This study aims to explore the effects of various hepatic steatosis conditions on histological outcomes in patients with significant inflammation and fibrosis in chronic hepatitis B (CHB) and analyze their impact on HBV virological suppression outcomes and biochemical improvement.

This retrospective study included 219 chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogues therapy. Each of these patients underwent two liver biopsies. Patients were categorized into four groups based on hepatic steatosis status: sustained non-hepatic steatosis (n = 118), new-onset hepatic steatosis (n = 33), sustained hepatic steatosis (n = 37), and disappeared hepatic steatosis (n = 31). We compared the liver biochemical parameters and histological changes before and after treatment. Logistic regression analysis was performed to evaluate characteristics associated with the improvement of significant liver inflammation (G ≥ 2), significant fibrosis (S ≥ 2), and the persistence of hepatic steatosis.

After treatment, the sustained non-steatosis group exhibited the highest rate of improvement in baseline significant inflammation (75.31%), while the sustained steatosis group had the lowest (42.31%, p = 0.008). The sustained steatosis group also had the highest rate of inflammation progression (15.38%, p = 0.020) and was identified as a risk factor for inadequate baseline inflammation improvement (p = 0.006, OR = 0.244, 95% CI 0.090-0.665). In terms of baseline significant liver fibrosis improvement, the sustained non-hepatic steatosis group showed the highest improvement rate (67.14%), while the sustained hepatic steatosis group had the lowest (28.00%, p = 0.006). The new-onset steatosis group had the highest rate of liver fibrosis progression (15.00%, p = 0.027), and sustained hepatic steatosis was a risk factor for poor baseline fibrosis improvement (p = 0.001, OR = 0.180, 95% CI 0.064-0.507). Furthermore, the sustained hepatic steatosis group showed the smallest decrease in liver enzyme markers ALT, GGT, and ALP post-treatment, with reductions of 22.11% (p = 0.023), 13.86% (p = 0.003), and 1.98% (p = 0.025), respectively. Logistic regression analysis revealed that high baseline BMI and LDL-C levels were significantly associated with persistent fatty liver, with high BMI (p = 0.042, OR = 1.109, 95% CI 1.004-1.226) and high LDL-C (p < 0.001, OR = 2.570, 95% CI 1.524-4.332).

In CHB patients with significant inflammation and fibrosis, the persistence of hepatic steatosis during antiviral treatment may impede the improvement of inflammation and fibrosis, leading to disease progression and biochemical abnormalities.

In recent years, the rising prevalence of obesity and metabolic syndrome has led to an increased number of individuals developing metabolic dysfunction-associated steatotic liver disease (MASLD). Furthermore, given the substantial global prevalence of chronic hepatitis B (CHB), instances of MASLD coexisting with CHB are becoming increasingly commonplace in clinical scenarios. Both conditions can lead to liver fibrosis, cirrhosis, and potentially hepatocellular carcinoma (HCC). However, the intricacies of the dual etiology, consequential outcomes, and associated risks of CHB concurrent with MASLD are still not fully understood.

A literature search was conducted on PubMed for articles published up to March 2024. The search keywords included nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic hepatitis B, liver fibrosis, hepatocellular carcinoma, nuclear factor erythroid 2-related factor 2, and oxidative stress.

This review examined recent studies on the interplay between MASLD and CHB. The coexistence of these conditions may facilitate the clearance of hepatitis B surface antigen from the serum and impede hepatitis B virus (HBV) replication. Conversely, individuals with coexisting CHB tend to exhibit a lower rate of hypertriglyceridemia and reduced serum triglyceride levels compared with those only having NAFLD. Nevertheless, these observations do not necessarily indicate universally positive outcomes. Indeed, MASLD and CHB may synergistically act as "co-conspirators" to exacerbate clinical manifestations, particularly liver fibrosis and HCC.

As our understanding of the interaction between steatosis and HBV infection becomes clearer, we can better assess the risk of advanced liver disease in patients with concurrent CHB and MASLD. These insights will support the exploration of potential underlying mechanisms and may provide recommendations for improving patient outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses to metabolic dysfunction-associated steatohepatitis (MASH) and is a major cause of liver cirrhosis. Although liver inflammation is the hallmark feature of MASH versus MASLD, the involvement of the peripheral immune cell compartments in disease progression is poorly understood, and single-cell profiles of peripheral immune cells in MASLD/MASH are not known.

Patients with MASLD/MASH and healthy volunteers have been prospectively enrolled in a cross-sectional study. Patients have been histologically stratified and further characterized by liver bulk RNA sequencing (RNA-Seq). Peripheral immune cells from patients and control blood samples have been comprehensively profiled using bulk and single RNA-Seq.

