Chronic Hepatitis Research Articles

Comparison of Non-invasive Biochemical Fibrosis Markers According to Obesity-Based Metabolic Profile in Chronic Liver Disease with Chronic Hepatitis B Etiology

Aim: The aim of this study is to investigate the impact of obesity on fibrosis by comparing fibrosis markers between obese and non-obese patients with Chronic Hepatitis B (CHB). Material and Method: A total of 172 CHB (50.6±9.4 mean aged) patients were included in this retrospective study. The patients were divided into two groups: Obese (n=72) and Non-obese (n=100). Inclusion criteria were those diagnosed with chronic hepatitis B and ≤ 50 IU/mL or undetectable HBV-DNA, and exclusion criteria were other chronic diseases other than CHB and pregnancy. The height, body weight, and waist circumferences were measured. BMI ≥30 kg/m2 was classified as the obese group. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma-glutamyl transferase, albumin, bilirubin, and prothrombin time were analyzed. Fibrosis-4 score (FIB-4) was calculated with the formula Age x AST / platelet count x √(ALT), and AST-Platelet Ratio Index (APRI) was calculated with the formula [AST/AST (upper limit of normal)]/ platelet count. Results: AST levels were significantly higher in obese patients (p

The value of serum Mac-2 binding protein glycosylation isomer in the diagnosis of liver fibrosis: a systematic review and meta-analysis

BackgroundThe early detection and intervention of liver fibrosis (LF) in patients with chronic liver disease is critical to their management. The accuracy of serum Mac-2 binding protein glycosylation isomer (M2BPGi) in the diagnosis of LF remains controversial. This study aimed to comprehensively assess the value of serum M2BPGi in diagnosing LF.MethodsThe PubMed, Embase, MEDLINE, Web of Science, and Cochrane Library databases were searched. The effect values were combined using a random-effects model. Meta-regression and subgroup analysis were used to explore the sources of heterogeneity. In addition, publication bias assessment and sensitivity analysis were conducted.ResultsThis study includes 12 studies with 2,416 patients. The pooled sensitivity, specificity, and AUROC of M2BPGi in the diagnosis of significant fibrosis (≥F2) were 0.65 (95% CI: 0.57–0.71), 0.79 (95% CI: 0.72–0.84), and 0.78 (95% CI: 0.74–0.81), respectively, while those for predicting extensive fibrosis (≥F3) were 0.76 (95% CI: 0.71–0.80), 0.75 (95% CI: 0.68–0.81), and 0.81 (95% CI: 0.77–0.84). Sensitivity analysis indicated stable results in this study. The disease type, cut-off values, study country, average age, and male proportion were the sources of heterogeneity in diagnosing significant fibrosis of M2BPGi (p < 0.05). Sample size, disease type, study country, publication year, cut-off values, average age, and male proportion were important sources of heterogeneity in diagnosing extensive fibrosis (p < 0.05).ConclusionSerum M2BPGi has good diagnostic performance for significant fibrosis and extensive fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), or nonalcoholic fatty liver disease (NAFLD) and is an effective, non-invasive, and convenient marker.Systematic Review Registrationhttps://inplasy.com/inplasy-2023-10-0086/.

Roseoside Is a Bioactive Compound in Kirengeshoma koreana Nakai Extract with Potent In Vitro Antiviral Activity Against Hepatitis C Virus.

Hepatitis C virus (HCV) is a pathogen that causes cirrhosis and hepatocellular carcinoma through chronic hepatitis C. This study focused on the anti-HCV activity of a 70% ethanol extract of Kirengeshoma koreana Nakai (KKE) and its bioactive chemical constituent(s). The KKE and its n-butanol (n-BuOH) fraction induced a significant reduction in HCV RNA levels without inducing cytotoxicity. A high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis revealed the presence of roseoside in the n-butanol fraction of the KKE, which inhibited HCV RNA replication in a concentration- and time-dependent manner without exerting cytotoxicity. Consistent with in silico molecular docking analysis data, roseoside targets and inhibits HCV NS5A/B replicase. Collectively, our findings demonstrate that roseoside is a chemical constituent in KKE that interferes with HCV replication by targeting NS5A/B replicase.

