Progression Of HBV-related Liver Disease Research Articles

Expression of 10 circulating cytokines/chemokines in HBV-related liver disease

BackgroundCytokines/chemokines play essential roles in the occurrence and progression of hepatitis B virus (HBV) infection. This study aimed to observe the expression patterns of 10 related cytokines/chemokines in the serum of healthy individuals, self-limited patients and HBV-infected patients at different stages of disease (chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular dysplastic nodules (DNs) and hepatocellular carcinoma (HCC)) and to analyze the relationships of these cytokines/chemokines with disease progression.MethodsThe levels of six cytokines (FGF-2, IFN-α2, IL-4, IL-6, IL-10 and VEGF-A) and four chemokines (GRO-α, IL-8, IP-10 and MCP-1) were quantified using Luminex multiplex technology.ResultsThere were no significant differences in the expression of the 10 cytokines/chemokines between healthy individuals and self-limited patients. The levels of IL-4, IL-6, and IL-8 increased significantly in the CHB and LC groups. IL-10 was highly expressed in the HCC group. The level of IP-10 was significantly greater in all liver disease groups (CHB, LC, DN and HCC) than in the HI and SL-HBV groups, while the level of GRO was significantly lower in all liver disease groups than in the HI and SL-HBV groups. The levels of the 10 cytokines/chemokines were not significantly different between the preoperative group and the two-day postoperative group. Significant increases in the levels of IL-4, VEGF-A and IL-8 and significant decreases in those of IL-10 and GRO-α were observed 3 months after surgery. Correlation analysis revealed that most of the cytokines/chemokines with significant correlation differences were positively correlated before and after HCC surgery.ConclusionOur results highlight the fluctuating status of specific cytokines in HBV infection-related disease progression. It is speculated that these cytokines may be used as serum markers to monitor dynamic changes during the progression of HBV-related liver disease and to predict patient prognosis.

Single-cell landscape of immune cells during the progression from HBV infection to HBV cirrhosis and HBV-associated hepatocellular carcinoma.

Immune cells play crucial roles in the development of chronic hepatitis B virus (HBV) infection, leading to cirrhosis and hepatocellular carcinoma (HCC). However, their functions at different disease stages are not fully understood. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the human liver immune microenvironment at different disease stages. We analyzed scRNA-seq data from 118,455 immune cells obtained from livers of six healthy individuals, four patients with HBV infection, five patients with HBV cirrhosis, and three patients with HBV-associated HCC. Our results showed an accumulation of scar-associated macrophages during disease progression, and we identified two relevant immune subsets, Macrophage-CD9/IL18 and macrophage-CD9/IFI6. Macrophage-CD9/IL18 expanded from HBV infection to cirrhosis, while macrophage-CD9/IFI6 expanded from cirrhosis to HCC. We verified the existence of Macrophage-CD9/IFI6 using multiplex immunofluorescence staining. We also found an increase in cytotoxic NK Cell-GNLY during progression from cirrhosis to HCC. Additionally, the proportion of CD4 T cell-TNFAIP3, CD8 T cell-TNF (effector CD8 T cells), and CD8 T cell-CD53 increased, while the proportion of Treg cells decreased from HBV infection to cirrhosis. The proportion of Treg and CD8 T cell-LAG3 (Exhausted CD8 T cell) enhanced, while the proportion of CD8 T cell-TNF (effector CD8 T cells) decreased from cirrhosis to HCC. Furthermore, GSEA enrichment analyses revealed that MAPK, ERBB, and P53 signaling pathways in myeloid cells were gradually inhibited from HBV infection to cirrhosis and HCC. Our study provides important insights into changes in the hepatic immune environment during the progression of HBV-related liver disease, which may help improve the management of HBV-infected liver diseases.