Twenty-two patients with fibrosis stage less than F3 have been histologically stratified into patients with low, medium, and high disease activity scores (NAFLD activity score [NAS]). In contrast to fibrosis, the NAS group correlated with noninvasive imaging readouts and blood biomarkers of liver damage and inflammation (ALT, AST). The prevalence of type 2 diabetes and obesity increased with the NAS stage. Bulk RNA-seq profiling of patient liver biopsies revealed gene signatures that were positively and negatively associated with NAS. Known marker genes for liver fibrosis where upregulated on RNA level. Blood bulk RNA-seq showed only moderate differences in patients versus healthy controls. In contrast, single-cell analysis of white blood cells revealed multiple alterations of immune (sub-)populations, including an increased abundance of immature B cells and myeloid suppressor cells in patients with MASLD/MASH as compared to healthy controls.

The study gives new insights into the pathophysiology of MASLD/MASH already manifesting relatively early in peripheral immune cell compartments. This opens new avenues for the development of new biomarker diagnostics and disease therapies.

One of the primary risk factors for hepatocellular carcinoma (HCC) is the hepatitis B virus (HBV). Exosomes have a significant impact on the dissemination of HBV-infected HCC. This study aimed to screen HBV exosome-related hub genes in HCC for a better understanding of the HCC pathogenic mechanism. First, multiple HBV-induced HCC datasets were collected from the Gene Expression Omnibus (GEO) database, and the exosome-related gene set was obtained from relevant literature. Nine HBV-related HCC exosome hub genes (HP, C9, APOA1, PON1, TTR, LPA, FCN2, FCN3, and MBL2) were selected through differential analysis and network analysis. An analysis of the receiver operation characteristic (ROC) revealed that these genes had good diagnostic value. These hub genes were primarily enriched in biological processes such as the citrate cycle tca cycle, phenylalanine metabolism, and fatty acid metabolism, according to gene set enrichment analysis (GSEA). Furthermore, this study predicted the miRNA (hsa-miR-590-5p) targeting LPA, as well as 12 lncRNAs (AL121655, SAP30-DT, LINC00472, etc.) targeting hsa-miR-590-5p. Finally, nelarabine, methylprednisolone, and methylprednisolone were predicted to be possible medications that target the hub gene based on the CellMiner database. To sum up, this work was crucial for discovering new biomarkers and comprehending the function of exosome-related genes in the growth of HBV-infected HCC.

Pyroptosis is a distinct form of cell death that plays a critical role in intensifying inflammatory responses. It primarily occurs via the classical pathway, non-classical pathway, caspase-3/6/7/8/9-mediated pathways, and granzyme-mediated pathways. Key effector proteins involved in the pyroptosis process include gasdermin family proteins and pannexin-1 protein. Pyroptosis is intricately linked to the onset and progression of non-alcoholic steatohepatitis (NASH). During the development of NASH, factors such as pyroptosis, innate immunity, lipotoxicity, endoplasmic reticulum stress, and gut microbiota imbalance interact and interweave, collectively driving disease progression. This review analyzes the molecular mechanisms of pyroptosis and its role in the pathogenesis of NASH. Furthermore, it explores potential diagnostic and therapeutic strategies targeting pyroptosis, offering new avenues for improving the diagnosis and treatment of NASH.

Oleanolic acid (OA) is recognized for its anticancer properties, which are similar to those of conventional chemotherapeutic agents used in clinical practice. However, its role in modulating the sensitivity of cancer cells to fluorouracil (5FU) has not yet been documented. This study aimed to examine the effects of OA and 5FU co-administration on hepatocellular carcinoma (HCC) and uncover the mechanisms involved. In this study, the efficacy of combination therapy with OA and 5FU in treating HCC was evaluated using the MTT cell proliferation assay, plate clone formation assay, Hoechst 33342 staining, western blot assay, and Ca2+ fluorescence probe. The results demonstrated that compared with the use of OA or 5FU alone, OA and 5FU combination therapy significantly inhibited the proliferation of HEPG2 cells and enhanced cell apoptosis and Ca2+ levels in HCC. Additionally, the inhibitory effect of OA and 5FU combination therapy on cell proliferation and apoptosis was partially reversed by the calcium channel blocker 2-aminoethyldiphenyl borate (2-APB). In summary, these findings indicated that synergistic treatment with OA and 5FU can enhance cell apoptosis, inhibit cell proliferation, and regulate Ca2+ signaling in HCC, providing new guidance for the clinical treatment of HCC.