Clinical validation of peripheral blood mononuclear cell DNA methylation markers for accurate early detection of hepatocellular carcinoma in Asian patients

BackgroundHepatocellular carcinoma (HCC), a leading cause of cancer-related deaths globally, poses significant challenges in early detection. Improved diagnostic accuracy can drastically influence patient outcomes, emphasizing the need for innovative, non-invasive biomarkers.Methods:This study utilized a cohort of 402 participants, including healthy controls, chronic hepatitis patients, and HCC patients from Bangladesh, to evaluate DNA methylation signatures in peripheral blood mononuclear cells (PBMC). We performed targeted next-generation sequencing on selected genes previously identified to assess their methylation dynamics. The development of M8 and M4 scores was based on these dynamics, using Receiver Operating Characteristic (ROC) analysis to determine their effectiveness in detecting early-stage HCC alongside existing markers such as epiLiver and alpha-fetoprotein (AFP).Results:Integration of M8 and M4 scores with epiLiver and AFP significantly enhances diagnostic sensitivity for early-stage HCC. The M4+epiLiver score achieves a sensitivity of 79.4% in Stage A HCC, while combining M4 with AFP increases sensitivity to 88.2–95.7% across all stages, indicating a superior diagnostic performance compared to each marker used alone.Conclusions:Our study confirms that combining gene methylation profiles with established diagnostic markers substantially improves the sensitivity of detecting early-stage HCC. This integrated diagnostic approach holds promise for advancing non-invasive cancer diagnostics, potentially leading to earlier treatment interventions and improved survival rates for high-risk patients.

CHRONIC HEPATITIS B VIRUS INFECTION: SYSTEMATIC REVIEW OF EPIDEMIOLOGY, MECHANISMS OF VIRAL PERSISTENCE AND TREATMENT OF THE CONDITION

Objective: The general objective of this study is to analyze the scientific production on chronic infection by the Hepatitis B virus, seeking to identify the main methods used in the treatment of this pathology. Methodology: This is a systematic review focused on understanding the main aspects that permeate chronic infection by the Hepatitis B virus. The research was guided by the question: “What are the main aspects that permeate chronic infection by the Hepatitis B virus, as well as what are the diagnostic and therapeutic resources used in clinical practice?”. To find answers, searches were performed in the PubMed database using five descriptors combined with the Boolean term “AND”. This resulted in 408 articles. Twenty-four articles were selected for analysis and 15 articles were used to compose the collection. Results: The eradication of hepatitis B depends on the combination of preventive and therapeutic efforts. The persistence of cccDNA in the liver, even after viral suppression, makes complete functional cure difficult. Antivirals such as entecavir and tenofovir are effective in reducing viral load, but they fail to eradicate the virus in most patients, requiring prolonged treatments. Furthermore, the variability in treatment responses, influenced by factors such as viral genotype and disease stage, highlights the need for personalized approaches to improve clinical management. In summary, despite advances, there are still important challenges to be addressed in the search for a cure for chronic hepatitis B. Conclusion: The systematic review highlighted the main aspects of chronic hepatitis B (CHB), emphasizing its challenges and advances in clinical management. Chronic hepatitis B virus (HBV) infection remains a serious public health problem, with complications such as liver cirrhosis and hepatocellular carcinoma. Prevention strategies, such as universal vaccination and immunoprophylaxis, are effective in reducing vertical transmission, especially in newborns, but global adherence still needs to improve, especially in areas of high prevalence.