Diversity and composition of gut microbiota in healthy individuals and patients at different stages of hepatitis B virus-related liver disease

BackgroundHepatitis B virus (HBV) causes chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. The evolution of human gut microbiota during the progression of HBV-related liver diseases remains unclear. Therefore, we prospectively enrolled patients with HBV-related liver diseases and healthy individuals. Through 16S ribosomal RNA amplicon sequencing, we characterized the gut microbiota of the participants and predicted the functions of microbial communities.ResultsWe analyzed the gut microbiota of 56 healthy controls and 106 patients with HBV-related liver disease [14 with resolved HBV infection, 58 with CHB, and 34 with advanced liver disease (15 with liver cirrhosis and 19 with hepatocellular carcinoma)]. Patients with HBV-related liver disease exhibited a higher degree of bacterial richness (all P < 0.05) than did healthy controls. Beta diversity analyses revealed a distinct clustering pattern between healthy controls and patients with HBV-related liver disease (all P < 0.05). The composition of bacteria (from the phylum level to the genus level) varied across the stages of liver disease. Linear discriminant analysis effect size revealed multiple taxa that differ significantly in abundance between healthy controls and patients with HBV-related liver disease; however, fewer differences were observed among patients with resolved HBV infection, those with CHB, and those with advanced liver disease. The ratio of Firmicutes to Bacteroidetes was increased in all three patient groups compared with the ratio in healthy controls (all P < 0.001). The analysis of the sequencing data by using PICRUSt2 revealed the changes in microbial functions with disease progression.ConclusionsThe diversity and composition of gut microbiota appear to vary significantly between healthy controls and patients at different stages of HBV-related liver disease. The understanding of gut microbiota may provide novel therapeutic options in these patients.

Prevalence of Co-infection of Hepatitis B and C with HIV in HIV-Positive Adolescents in Anambra State, South-East Nigeria

Purpose: HIV accelerates the progression of HBV-related liver disease which may be as a result of the effect of HAART on the liver. This study evaluated the frequency of hepatitis B and C co-infection, and the viral load suppression rate among children and adolescents receiving ART in six HIV program centers in Anambra State, Nigeria. Methods: A multi-facility cross-sectional study was conducted among HIV-infected children and adolescents currently receiving antiretroviral treatment (ART) in six selected HIV/AIDS program healthcare facilities in Anambra State between March 2018 and February 2020. The HBsAg and HCV antibody screening were done using LabACON (HangzhouBiotest Biotech C0, China). The HIV viral load of the patients was determined according to the national HIV program algorithm using the RocheCOBASAmpliPrep COBAS TaqMan (CAP/CTM) HIV-1 test, version 2.0. All the patients Data were analyzed using SPSS version 23 and test of significance set at p-value of 0.05. Results: Of the 308 children and adolescent HIV positive cohorts tested for hepatitis B and C, 156/308 (50.6%) were males. Fourteen of the 308 (4.5%) tested positive for HBV while 34/308 (11.0%) tested positive for HCV. The male participants were frequently infected with HBV 10/156 (6.4) than their female counterparts 4/152(2. 6%). Among the children and adolescents, 3/94 (3.2%) and 11/214 (5.1%) were positive for HBV respectively, while the HCV antibody was present in 9/94 (9.6%) of children and 25/214 (11.7%) of adolescents (p = 0.24 and p = 0.72). Conclusions: The estimated prevalence of HIV/HBV and HIV/HCV dual infections in this cohort of Anambra HIV-infected children and adolescents on ART was 15.5%. Keywords: Seroprevalence, HBV, HCV, HIV, Children, Adolescents, ART, Anambra State

Serum Fibroblast Growth Factor 19 as a Biomarker in Hepatitis B Virus-Related Liver Disease