Observational studies have found that HMGCR inhibitors can be used to treat chronic viral hepatitis. In this study, to explore the potential mechanism of HMGCR inhibitors in treating Chronic hepatitis B (CHB), two-sample and two-step Mendelian randomization (MR) were used to investigate the causal relationship between HMGCR inhibitors and the mediating role of circulating metabolites. GWAS data of expression quantitative trait loci eQTLs of HMGCR inhibitors, 168 circulating metabolites, CHB, and myocardial infarction were obtained from the IEUOpenGWAS project. Random effects inverse-variance weighted (IVW) was the main causal analysis method, and the MR-Egger regression method was used as a supplementary analysis method. Cochran's Q test and I2 statistic were used to determine the heterogeneity of SNPs. The intercept terms of the MR-Egger method and MR-PRESSO were used for pleiotropy analysis, and leave-one-out was used for sensitivity analysis. Mediation effect analysis was used to evaluate the mediating role of the circulating metabolites. Genetic variations in the drug target genes of HMGCR inhibitors were associated with a reduced risk of chronic hepatitis B and myocardial infarction (P < 0.05). Eight circulating metabolites had a significant causal relationship with HMGCR inhibitors and CHB. After further calculation of the mediation effect, citrate was used as a mediating variable between HMGCR inhibitors and CHB, with a mediation effect of - 0.015 and a mediation ratio of 9.769%. HMGCR inhibitors can significantly reduce the risk of CHB, and the circulating metabolite citrate may mediate this association. However, this study has certain limitations. The short-term effects of HMGCR inhibitors on CHB could not be assessed, and partial overlap between the GWAS data for HMGCR inhibitors and circulating metabolites may introduce bias in estimating causal effects.

Steatotic liver disease (SLD) is prevalent among individuals with chronic hepatitis B virus (CHB), yet its impact on clinical outcomes remains controversial.

We used electronic health record data from 98 US healthcare-delivery systems to compare adults with (CHB-SLD) and without SLD (CHB-wo-SLD) from 2000 to 2024. We applied 1: 1 propensity score matching to balance cohorts by demographic and clinical characteristics. We further performed sensitivity analyses in the presence or absence of cirrhosis. We compared incidence rates (IR) and hazard ratios (HRs) of all-cause mortality, hepatocellular carcinoma (HCC), end-stage liver disease (ESLD) events, and detectable HBsAg and HBeAg as markers of seroclearance.

Among 124,932 individuals with CHB (12.43% CHB-SLD), there were 470,707 person-years of observations (median follow-up 2.95 years). Compared with CHB, individuals with CHB-SLD had a lower mortality risk (HR 0.44, 95% CI 0.40-0.48). Fibrosis risk was higher among those with CHB-SLD (vs CHB-wo-SLD) (HR 1.93, 95% CI 1.71-2.19); however, cirrhosis risk was comparable (HR 1.06, 95% CI 0.96-1.18) between cohorts, while HCC risk was lower in the CHB-SLD cohort (HR 0.83, 95% CI 0.70-0.96). The CHB-SLD cohort also had significantly reduced risks of ESLD events, including ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, and hepatorenal syndrome (all p < 0.001). Additionally, detectable HBsAg and HBeAg IRs and HRs were lower among CHB-SLD compared to the CHB-wo-SLD cohort: 26.83 vs. 31.96 per 1,000 person-years (HR 0.80, 95% CI 0.73-0.87) and 8.52 vs. 11.36 per 1,000 person-years (HR 0.74, 95% CI 0.65-0.85), respectively. Sensitivity analyses stratified by cirrhosis status supported these findings.

CHB-SLD status was associated with more favorable outcomes, highlighting the complexity of CHB and SLD interactions.

Early assessment of hepatocellular carcinoma (HCC) risk could improve long-term outcomes in people with chronic hepatitis B virus (HBV) infection. Some existing HCC predictive scores are not easily implementable. We developed easy-to-use HCC predictive scores based on behavioural and routine bio-clinical data in people with chronic HBV infection.

Eight-year follow-up data was analysed from people with chronic HBV infection enrolled in the French ANRS CO22 HEPATHER cohort. Patients were randomly split into two samples (training/testing). A multivariable Cox model for time to HCC was estimated on the training sample. The HCC predictive score was computed by summing the points assigned to model predictors, normalising their coefficients over a 10-year age increment, and rounding to the nearest integer. The Youden index identified the score's optimal risk threshold. Comparisons with existing predictive scores were performed on the testing sample.

In the study population (N = 4370; 63% of men; 65% of < 50 years old), 56 HCC cases occurred during 25,900 follow-up person-years. Two HCC predictive scores were defined: SADAPTT (daily soft drink consumption, age, hepatitis Delta infection, unhealthy alcohol use, platelet count, heavy tobacco smoking, and HBV treatment) and ADAPTT (the same predictors except for daily soft drink consumption), with ranges 0-13 and 0-14, respectively, and values ≥ 3 indicating a high HCC risk. Their performances were similar to existing scores.

We developed two effective behaviour-based HCC predictive scores, implementable in many settings, including primary care and decentralised areas. Further studies are needed to validate these scores in other datasets.

Soft actuators are one of the most promising technological advancements with potential solutions to diverse fields' day-to-day challenges. Soft actuators derived from hydrogel materials possess unique features such as flexibility, responsiveness to stimuli, and intricate deformations, making them ideal for soft robotics, artificial muscles, and biomedical applications. This review provides an overview of material composition and design techniques for hydrogel actuators, exploring 3D printing, photopolymerization, cross-linking, and microfabrication methods for improved actuation. It examines applications of hydrogel actuators in biomedical, soft robotics, bioinspired systems, microfluidics, lab-on-a-chip devices, and environmental, and energy systems. Finally, it discusses challenges, opportunities, advancements, and regulatory aspects related to hydrogel actuators.