Chronic Hepatitis D Virus Infection and Its Treatment: A Narrative Review

More than 12 million individuals worldwide are chronically infected with the hepatitis D virus (HDV). HDV infection is the most severe form of viral hepatitis since it requires hepatitis B virus co-infection and accelerates progression to cirrhosis and hepatocellular carcinoma. Therefore, treatment modalities to slow the progression of the disease are essential but not yet available. In addition, no antiviral treatment to date has been shown to reliably eradicate HDV. Pegylated interferon (PEG-IFN) is the only universally used treatment to suppress HDV RNA replication and improve liver inflammation and fibrosis. This treatment can be completed in 12–18 months, but cure rates remain low, and success does not reliably increase with the addition of a nucleos(t)ide analog. PEG-IFN therapy is also limited by poor tolerability and multiple adverse effects, including neutropenia, thrombocytopenia, and neuropsychiatric symptoms. Newer antiviral therapies in development target unique aspects of HDV viral replication and show promising results in combination with PEG-IFN for long-term HDV RNA suppression. These newer antiviral therapies include buleviritide (which blocks HDV entry), lonafarnib (which prevents HDV assembly), and REP-2139 (which prevents HDV export). In this manuscript, we discuss the characteristics of HDV infection and review the new antiviral therapies approved for treatment and those under investigation.

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.

Mother-to-child Transmission using the National HBV Perinatal Prevention Data in Korea, 2002-2021

Abstract Aims To define risk factors associated with mother-to-child transmission (MTCT) and to create supporting evidence for the National Hepatitis B Perinatal Prevention Program (HBPPP) in Korea. Methods We analyzed HBPPP mother-infant pair data enrolled from 2002 to 2021. The major outcome was the HBsAg status of the infant resulting from post-vaccination serological testing. Additionally, we used prescription records of antivirals against the hepatitis B virus (telbivudine, tenofovir disoproxil fumarate) from 2010 to 2021 by data linkage with the National Health Insurance claims data. To select significant risk factors by maternal HBeAg status based on the data from 34 to 42 weeks of pregnancy, multivariate logistic regression analysis was used. Results Data from 232,242 mother-infant pairs were analyzed. Among 154,331 (66.5%) infants with post-vaccination serological testing results, 3,620 (2.3%) were HBsAg-positive. The incidence of MTCT has shown a decreasing trend, from 4.1% in 2002 to 1.0% in 2021. However, the rate was high at 5.5% (1822/32986) for infants of HBeAg-positive mothers. Maternal antiviral prescription during the pregnancy period, old age, HBeAg negative, delivery type (C-section), and breastfeeding were significant factors in decreasing the risk of MTCT. Among the HBeAg-positive, there was a significant difference in the antiviral prescription 0.7% (11/1692) compared to the non-prescription 4.9% (789/16264) [aOR, 7.71; 95% CI, 4.24-14.02]. The result was similar for the HBeAg-negative group, 0.7% (302/44888). Conclusions To eradicate the hepatitis B virus on a national level, MTCT must be further reduced. To achieve this, it is necessary to introduce strong additional preventive measures, including quantitative HBV DNA testing for mothers with chronic hepatitis B and administering antiviral prophylaxis at the third trimester of pregnancy with HBV-DNA ≥200,000 IU/mL into the HBPPP. Key messages • The incidence of mother-to-child transmission has shown a decreasing trend, from 4.1% in 2002 to 1.0% in 2021. • Maternal antiviral prescription, old age, HBeAg negative, delivery type (C-section), and breastfeeding were significantly decrease the risk of mother-to-child transmission.