Background: Past research has found that fibroblast growth factor 19 (FGF19) is associated with several hepatic disorders, such as alcoholic liver disease and primary biliary cirrhosis. However, there is currently a lack of relevant studies on the relationship between FGF19 and hepatitis B virus (HBV)-related liver disease. Objectives: This study aimed to assess the role of serum FGF19 as a new biomarker for HBV-related liver disease and provide scientific data to show the clinical value of this biomarker. Methods: A retrospective study included 37 patients with chronic hepatitis B (CHB), 33 patients with HBV-related cirrhosis (HBV-cirrhosis), and 32 patients with HBV-related hepatocellular carcinoma (HBV-HCC). Furthermore, 33 normal people were randomly selected as healthy controls. The serum levels of FGF19 were measured by ELISA. Results: Serum FGF19 levels were increased sequentially in the CHB group, HBV-cirrhosis group, and HBV-HCC group. Furthermore, serum FGF19 levels positively correlated with alpha-fetoprotein, prothrombin time, international normalized ratio, total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl-transferase, alkaline phosphatase, total bile acid, serum markers for liver fibrosis, ascites, cirrhosis, Child-Pugh classification and model for end-stage liver disease sodium (MELD-Na) score, while negatively correlated with platelet count, prothrombin activity, and albumin. The diagnostic threshold of serum FGF19 for HBV-related HCC was 165.32 pg/mL, with a sensitivity of 81.25% and specificity of 58.57%. Conclusions: Serum FGF19 levels are positively associated with cholestasis, hepatocyte damage, and liver fibrosis but negatively correlated with liver synthetic function and liver functional reserve in HBV-related liver disease. Diverse changes in serum FGF19 may be used as a predictive marker for the progression of HBV-related liver disease. In addition, serum FGF19 has a potential role in monitoring carcinogenesis in patients with HBV-related liver disease.

Chloride intercellular channel 3 suppression‐mediated macrophage polarization: a potential indicator of poor prognosis of hepatitis B virus‐related acute‐on‐chronic liver failure

Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are important mediators of immune responses can be subclassified into two main phenotypes: classically activated and alternatively activated. However, few studies have investigated changes to macrophage polarization in HBV-related liver diseases. Therefore, we investigated the functional status of monocyte-derived macrophages (MDMs) from patients with mild chronic hepatitis B (n = 226), HBV-related compensated cirrhosis (n = 36), HBV-related decompensated cirrhosis (n = 40), HBV-ACLF (n = 62) and healthy controls (n = 10), as well as Kupffer cells (KCs) from patients with HBV-ACLF (n = 3). We found that during the progression of HBV-related liver diseases, the percentage of CD163+ CD206+ macrophages increased, while the percentage of CD80+ human leukocyte antigen-DR+ macrophages decreased significantly. MDMs and KCs mainly exhibited high CD163+ CD206+ expression in patients with HBV-ACLF, which predicted poor clinical outcome and higher liver transplantation rate. Transcriptome sequencing analysis revealed that chloride intracellular channel-3 (CLIC3) was reduced in patients with HBV-ACLF, indicating a poor prognosis. To further study the effect of CLIC3 on macrophage polarization, human monocytic THP-1 cell-derived macrophages were used. We found that classical and alternative macrophage activation occurred through nuclear factor kappa B (NF-κB) and phosphoinositide 3-kinase/protein kinase B pathways, respectively. CLIC3 suppression inhibited NF-κB activation and promoted the alternative activation. In conclusion, macrophage polarization gradually changed from classically activated to alternatively activated as HBV-related liver diseases progressed. Both CLIC3 suppression and increased alternatively activated macrophage percentage were potential indicators of the poor prognosis of patients with HBV-ACLF.

Comparative analysis of HBV basic core promoter/pre-core gene mutations and viral quasispecies diversity in HIV/HBV co-infected and HBV mono-infected patients.

Human immunodeficiency virus (HIV)/hepatitis B virus (HBV) co-infection accelerates the progression of HBV-related liver diseases. HBV basic core promoter (BCP)/pre-core (preC) gene mutations may be one of the most important risk factors. In this study, atotal of 230 patients were recruited, and 199 patients whose HBV BCP/preC gene were successfully amplified and sequenced, including 99 HIV/HBV co-infected and 100 HBV mono-infected patients. Next-generation sequencing was used for detection of BCP/preC mutations which were then compared in patients with different HBV genotypes and different HBeAg statuses, and 1% and 20% cutoff values were defined to evaluate the mutations. HBV quasispecies diversity was also compared in HIV/HBV co-infected and HBV mono-infected patients. Among the patients infected with HBV genotype C and HBeAg-negative status, the frequency of A1762T/G1764A double mutations was significantly lower in HIV/HBV co-infected patients than in HBV mono-infected patients (53.3% vs. 100.0%, P = 0.008) regardless of the 1% or 20% cutoff value level. However, A1762T/G1764A double mutations did not differ in the other groups (P >0.05). Viral quasispecies diversity was lower in HIV/HBV co-infected patients than in HBV mono-infected patients (P Keywords: human immunodeficiency virus, hepatitis B virus; mutations; viral quasispecies; next-generation sequencing.