Due to the high prevalence of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis B virus (HBV) infection, a significant proportion of patients suffer from both conditions simultaneously. The management of NAFLD in patients with concurrent HBV infection presents unique challenges, primarily due to the complex interplay between these two diseases. Nanomaterials have gained widespread attention due to their ability to overcome the limitations of conventional therapies. This review provides an overview of the current advances in therapeutic nanomaterials for NAFLD and explores their potential applications for personalized and effective management in patients with concurrent HBV infection. Furthermore, we discuss the challenges and future directions in the development of nanomaterials for the treatment of coexisting liver diseases.

To evaluate liver complications in patients with chronic hepatitis B, both with and without cardiometabolic comorbidities, and to compare the incidence of cardiometabolic comorbidities in these patients with that of the general population.

This nationwide registry-based cohort study included data from 2002-2020. In the primary analysis, we used multivariate Poisson regression to estimate the incidence rate and incidence rate ratio of liver complications in patients with chronic hepatitis B, stratified by the presence of cardiometabolic comorbidities. In the secondary analysis, we compared the incidence rate of developing cardiometabolic comorbidities in patients with chronic hepatitis B to those of the general population. Both analyses were adjusted for sex, age, and country of origin, while the primary analysis was additionally adjusted for time since cardiometabolic comorbidity diagnosis and calendar year.

The primary analysis included 4731 patients with chronic hepatitis B, of whom 532 (11%) had at least one cardiometabolic comorbidity. The unadjusted overall incidence rate of liver complications in patients with cardiometabolic comorbidities was 1.0 per 100 person-years (95% confidence intervals: 0.84-1.30) compared to 0.4 per 100 person-years (95% confidence intervals: 0.30-0.42) in those without. The incidence rate ratio for liver complications was highest in the first year following the diagnosis of cardiometabolic comorbidity. The incidence rate ratio for developing cardiometabolic comorbidities in the chronic hepatitis B cohort compared to the general population, was 1.10 (95% confidence intervals: 1.02-1.19). Sensitivity analyses revealed a higher incidence rate ratio for type 2 diabetes and hypertension but a lower incidence rate ratio for hypercholesterolemia.

Patients with chronic hepatitis B and cardiometabolic comorbidities exhibit a higher incidence of liver complications, particularly in the first year following comorbidity diagnosis compared to those without comorbidities. Furthermore, patients with chronic hepatitis B have a higher incidence of cardiometabolic comorbidities than the general population.

The intersection between metabolic-associated steatotic liver disease (MASLD) and chronic hepatitis B virus (HBV) infection is an emerging area of research with significant implications for public health and clinical practice. Wang et al's study highlights the complexities of managing patients with concurrent MASLD and HBV. The findings revealed that patients with concurrent MASLD-HBV exhibited more severe liver inflammation and fibrosis, whereas those with HBV alone presented a better lipid profile. The growing recognition of metabolic dysfunction in liver disease, reflected in the shift from nonalcoholic liver disease to MASLD, demands updates to clinical guidelines, particularly for patients with dual etiologies. Understanding the biological interactions between MASLD and HBV could lead to novel therapeutic approaches, emphasizing the need for personalized treatment strategies. The coexistence of MASLD and HBV presents therapeutic challenges, particularly in managing advanced fibrosis and cirrhosis, which are more likely in these patients. The aim of this editorial is to analyze the interaction between MASLD and HBV, highlight the pathophysiological mechanisms that exacerbate liver disease when both conditions coexist, and discuss the clinical implications of the findings of Wang et al.

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.

Co-existing chronic hepatitis B virus (CHB) infection and metabolic dysfunction associated steatotic liver disease (MASLD) can exert complex effects on hepatic metabolism, requiring mechanistic study. CHB participants were assessed for MASLD and the impact of hepatic steatosis/metabolic syndrome (MetS) on novel viral and immunological markers. In this prospective, cohort study, untreated CHB subjects were assessed for liver disease by non-invasive tests (i.e. FibroScan, controlled attenuation parameter, CAP). Subjects were tested for cytokines and IFN-γ ELISPOT assay to HBV Surface (S) and Core (C) proteins. Standard HBV serological, exploratory biomarkers and deep sequencing of HBV S and C genes were performed. In 53 subjects (median age 45 years [SD = 10.6], 35% F, 56% Asian, 20% Black, 3% White), 94% (50) HBeAg negative, 63% genotype B/C, mean HBV DNA 3.2 log10 IU/mL (SD = 1.8), quantitative HBsAg 2.9 log10 IU/mL (SD = 1.2) and HBV pgRNA 2.1 log10 copies/mL (SD = 1.3). In enrolled subjects, the mean ALT was 41.9 U/L (SD = 24.0), FibroScan was 5.7 kPa (SD = 1.9) and CAP was 306.4 dB/m (SD = 49.0). The mean BMI was 28.2 kg/m2 (SD = 4.2), 20% (11/53) had diabetes, 35% (19/53) dyslipidaemia and 24% (13/53) hypertension. Subjects with MetS and steatosis showed lower HBV markers (p < .01), higher HBV S diversity (p = .02) and greater frequency of HBV variants associated with host-anti-viral immune escape. Pro-inflammatory cytokine levels and HBV-specific cellular responses were higher in participants with hepatic steatosis. In CHB, MASLD/hepatic steatosis was associated with HBV variants and systemic immune responses potentially impacting liver disease progression despite low-level viraemia.

