class Lachnobacterium genus, Dialister genus, Ruminococcus genus, and Roseburia genus (AUC = 0.670, 0.668, 0.667, and 0.660, respectively); and Firmicutes phylum Erysipelotrichi class (AUC = 0.656). Combining three of these taxa resulted in high discriminative power (p = 0.000585) with a sensitivity and specificity of 0.761 and 0.750, respectively. A similar trend was observed in the subgroup analysis based on liver reserve capacity. Even after adjusting for factors related to liver reserve capacity in the multivariate analysis, an association between these bacterial genera and HCC was confirmed. Our results suggest that gut microbiota may be associated with the prevalence of HCC in HBV patients. Full article

Background: Systematic infectious screening is recommended before initiation of biologic therapies in chronic inflammatory rheumatic diseases (CIRDs), yet the clinical impact of this strategy in low-prevalence settings remains insufficiently characterized. This study aimed to evaluate the proportion of abnormal findings and their impact on treatment management. Methods: We conducted a retrospective single-center study including adult patients with CIRDs who underwent systematic pre-biologic infectious screening between January 2019 and June 2025. Screening included HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), interferon-γ release assay (IGRA), and chest radiography. The primary outcome was the proportion of abnormal results and their impact on biologic initiation. Results: A total of 418 patients was included (mean age 48.2 ± 14.6 years; 69.1% female). No active HIV, HBV, or HCV infections were detected. Past HBV infection markers were identified in 2.6% of patients, and anti-HCV antibodies in 0.7%, all without detectable viremia. None of these findings required modification of biologic therapy. IGRA positivity was observed in 4.3% of patients and indeterminate results were seen in 3.1%. Preventive antituberculous therapy was initiated in most newly identified IGRA-positive cases, leading to delayed biologic initiation in several patients. Chest radiography yielded limited additional diagnostic value. Conclusions: In this population, systematic pre-biologic infectious screening identified few clinically actionable viral infections, whereas latent tuberculosis screening represented the main determinant of therapeutic modification. These findings support continued emphasis on tuberculosis risk assessment and warrant further prospective studies to evaluate optimized and potentially targeted screening strategies incorporating cost-effectiveness analyses. Full article

Aging-associated dyslipidemia and chronic low-grade inflammation contribute to atherosclerosis and cardiovascular risk. As a blend of long-chain aliphatic alcohols, policosanol from insect wax (PIW) has been documented to regulate lipid metabolism. However, the effects of PIW on atherosclerosis remain insufficiently characterized. In this study, ApoE^−/− mice fed a high-fat diet were concurrently administered PIW (75 and 150 mg/kg) for eight weeks. PIW was associated with weight gain reduction and improvement in lipid profile, particularly a decrease in triglycerides and total cholesterol. PIW also lowered circulating inflammatory biomarkers (IL-6, TNF-α, and C-reactive protein). Histopathological analyses revealed attenuated hepatic injury and reduced aortic lipid deposition and lesion features. In parallel, PIW reduced serum endothelin-1 and oxidized LDL levels and modulated aortic ET-1, MMP-9/TIMP-1 balance, and LOX-1/NF-κB-related protein signals. Notably, as PIW was administered concurrently with high-fat diet induction, these findings should be interpreted within a preventive intervention framework. Collectively, PIW help attenuate HFD-associated atherosclerotic features and hold promise as a functional food ingredient for cardiovascular health and healthy aging. Full article