Fecal Microbiota Transplantation Slows the Progression of HBV-Related Liver Diseases and Induces Virologic Response in Patients with HBV Infection

Aims: Healthy gut microbiome plays a crucial role in the treatment of Hepatitis B Virus (HBV) infection and chronic liver disease. Based on existing studies, we aimed to explore the difference in the efficacy of Fecal Microbiota Transplantation (FMT) in patients with different stages of HBV-related chronic liver disease. Methods: In this study, 10 HBV patients with HBeAg-negative infection, 8 patients with Chronic Hepatitis B (CHB) infection, and 8 patients with hepatitis B cirrhosis Child-Pugh score A, 9 patients with hepatitis B cirrhosis Child-Pugh score B/C were treated with FMT. Results: Our results demonstrated that continuous FMT treatment improved liver function, controlled the replication of HBV-DNA, enhanced the intestinal mucosal barrier function, relieve the degree of liver fibrosis and postponed the progression of HBV-related chronic liver disease. The result of 16S ribosomal RNA (rRNA) sequencing indicated that the individual genus and composition of the bacteria in the feces of patients gradually approached the structure seen in case of the feces of healthy donors; the number of specific Operational Taxonomic Units (OTUs) in the stool samples of patients gradually decreased. Conclusion: Our study further confirmed that FMT could be a novel and effective treatment strategy for patients with chronic HBV infection.

Featured Gut Microbiomes Associated With the Progression of Chronic Hepatitis B Disease.

Dysbiosis of gut microbiota during the progression of HBV-related liver disease is not well understood, as there are very few reports that discuss the featured bacterial taxa in different stages. The aim of this study was to reveal the featured bacterial species whose abundances are directly associated with HBV disease progression, that is, progression from healthy subjects to, chronic HBV infection, chronic hepatitis B to liver cirrhosis. Approximately 400 fecal samples were collected, and 97 samples were subjected to 16S rRNA gene sequencing after age and BMI matching. Compared with the healthy individuals, significant gut microbiota alterations were associated with the progression of liver disease. LEfSe results showed that the HBV infected patients had higher Fusobacteria, Veillonella, and Haemophilus abundance while the healthy individuals had higher levels of Prevotella and Phascolarctobacterium. Indicator analysis revealed that 57 OTUs changed as the disease progressed, and their combination produced an AUC value of 90% (95% CI: 86–94%) between the LC and non-LC groups. In addition, the abundances of OTU51 (Dialister succinatiphilus) and OTU50 (Alistipes onderdonkii) decreased as the disease progressed, and these results were further verified by qPCR. The LC patients had the higher bacterial network complexity, which was accompanied with a lower abundance of potential beneficial bacterial taxa, such as Dialister and Alistipes, while they had a higher abundance of pathogenic species within Actinobacteria. The compositional and network changes in the gut microbiota in varied CHB stages, suggest the potential contributions of gut microbiota in CHB disease progression.