Background: The concurrent presence of chronic hepatitis B virus (CHB) infection and metabolic dysfunction-associated steatotic liver disease (MASLD) presents a unique clinical scenario with implications that are not yet fully understood. This study aims to characterize the distinct clinical and virological features of CHB in the context of MASLD and evaluate its impact on disease progression and outcomes. Methods: Utilizing a comprehensive health maintenance organization database, this study included 1186 patients with CHB from 2000-2020. Patients were categorized into two groups: CHB-MASLD (n = 188) and CHB alone (n = 998). CHB diagnosis was confirmed by serological markers, while MASLD was diagnosed based on imaging and cardiometabolic risk factors. Comparative analysis and multiple regression models were applied to assess variables related to viral parameters and clinical outcomes. Results: The CHB-MASLD group was older (mean age of 45.2 vs. 39.1, p < 0.001) with higher rates of obesity (46.8% vs. 23.8%, p < 0.001), diabetes (36.2% vs. 17.3%, p < 0.001), and dyslipidemia. Distinct viral profiles included higher HBeAg negativity (96.2%), a higher rate of HBeAg-negative infection (70.4% vs. 63.8%; p < 0.001), and increased HBeAg seroconversion under treatment. Cirrhosis was more prevalent in the CHB-MASLD group (9.6% vs. 4.4%, p = 0.007), while HCC rates were comparable. Multivariate analysis identified age, male gender, chronic active hepatitis, and diabetes as predictors of cirrhosis. Conclusions: CHB-MASLD patients were distinguished by a higher prevalence of metabolic features, along with a distinct viral profile marked by increased chronic HBeAg infection, higher rates of HBeAg seroconversion, and a potential association with worse disease outcomes.

Liver cirrhosis is a complex disease that may result in increased morbidity and mortality following bariatric surgery (BS). This study aimed to explore the outcome of BS in patients with unexpected cirrhosis, focusing on postoperative complications and the progression of liver disease.

A retrospective study of bariatric patients with cirrhosis from four centers in China between 2016 and 2023 was conducted, with follow-up for one year after BS. The primary outcome was the safety of BS in patients with unexpected cirrhosis, while the secondary outcome was the metabolic efficacy of BS in this group postoperatively.

A total of 47 patients met the study criteria, including 46 cases of Child-Pugh class A cirrhosis and 1 case of Child-Pugh B. Pathological examination confirmed nodular cirrhosis in 21 patients (44.68%), pseudolobule formation in 1 patient (2.13%), lipedema degeneration with inflammatory cell infiltration in 3 patients (6.38%), and chronic hepatitis in 1 patient (2.13%). The average percentage of total weight loss was 29.73 ± 6.53% at one year postoperatively. During the 30-day postoperative period, the complication rate was 6.38%, which included portal vein thrombosis, gastrointestinal bleeding, and intra-abdominal infection. Moreover, no cases of liver decompensation or mortality were reported during the follow-up period. The remission rates of comorbidities among 41 patients one year after surgery were as follows: dyslipidemia 100%, type 2 diabetes 82.61%, hypertension 84.62%, and obstructive sleep apnea syndrome 85.71%.

BS can be safely performed in patients with unexpected cirrhosis in the compensated stage of liver disease, with low postoperative morbidity and no mortality observed during one-year follow-up.

This study aimed to investigate the immunogenicity of the hepatitis B virus (HBV) vaccine by applying a normal and high-dose hepatitis B virus vaccination program in the mice modeling of non-alcoholic fatty liver disease (NAFLD). NAFLD was induced in mouse livers via diet. At the 10-week mark, both groups were divided into 3 subgroups. While the standard dose vaccination program was applied on days 0, 7, and 21, two high-dose programs were applied: one was applied on days 0 and 7, and the other was applied on days 0, 7, and 21. All mice were euthanized. Blood samples from anti-HB titers; T follicular helper, T follicular regulatory, CD27+, and CD38+ cells; and the liver, spleen, and thymus were taken for histopathologic evaluation. NAFLD subgroups receiving high doses showed higher hepatocyte ballooning scores than normal-dose subgroup. There were differences in CD27+ and CD27+CD38+ cells in animals fed on different diets, without any differences or interactions in terms of vaccine protocols. In the NAFLD group, a negative correlation was observed between anti-HB titers and T helper and CD27+ cells, while a positive correlation was observed with CD38+ cells. NAFLD induced changes in immune parameters in mice, but there was no difference in vaccine efficacy among the applied vaccine protocols. Based on this study's results, high-dose vaccination protocols are not recommended in cases of NAFLD, as they do not enhance efficacy and may lead to increased liver damage.