Background: Chronic hepatitis B virus (HBV) infection remains a major global health challenge and a leading cause of liver cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6), a key pro-inflammatory cytokine, plays an important role in immune regulation and hepatic inflammation. However, its relationship with HBV viral load and disease severity remains incompletely understood. Methods: A hospital-based cross-sectional study was conducted among 293 HBsAg-positive patients. Serum IL-6 levels were measured using ELISA, and HBV DNA was quantified using real-time quantitative PCR. Patients were stratified according to viral load. Statistical analyses included non-parametric tests, Spearman correlation, principal component analysis (PCA), and multiple linear regression. Results: The median age was 45 years (IQR: 34–57), among which 54.6% were male. The median HBV DNA was 3.37 log₁₀ IU/mL (IQR: 2.45–3.75), and IL-6 concentration was 2.38 log₁₀ pg/mL (IQR: 2.21–2.49). IL-6 levels increased significantly across viral load categories (p < 0.001) and were higher in HBeAg-positive patients (p = 0.002), with no significant differences across age, sex, or cirrhosis. IL-6 levels correlated with HBV DNA (r = 0.40, p < 0.001). PCA identified distinct viral-inflammatory and biochemical axes. Regression analysis confirmed HBV DNA as the significant independent predictor (β = 0.461, p < 0.001; adjusted R² = 0.206). Conclusion: IL-6 was closely associated with HBV DNA levels, while the association with conventional biochemical markers of hepatocellular injury was significantly less in this cohort, suggesting that IL-6 may serve as an adjunct biomarker of disease activity in patients with chronic hepatitis B. Full article

Background/Objective: Long-term tenofovir disoproxil fumarate (TDF) therapy is associated with progressive bone mineral density loss in patients with chronic hepatitis B (CHB), yet existing fracture risk algorithms, such as FRAX, were not designed for this population. We aimed to develop and internally validate a clinical nomogram for identifying TDF-associated osteoporosis using penalized regression on demographic, virological, and biochemical predictors. Methods: In this single-center retrospective cohort study, 237 adult CHB patients receiving TDF for at least 12 months underwent dual-energy X-ray absorptiometry (DXA). Osteoporosis was defined as a T-score of −2.5 or lower at the lumbar spine or femoral neck. Thirteen candidate predictors were evaluated using LASSO regression with 10-fold cross-validation; selected variables were entered into an unpenalized multivariable logistic regression model; internal validation employed bootstrap resampling with 200 replications to derive optimism-corrected estimates of discrimination and calibration. The clinical utility was assessed using decision curve analysis (DCA). Results: Osteoporosis prevalence was 15.2% (n = 36). LASSO selected three predictors: prior fragility fracture (OR 11.45, 95% CI 4.82–27.15), the Charlson Comorbidity Index (OR 1.45 per unit, 95% CI 1.15–1.85), and alkaline phosphatase. The model demonstrated strong discrimination (apparent C-index 0.860; optimism-corrected 0.845) with excellent calibration (slope 0.94, intercept 0.02; Brier score 0.095). At a 0.15 probability threshold, sensitivity was 86.0%, specificity 78.0%, and negative predictive value 97.0%. DCA confirmed superior net clinical benefit over default strategies across the 0.10–0.30 threshold range; a pre-specified sensitivity analysis excluding fracture history retained meaningful discrimination (corrected C-index 0.791). Conclusions: This nomogram offers a clinically actionable, disease-specific tool for stratifying osteoporosis risk in TDF-treated CHB patients, particularly well suited for safely deferring DXA imaging in low-risk individuals. External validation in multicenter and ethnically diverse cohorts is required before widespread implementation. Full article

Therapeutic vaccines are a key strategy to achieve the goal of “functional cure” of chronic viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), and Epstein–Barr virus (EBV). Various platforms (such as viral vectors, nucleic acid vaccines, recombinant proteins, etc.) have successfully induced strong virus-specific T-cell responses in early trials, but their clinical efficacy is still limited by the immunosuppressive environment formed by the host. The core bottlenecks are severe T-cell exhaustion, viral immune escape, and various forms of local immune tolerance. Therefore, the field is moving toward combination therapies, including reduction of viral load, targeting of immune activation, and inhibition of inhibitory signaling pathways. This article summarizes the preclinical and clinical progress of therapeutic vaccines in the past decade, analyzes the major challenges in vaccine development, and discusses the future development directions in this field. Full article