Real world experience in treatment of chronic hepatitis C in patients with compensated and decompensated cirrhosis

Real world experience in treatment of chronic hepatitis C in patients with compensated and decompensated cirrhosis

Epidemiology of hepatitis C from 2015 to 2022 in a central Italian region: the OPT-HepaC project

Abstract Background Chronic hepatitis C virus (HCV) infection is a major global public health problem. This study investigated the evolving landscape of HCV in Tuscany (Italy) from 2015 to 2022, considering demographic shifts, clinical profiles, treatment regimens, and outcomes. Methods The study was conducted in order to characterize HCV-positive patients who started treatment between 2015 and 2022 in Tuscan prescribing centers. The study was part of OPT-HepaC, a project funded by Regional Health Service. Data on demographics, clinical history and outcomes were collected. Three different temporal eras were analysed: the period before andfter the universal availability of direct-acting antivirals (DAA) and the COVID-19 era. Treatment’s effectiveness was evaluated by the Sustained Virological Response (SVR12), assessed 12 weeks after the end of treatment. Outcomes included SVR12, non-SVR12 and lost to follow-up (LTFU). ANOVA, Kruskal-Wallis test and multinomial logistic regression were used for statistical analysis. Results 6882 HCV patients (age: 58.88±14.21) were treated by the centres participating at the study. Males (56.4%) and Italian (91.8%) were predominant. Sociodemographic and variable characteristics vary across the time. While the overall SVR12 remained stable over time (χ2(2)=0.357, p = 0.837), the LTFU rate significantly increased during the COVID-19 era. Facilitating factors for the non-SVR12 and LTFU outcomes were male gender (Odds Ratio (OR)=2.134, p = 0.006)/cirrhosis (OR = 1.713, p = 0.040)/HIV co-infection (OR = 3.251, p = 0.005) and DAA treatment of third generation (OR = 4.187, p = 0.006), respectively. Conclusions The study provides a comprehensive view of the HCV landscape, highlighting demographic changes, treatment regimens and outcomes. The COVID-19 pandemic affected service delivery, delaying HCV diagnosis/treatment and influencing the LTFU rate. Despite challenges, the region maintained high SVR12 rates, emphasizing the importance of sustained efforts in HCV care. Key messages • The study highlights the dynamic nature of HCV management in Tuscany. • The study emphasises the need for continuous adaptation to public health challenges, providing insights for future public health strategies.

Asiatic acid inhibits HBV cccDNA transcription by promoting HBx degradation

BackgroundHepatitis B virus (HBV) infection is a persistent global public health problem, and curing for chronic hepatitis B (CHB) through the application of existing antiviral drugs is beset by numerous challenges. The viral protein HBx is a critical regulatory factor in the life cycle of HBV. Targeting HBx is a promising possibility for the development of novel therapeutic strategies.MethodsThe Nano-Glo® HiBiT Lysis Detection System was used to screen the herbal monomer compound library for compounds that inhibit HBx expression. Western blotting was used to examine proteins expression. Southern blotting or Northern blotting were used to detect HBV DNA or HBV RNA. ELISA was performed to detect the HBsAg level. The effect of asiatic acid on HBV in vivo was investigated by using recombinant cccDNA mouse model.ResultsAsiatic acid, an extract of Centella asiatica, significantly reduced the HBx level. Mechanistic studies demonstrated that asiatic acid may promote the degradation of HBx in an autophagy pathway-dependent manner. Subsequently, asiatic acid was found to reduce the amount of HBx bound to covalently closed circular DNA (cccDNA) microchromosomes, and repressive chromatin modifications then occurred, ultimately inhibiting cccDNA transcriptional activity. Moreover, in HBV-infected cells and a mouse model of persistent HBV infection, asiatic acid exhibited potent anti-HBV activity, as evidenced by decreased levels of HBV RNAs, HBV DNA and HBsAg.ConclusionsAsiatic acid was identified as a compound that targets HBx, revealing its potential for application as an anti-HBV agent.