Background: Chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD) are significant causes of chronic liver disease, potentially leading to liver cirrhosis and hepatocellular carcinoma. Moreover, the coexistence of CHB and NAFLD is increasingly common, although the relationship between NAFLD and inactive CHB infection remains poorly understood. Objectives: This study aimed to investigate the prevalence of NAFLD among patients with inactive CHB, identify risk factors for NAFLD, and determine predictors of significant fibrosis in these patients. Methods: This single-center cross-sectional study targeted patients with inactive CHB at Sultan Qaboos University Hospital from January 2010 to November 2021. Results: A total of 425 patients with inactive CHB were identified, of which 53.1% were male and 62.6% were aged 40-60 years. The prevalence of NAFLD was 47.8%. Various independent factors were associated with NAFLD, including type 2 diabetes mellitus, elevated low-density lipoprotein levels, high hemoglobin levels, low platelet counts, and normal alpha-fetoprotein levels. Significant associations were noted between NAFLD and significant fibrosis, with 10.5% of CHB patients with NAFLD exhibiting significant fibrosis compared to 1.4% of those without NAFLD. Other significant parameters included male gender, increased age, high alanine transaminase levels, elevated hemoglobin, and decreased platelet levels. Conclusions: The high prevalence of NAFLD in patients with inactive CHB and its associations with increased fibrosis and cirrhosis risk underscore the need for comprehensive management strategies for these patients.

Hepatitis B Virus (HBV) is a stealthy and insidious pathogen capable of inducing chronic necro-inflammatory liver disease and hepatocellular carcinoma (HCC), resulting in over one million deaths worldwide per year. The traditional understanding of Chronic Hepatitis B (CHB) progression has focused on the complex interplay among ongoing virus replication, aberrant immune responses, and liver pathogenesis. However, the dynamic progression and crucial factors involved in the transition from HBV infection to immune activation and intrahepatic inflammation remain elusive. Recent insights have illuminated HBV's exploitation of the sodium taurocholate co-transporting polypeptide (NTCP) and manipulation of the cholesterol transport system shared between macrophages and hepatocytes for viral entry. These discoveries deepen our understanding of HBV as a virus that hijacks hepatocyte metabolism. Moreover, hepatic niche macrophages exhibit significant phenotypic and functional diversity, zonal characteristics, and play essential roles, either in maintaining liver homeostasis or contributing to the pathogenesis of chronic liver diseases. Therefore, we underscore recent revelations concerning the importance of hepatic niche macrophages in the context of viral hepatitis. This review particularly emphasizes the significant role of HBV-induced metabolic changes in hepatic macrophages as a key factor in the transition from viral infection to immune activation, ultimately culminating in liver inflammation. These metabolic alterations in hepatic macrophages offer promising targets for therapeutic interventions and serve as valuable early warning indicators, shedding light on the disease progression.

Clinical research has suggested that chronic HBV infection exerts a certain effect on the occurrence of cardiovascular disease by regulating cholesterol metabolism in liver cells. High serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio plays a certain role in the above regulation, and it serves as a risk factor for cardiovascular disease. However, whether the ApoB/ApoA1 ratio is correlated with chronic HBV infection and its disease progression remains unclear. In accordance with the inclusion and exclusion criteria, all 378 participants administrated at Renmin Hospital of Wuhan University from March 2021 to March 2022, fell into Healthy Control (HC) group (50 participants), Hepatocellular carcinoma (HCC) group (107 patients), liver cirrhosis (LC) group (64 patients), chronic hepatitis B (CHB) group (62 patients), chronic hepatitis C (CHC) group (46 patients) and Hepatitis E Virus (HEV) group (49 patients). Serum ApoA1 and ApoB concentrations were measured at admission, and the ApoB/ApoA1 ratio was determined. The levels of laboratory parameters in the respective group were compared and ApoB/ApoA1 ratios in HCC patients and LC patients with different severity were further analyzed. ROC curves were plotted to analyze the early diagnostic ability of ApoB/ApoA1 ratio for HBV-associated HCC. Logistic regression and restricted cubic spline analysis were used to explore the correlation between ApoB/ApoA1 ratio and LC and HCC risk. A comparison was drawn in terms of ApoB/ApoA1 ratio between the groups, and the result was expressed in descending sequence: HEV group > CHB group > LC group > HCC group > CHC group > HC group, early-stage HCC < middle-stage HCC < advanced-stage HCC, Class A LC < Class B LC < Class C LC. Serum ApoB/ApoA1 ratio combined diagnosis with AFP exhibited the capability of increasing the detection efficacy and specificity of AFP for HCC and AFP-negative HCC. The incidence of LC and HCC in the respective logistic regression model showed a negative correlation with the serum ApoB/ApoA1 ratio in CHB patients (P < 0.05). After all confounding factors covered in this study were regulated, the result of the restricted cubic spline analysis suggested that in a certain range, serum ApoB/ApoA1 ratio showed an inverse correlation with the prevalence of LC or HCC in CHB patients. Serum ApoB/ApoA1 ratio in CHB patients may be conducive to identifying high-risk patients for HCC or LC, such that LC and HCC can be early diagnosed and treated.