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory/fibrotic form, metabolic-dysfunction-associated steatohepatitis (MASH), represent a growing global health burden. This progression is driven by complex mechanisms involving metabolic dysregulation, chronic inflammation, oxidative stress, and progressive fibrosis. To date, effective pharmacological therapies remain limited. Pentacyclic triterpenes have attracted increasing attention due to their broad biological activities and ability to modulate multiple molecular pathways implicated in chronic liver disease. This review aims to provide a mechanistic overview of the potential role of pentacyclic triterpenes in MASLD and MASH. Methods: A literature review was conducted using major scientific databases (PubMed and Web of Science) to identify experimental studies investigating pentacyclic triterpenes in metabolic liver diseases. Selected studies were analyzed according to triterpene structural classification, reported bioactivities, molecular targets, and experimental evidence from in vitro and in vivo models of MASLD/MASH or related pathogenic processes. Results: Pentacyclic triterpenes, especially ursolic acid, oleanolic acid, and glycyrrhizin, exhibit hepatoprotective effects including regulation of lipid metabolism, attenuation of oxidative and endoplasmic reticulum stress, suppression of pro-inflammatory signaling, inhibition of inflammasome activation, and reduction in hepatic stellate cell activation and extracellular matrix deposition. These effects involve modulation of signaling pathways, including AMPK, NF-κB, NLRP3, TGF-β, FXR, and MAPK. Preclinical evidence demonstrates improvements in steatosis, inflammation, and fibrosis in experimental models. Conclusions: Pentacyclic triterpenes emerge as multitarget modulators of MASH pathophysiology. However, translating preclinical evidence into well-designed clinical trials is necessary to validate their safety and efficacy in humans. Full article

Background: Viral replication is a major factor in chronic hepatitis B (CHB). Still, the extent to which host metabolic dysfunction contributes to fibrosis risk remains unclear, particularly in studies that follow patients over time. Because most research relies solely on baseline assessments, it may overlook how metabolic changes and fibrosis interact as the disease progresses. Methods: We conducted a retrospective longitudinal cohort study of 304 adults with CHB using electronic medical records collected across 4 visits over 18 months. Repeated metabolic parameters and non-invasive fibrosis indices were examined using population-averaged and mixed-effects models. The associations we observed represent time-specific co-variation between exposures and outcomes measured at the same time point, rather than earlier predictors of later outcomes. Results: Across 1216 person-visits, 421 visit-level fibrosis risk events were recorded (34.6%). Incident clustered metabolic abnormalities occurred at a rate of 21.43 per 100 person-years. Among the metabolic syndrome components, insulin resistance showed the most consistent independent association with visit-level fibrosis risk status. In contrast, after adjustment, longitudinal trends in BMI, lipid measures, and transaminases did not independently distinguish patients with fibrotic progression. A practical clinical model based on age, AST, platelet count, and fasting glucose demonstrated moderate discrimination across risk strata (AUC = 0.772). Conclusions: In CHB, insulin resistance is consistently linked to visit-level fibrosis risk status. Longitudinal metabolic monitoring using routine clinical data provides a practical, scalable way to assess fibrosis risk, especially in resource-limited settings. These findings support incorporating time-based metabolic assessment into CHB care pathways alongside virological factors. Full article

Background: Hepatocellular carcinoma (HCC) develops predominantly from chronic liver injury, with diet representing a clinically actionable yet mechanistically complex modulator of hepatic carcinogenesis. Despite advances in immunotherapy, long-term survival remains poor, underscoring the need for complementary preventive and adjunctive strategies. Methods: We conducted a narrative review of epidemiological, experimental, and clinical literature on dietary patterns, polyphenols, and non-polyphenol nutraceuticals for HCC prevention and management, with a focus on underlying molecular and cellular mechanisms. Results: Dietary polyphenols and selected nutraceuticals exert pleiotropic effects on signaling pathways implicated in HCC, including NF-κB, STAT3, TGF-β/SMAD, PI3K/AKT, and Wnt/β-catenin, while modulating hepatic stellate cell activation, immune cell polarization, and microbiome-derived metabolites. Preclinical studies suggest that some compounds may enhance antitumor immunity and sensitize tumors to systemic therapies; however, clinical translation is constrained by limited bioavailability, pharmacokinetic variability, formulation heterogeneity, and a lack of high-quality trials. Conclusions: This review highlights the potential of dietary patterns and nutraceuticals in HCC prevention and as adjunctive therapies. It outlines key translational priorities, including etiologic stratification, biomarker-driven trial design, and rigorous safety evaluation. Full article