The characterization of serum proteomics and metabolomics across the cancer trajectory in chronic hepatitis B‐related liver diseases

AbstractHepatocellular carcinoma (HCC) is a deadly cancer that emerges from a continuous progression of liver cells from normal to abnormal, often following infections by hepatitis B/C viruses (HBV/HCV), liver fibrosis, and liver cirrhosis (LC), ultimately culminating in cancer. However, there is currently limited systematic molecular analysis of biomarkers at different stages of HCC progression using multi‐omics approaches. We carried out an innovative pipeline by utilizing targeted proteomics and metabolomics to identify potential biomarkers for early detection of HCC in 316 participants, including healthy adults and patients diagnosed with HBV, HCV, LC, and HCC from three independent cohorts. We first established a detailed database of candidate biomarkers for HCC containing 3059 proteins and 103 metabolites, and identified pivotal candidates implicated in the progressive trajectory of liver cancers. Through our developed DeepPRM, scheduled multiple reaction monitoring (MRM)‐targeted approach, and machine learning‐based computational pipeline, we identified an eight‐biomolecular‐based combination with an accuracy rate of 91.43% for early diagnosis of HCC, and a 12‐biomolecular‐based combination with an accuracy rate of 80.00% for detecting changes in HBV–LC progression. These two biomarker combinations significantly improved accuracy compared to traditional tumor biomarkers. Our extensive analysis provides valuable proteomic and metabolomic data resources that will contribute to a deeper understanding of liver disease progression and enhance the identification of potential therapeutic targets.

Mitochondrial Dysfunction-Molecular Mechanisms and Potential Treatment approaches of Hepatocellular Carcinoma.

Primary liver cancer (PLC), also known as hepatocellular carcinoma (HCC), is a common type of malignant tumor of the digestive system. Its pathological form has a significant negative impact on the patients' quality of life and ability to work, as well as a significant financial burden on society. Current researches had identified chronic hepatitis B virus infection, aflatoxin B1 exposure, and metabolic dysfunction-associated steatotic liver disease (MASLD) as the main causative factors of HCC. Numerous variables, including inflammatory ones, oxidative stress, apoptosis, autophagy, and others, have been linked to the pathophysiology of HCC. On the other hand, autoimmune regulation, inflammatory response, senescence of the hepatocytes, and mitochondrial dysfunction are all closely related to the pathogenesis of HCC. In fact, a growing number of studies have suggested that mitochondrial dysfunction in hepatocytes may be a key factor in the pathogenesis of HCC. In disorders linked to cancer, mitochondrial dysfunction has gained attention in recent 10years. As the primary producer of adenosine triphosphate (ATP) in liver cells, mitochondria are essential for preserving cell viability and physiological processes. By influencing multiple pathological processes, including mitochondrial fission/fusion, mitophagy, cellular senescence, and cell death, mitochondrial dysfunction contributes to the development of HCC. We review the molecular mechanisms of HCC-associated mitochondrial dysfunction and discuss new directions for quality control of mitochondrial disorders as a treatment for HCC.

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.

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.

Factors associated with low hepatitis B surface antigen levels in chronic hepatitis B patients treated with nucleot(s)ide analogs.

Several studies have reported that chronic hepatitis B (CHB) patients with low hepatitis B surface antigen (HBsAg) levels (100 or 10IU/mL) at the cessation of nucleot(s)ide analogs (NA) have a favorable prognosis. In this retrospective study, we evaluated the duration of NA treatment and the factors associated with achieving these low HBsAg levels. We also examined the relationship between HBsAg and hepatitis B core-related antigen (HBcrAg) levels at the time of NA discontinuation and subsequent clinical outcomes. This study included 153 CHB patients who initiated NA therapy at our hospital, received treatment, and were followed up for over 1year. The cumulative incidence rates of achieving low HBsAg levels at 5 and 10years post-NA administration were as follows: 19.0% and 29.2% for HBsAg <100IU/mL, 13.8% and 17.6% for HBsAg <10IU/mL, and 9.5% and 13.5% for HBsAg <0.05IU/mL, respectively. Hepatitis B virus genotypes other than genotype C (hazard ratio [HR] 3.47; p<0.001) and an HBsAg level <1000IU/mL at the start of NA therapy (HR 2.49; p=0.008) were significantly associated with achieving HBsAg levels <100IU/mL. Among 27 patients who discontinued NA therapy, 5 patients with HBsAg levels <100IU/mL and HBcrAg levels <3logU/mL at the time of discontinuation did not experience virological relapse. The cumulative rates of achieving HBsAg levels <100IU/mL were relatively high. Discontinuation of NA may be considered based on HBsAg and HBcrAg levels during the course of NA therapy.