Recently, metabolic associated steatotic liver disease (MASLD) became the leading cause of chronic liver disease worldwide and one of the most frequent causes of hepatocellular carcinoma (HCC). Nonetheless, in this epidemiological trend, viral hepatitis remains the major driver in hepatic carcinogenesis. Globally, hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma, with an overall attributable risk of approximately 40%, followed by hepatitis C virus (HCV), which accounts for 28-30% of cases, with significant geographic variations between the Eastern and Western world. Considering all the etiologies, HCC risk increases proportionally with the progression of liver disease, but the risk is consistently higher in patients with viral triggers. This evidence indicates that both direct (due to the oncogenic properties of the viruses) and indirect (through the mechanisms of chronic inflammation that lead to cirrhosis) mechanisms are involved, alongside the presence of co-factors contributing to liver damage (smoking, alcohol, and metabolic factors) that synergistically enhance the oncogenic process. The aim of this review is to analyze the oncogenic role of hepatitis viruses in the liver, evaluating epidemiological changes and direct and indirect viral mechanisms that lead to liver cancer.

To assess the utility of fat fraction quantification using quantitative multi-echo Dixon for evaluating tumor proliferation and microvascular invasion (MVI) in hepatocellular carcinoma (HCC).

A total of 66 patients with resection and histopathologic confirmed HCC were enrolled. Preoperative MRI with proton density fat fraction and R2* mapping was analyzed. Intratumoral and peritumoral regions were delineated with manually placed regions of interest at the maximum level of intratumoral fat. Correlation analysis explored the relationship between fat fraction and Ki67. The fat fraction and R2* were compared between high Ki67(>30%) and low Ki67 nodules, and between MVI negative and positive groups. Receiver operating characteristic (ROC) analysis was used for further analysis if statistically different.

The median fat fraction of tumor (tFF) was higher than peritumor liver (5.24% vs 3.51%, P=0.012). The tFF was negatively correlated with Ki67 (r=-0.306, P=0.012), and tFF of high Ki67 nodules was lower than that of low Ki67 nodules (2.10% vs 4.90%, P=0.001). The tFF was a good estimator for low proliferation nodules (AUC 0.747, cut-off 3.39%, sensitivity 0.778, specificity 0.692). There was no significant difference in tFF and R2* between MVI positive and negative nodules (3.00% vs 2.90%, P=0.784; 55.80s-1 vs 49.15s-1, P=0.227).

We infer that intratumor fat can be identified in HCC and fat fraction quantification using quantitative multi-echo Dixon can distinguish low proliferative HCCs.

Background: The combined effect of hepatitis B virus infection and metabolic dysfunction-associated steatotic liver disease (MASLD) on hepatocellular carcinoma (HCC) risk remains unclear. The current study sought to elucidate the impact of MASLD on HCC progression in chronic hepatitis B (CHB) patients. Method: This retrospective cohort study included CHB patients who had undergone liver biopsy and abdominal imaging at the Guangdong Provincial Hospital of Chinese Medicine between 2013 and 2019. We investigated the correlation between MASLD and HCC risk, and inverse probability treatment weighting (IPTW) was used to adjust for patient characteristics. Results: A total of 1,613 patients were included, and 483 (29.9%) were diagnosed with MASLD. Over a median follow-up period of 5.02 years, 36 (2.2%) developed HCC, comprising 4.8% (23/483) of those with MASLD and 1.2% (13/1,130) of those without. Those with MASLD had a significantly higher cumulative incidence of HCC than those without (p < 0.001). The presence of MASLD was associated with a higher risk of HCC (adjusted hazard ratio [HR], 3.996; 95% confidence interval [CI], 2.007-7.959; p < 0.001). After adjustment using IPTW, the patients with MASLD retained a higher cumulative incidence of HCC (p < 0.001). Moreover, MASLD was found to be an independent risk factor for the development of HCC (adjusted HR, 10.191; 95% CI, 4.327-24.002; p < 0.001). However, among patients with MASLD, there were no significant differences in the cumulative risk of HCC between patients with and without overweight, between those with <2 and ≥2 cardiometabolic risk factors (CMRFs), between those with <3 and ≥3 CMRFs, or between those with <4 and ≥4 CMRFs (p = 0.110, p = 0.087, p = 0.066, and p = 0.490, respectively). Conclusion: The presence of MASLD is associated with a higher risk of HCC in patients with CHB. Notably, this higher risk is present in patients with MASLD, irrespective of the presence or absence of overweight or the number of CMRFs they have.