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.

Nucleos(t)ide analogues potentially activate T lymphocytes through inducing interferon expression in hepatic cells and patients with chronic hepatitis B

Chronic hepatitis B (CHB) leads to liver inflammation and dysfunction, resulting in liver fibrosis and cancer. Nucleos(t)ide analogues (NAs), inhibitors of hepatitis B virus (HBV), specifically suppress HBV replication. We proposed that immune modulation benefits seroconversion by HBsAg loss. However, activation of T lymphocytes also deteriorates hepatic inflammation. Therefore, we intended to investigate the T cell status and its relationship with hepatic functions in CHB patients treated with NAs. Serum markers, including liver function markers AST, ALT, and HBV-infected markers HBV DNA, HBsAg, HBeAg, and HBsAb were measured in the clinical routine. The T cell levels and markers, including CD69, CD107a, CXCR3, and PD-1 were investigated using flow cytometry. Meanwhile, IFNγ, IL-2, and CXCL10 as immune activation markers in the PBMCs were investigated using qPCR. To validate the effects of NAs on T cell status, qPCR and flow cytometry were used to investigate the gene expression in the HepG2 and PLC5 cells treated with NAs, and in the healthy PBMCs treated with the cell-cultured supernatant. We found that NAs significantly suppressed HBV DNA and reduced AST and ALT levels in the CHB patients. Meanwhile, AST and ALT were both positively correlated with activation marker CD107a in CD8+ T cells. In addition, we found that the CHB patients with seroconversion exhibited a higher CD4/CD8 ratio (p < 0.05) compared to non-seroconversion. We demonstrated that NAs potentially induced IFNs and PD-L1 expression in HepG2 and PLC5 cells. Moreover, the collected supernatant from NAs-treated HepG2 significantly activated PBMCs. This study revealed that the reduction of HBV by NAs may be the reason leading to less AST and ALT levels. We further demonstrated that NAs induced IFN expression in hepatic cells to potentially activate T lymphocytes, which was positively associated with AST and ALT levels in the CHB patients. The results may explain the phenomena in clinical that when the virus is reactivated by aborted use of NAs, it causes consequent T cells-mediated severe acute-on-chronic liver injury.

Incidence rates of hepatocellular carcinoma based on risk stratification in steatotic liver disease for precision medicine: A real-world longitudinal nationwide study.