The co-occurrence of chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) has drawn considerable attention due to its impact on disease outcomes. This study aimed to investigate the association between hepatic steatosis and hepatitis B virus (HBV) and analyzed the influence of hepatic steatosis on hepatitis B virology in patients with CHB.

In this cross-sectional study, 272 patients infected with HBV who were treatment-naïve or had ceased antiviral treatment for > 6 months were categorized into the CHB group (n = 128) and CHB + MAFLD group (n = 144). Furthermore, based on whether HBV DNA was higher than 2000 IU/mL, patients were categorized into the high-level HBV DNA group (n = 129) and the low-level HBV DNA group (n = 143). The impact of hepatic steatosis on hepatitis B virology was analyzed within the CHB cohort. Multivariate logistic regression analysis was employed to identify independent factors influencing pre-genomic RNA (pgRNA) levels below the lower limit of detection (LLD) in patients with CHB.

Among the 272 patients, compared with CHB group, HBV DNA levels (4.11 vs. 3.62 log10 IU/mL, P = 0.045), hepatitis B surface antigen (HBsAg) levels (3.52 vs. 3.20 log10 IU/mL, P = 0.008) and the hepatitis B e antigen (HBeAg) positive rate (33.6% vs. 22.2%, P = 0.036) were significantly decreased in the CHB + MAFLD group; In 143 low-level HBV DNA patients, the CHB + MAFLD group exhibited decreased levels of pgRNA and HBsAg compared to the CHB group. However, in 129 high-level HBV DNA patients, a more significant decrease was observed in pgRNA (3.85 vs 3.35 log10 copies/mL, P = 0.044) and HBsAg (3.85 vs 3.59 log10 IU/mL, P = 0.033); Spearman correlation analysis revealed a negative correlation between hepatic steatosis and pgRNA (r =  - 0.529, P < 0.001), HBV DNA (r =  - 0.456, P < 0.001), HBsAg (r =  - 0.465, P < 0.001) and HBeAg (r =  - 0.339, P < 0.001) levels; Multivariate logistic regression analysis identified HBV DNA (odds ratio [OR] = 0.283, P < 0.001), HBsAg (OR = 0.300, P < 0.001), and controlled attenuation parameter (CAP) values (OR = 1.013, P = 0.038) as independent factors influencing pgRNA levels below the LLD in patients with CHB.

This study establishes a negative correlation between hepatic steatosis and hepatitis B virology, demonstrating decreased HBV expression in patients with CHB + MAFLD.

The intricate interplay between viral infections and non-alcoholic fatty liver disease (NAFLD) presents a fascinating and clinically significant intersection of virology and hepatology. This review article delves into the complex relationship between hepatitis B virus (HBV), hepatitis A virus (HAV), hepatitis E virus (HEV), and NAFLD. It outlines the shared mechanisms linking viral infections to NAFLD development, including their effects on lipid metabolism, immune responses, inflammation, and gut microbiota. The clinical implications of this interplay are explored, including challenges in diagnosis and management and potential therapeutic strategies. The review emphasises the need for a comprehensive understanding of these interactions as they impact disease progression, risk stratification, and treatment decisions. Furthermore, it highlights the importance of integrated approaches and personalised treatment paradigms for optimising patient care. As we navigate this intricate crossroads, the insights gained can reshape our understanding of liver health and contribute to more effective strategies for managing viral infections and NAFLD.

Interaction between infectious agents and liver tissue, as well as repeated and extreme biological events beyond adaptive capacities, may result in pathological conditions predisposing people to development of primary liver cancers (PLCs). In adults, PLCs mainly comprise hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Various infectious agents in the hepatic microenvironment can destabilize normal liver cell functions by modulating the Wnt/β-catenin pathway components. Among them, hepatotropic viruses B, C, and D are involved in Wnt/β-catenin signaling dysregulation. Other microbial agents, including oncogenic viruses such as Epstein-Barr virus (EBV) and human papilloma virus (HPV), bacteria, e.g., Mycoplasma hyorhinis and Salmonella Typhi, the protozoan parasite Toxoplasma gondii, the fungus Aspergillus flavus, and liver flukes such as Clonorchissinensis or Opisthorchis viverrini, may induce malignant transformation in hepatocytes or in target cells of the biliary tract through aberrant Wnt signaling activation. This review focuses on new insights into infectious agents implicated in the deregulation of Wnt signaling and PLC development. Since the Wnt/β-catenin pathway is a driver of cancer following viral and bacterial infections, molecules inhibiting the complex axis of Wnt signaling could represent novel therapeutic approaches in PLC treatment.