Detailed subgroup incidence rates for steatotic liver disease (SLD)-related hepatocellular carcinoma (HCC) are critical to inform practice and public health interventions but remain sparse. We aimed to fill in this gap. In a retrospective cohort study of adults with SLD from the United States (US) Merative Marketscan Research Databases (1/2007 to 12/2021), we estimated HCC incidence stratified by sex, age, cirrhosis, diabetes mellitus (DM), and a combination of all these 4 factors. We excluded patients with significant alcohol use and chronic viral hepatitis. We analyzed data from 741,816 patients with SLD (mean age 51.5 ± 12.8 years, 46% male, 14.7% cirrhosis). During a 2,410,166 person-years (PY) follow-up, 1,740 patients developed HCC. The overall HCC incidence yielded 0.72 per 1,000 PY (95% confidence interval [CI, 0.68, 0.75]). The incidence was higher in males (0.95, 95% CI [0.89, 1.01]) compared to females (0.52, 95% CI [0.48, 0.56]) (p < 0.001). For those with cirrhosis, the incidence was significantly higher at 4.29 (95% CI [4.06, 4.51]) compared to those without cirrhosis (0.14, 95% CI [0.13, 0.16]) (p < 0.001). Additionally, the incidence was higher in patients with DM (1.19, 95% CI [1.12, 1.26]) compared to those without DM (0.41, 95% CI [0.38, 0.44]) (p < 0.001). Chronic kidney disease (CKD) was also associated with a higher HCC incidence of 2.20 (95% CI [2.00, 2.41]) compared to those without CKD (0.58, 95% CI [0.55, 0.62]) (p < 0.001). Similarly, individuals with cardiovascular disease (CVD) had a higher HCC incidence of 1.89 (95% CI [1.75, 2.03]) compared to those without CVD (0.51, 95% CI [0.48, 0.54]) (p < 0.001). Finally, the incidence of HCC was significantly higher in patients with non-liver cancer (3.90, 95% CI [3.67, 4.12]) compared to those without other cancers (0.29, 95% CI [0.26, 0.31]) (p < 0.001). On further stratification, HCC incidence incrementally rose by 10-year age intervals, male sex, cirrhosis, and DM, reaching 19.06 (95% CI [16.10, 22.01]) and 8.44 (95% CI [6.78, 10.10]) in males and females, respectively, but only 0.04 for non-diabetic, noncirrhotic aged <40 years patients in both sexes. The main limitation of this methodology is the potential misclassification of the International Classification of Diseases (ICD) codes inherent in claims database studies. This nationwide study provided robust granular estimates for SLD-related HCC incidence stratified by several key risk factors. In addition to cirrhosis, future surveillance strategies, prevention, public health initiatives, and future research models should also take into account the impact of sex, age, and DM.

Metagenome-based characterization of the gut bacteriome, mycobiome, and virome in patients with chronic hepatitis B-related liver fibrosis.

The gut microbiota is believed to be directly involved in the etiology and development of chronic liver diseases. However, the holistic characterization of the gut bacteriome, mycobiome, and virome in patients with chronic hepatitis B-related liver fibrosis (CHB-LF) remains unclear. In this study, we analyzed the multi-kingdom gut microbiome (i.e., bacteriome, mycobiome, and virome) of 25 CHB-LF patients and 28 healthy individuals through whole-metagenome shotgun sequencing of their stool samples. We found that the gut bacteriome, mycobiome, and virome of CHB-LF patients were fundamentally altered, characterized by a panel of 110 differentially abundant bacterial species, 16 differential fungal species, and 90 differential viruses. The representative CHB-LF-enriched bacteria included members of Blautia_A (e.g., B. wexlerae, B. massiliensis, and B. obeum), Dorea (e.g., D. longicatena and D. formicigenerans), Streptococcus, Erysipelatoclostridium, while some species of Bacteroides (e.g., B. finegoldii and B. thetaiotaomicron), Faecalibacterium (mainly F. prausnitzii), and Bacteroides_A (e.g., B. plebeius_A and B. coprophilus) were depleted in patients. Fungi such as Malassezia spp. (e.g., M. japonica and M. sympodialis), Candida spp. (e.g., C. parapsilosis), and Mucor circinelloides were more abundant in CHB-LF patients, while Mucor irregularis, Phialophora verrucosa, Hortaea werneckii, and Aspergillus fumigatus were decreases. The CHB-LF-enriched viruses contained 18 Siphoviridae, 12 Myoviridae, and 1 Podoviridae viruses, while the control-enriched viruses included 16 Siphoviridae, 9 Myoviridae, 2 Quimbyviridae, and 1 Podoviridae_crAss-like members. Moreover, we revealed that the CHB-LF-associated gut multi-kingdom signatures were tightly interconnected, suggesting that they may act together on the disease. Finally, we showed that the microbial signatures were effective in discriminating the patients from healthy controls, suggesting the potential of gut microbiota in the prediction of CHB-LF and related diseases. In conclusion, our findings delineated the fecal bacteriome, mycobiome, and virome landscapes of the CHB-LF microbiota and provided biomarkers that will aid in future mechanistic and clinical intervention studies.