Soluble fibrinogen-like protein 2 levels in patients with hepatitis B virus-related liver diseases

BackgroundClinical progression of HBV-related liver diseases is largely associated with the activity of HBV-specific T cells. Soluble fibrinogen-like protein 2 (sFGL2), mainly secreted by T cells, is an important effector molecule of the immune system.MethodssFGL2 levels were determined by ELISA assays in sera of 296 HBV patients clinically classified into the subgroups of acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC) and patients with LC plus HCC. As control group, 158 healthy individuals were included. FGL2 mRNA was quantified by qRT-PCR in 32 pairs of tumor and adjacent non-tumor liver tissues.ResultssFGL2 levels were elevated in HBV patients compared to healthy controls (P < 0.0001). In the patient group, sFGL2 levels were increased in AHB compared to CHB patients (P = 0.017). sFGL2 levels were higher in LC patients compared to those without LC (P = 0.006) and were increased according to the development of cirrhosis as staged by Child-Pugh scores (P = 0.024). Similarly, HCC patients had increased sFGL2 levels compared to CHB patients (P = 0.033) and FGL2 mRNA was up-regulated in tumor tissues compared to adjacent non-tumor tissues (P = 0.043). In addition, sFGL2 levels were positively correlated with HBV-DNA loads and AST (Spearman’s rho = 0.21, 0.25 and P = 0.006, 0.023, respectively), but reversely correlated with platelet counts and albumin levels (Spearman’s rho = − 0.27, − 0.24 and P = 0.014, 0.033, respectively).ConclusionssFGL2 levels are induced by HBV infection and correlated with the progression and clinical outcome of HBV-related liver diseases. Thus, sFGL2 may serve as a potential indicator for HBV-related liver diseases.

Role of Functional IFNL4, IFNLR1, IFNA, IFNAR2 Polymorphisms in Hepatitis B virus-related liver disease in Han Chinese population.

Recent studies show that variants in some interferon genes together with interferon receptor genes are associated with the outcome of infectious diseases. We examined the association between the risk of hepatitis B virus (HBV)-related liver disease and the functional polymorphisms within IFNL4, IFNLR1, IFNA1, IFNA2, IFNA5 and IFNAR2 genes (14 loci in all) in a Han Chinese population. A total of 3128 people participated and were divided into 5 groups: healthy controls, natural clearance, chronic hepatitis B(CHB), liver cirrhosis and hepatocellular carcinoma (HCC). Significant associations were observed for 4 variants in IFNAR2, IFNLR1 with HBV infection, and IFNLR1-rs4649203 was associated with HBV recovery. Moreover, we demonstrated the clear relevance of 5 polymorphisms in IFNA1, IFNA2, IFNL4 with HCC. Three SNPs in IFNL4 gene may be important susceptible factors for the progression of HBV-related liver disease by trend chi-square test. The IFNL4 haplotype conformed by rs12971396_G, rs8113007_T and rs7248668A was more frequent in HCC than CHB and LC group. Three polymorphisms in the 5' region of the IFNL4 gene are associated with the progression of HBV-related liver disease. IFNA1- rs1831583 and IFNA2- rs649053 are associated with the development of HCC. IFNLR1- rs4649203, rs7525481 are predictors for HBV infection, and rs4649203 is a predictor of spontaneous clearance. IFNAR2 -rs1051393, rs12233338 may be predictive markers of HBV infection in the Chinese population.

Interferon-stimulated gene 15 in hepatitis B-related liver diseases

This study investigates the association of Interferon-stimulated gene 15 (ISG15) polymorphisms, ISG15 serum levels and expression with HBV-related liver diseases. The ISG15 promoter and the two exons of the gene were screened for polymorphisms in 766 HBV-infected patients and in 223 controls. Soluble ISG15 levels were measured by ELISA. ISG15 mRNA expression was quantified by qRT-PCR in 36 tumor and adjacent non-tumor tissues. The exon 2 allele rs1921A was found associated with decreased progression of HBV-related liver diseases (LC vs. CHB: OR = 0.6, 95%CI = 0.4-0.8, adjusted P = 0.003; HCC vs. CHB: OR = 0.6, 95%CI = 0.4-0.9, adjusted P = 0.005). The rs1921AA genotype was associated with low levels of AST, ALT and total bilirubin, but with high prothrombin levels (P < 0.05). ISG15 serum levels were higher among HBV patients compared to controls (P < 0.0001) and positively associated with HBV-related liver diseases, with highest levels among LC patients. ISG15 levels were correlated with HBV-DNA loads (P = 0.001). In non-tumor tissues from HCC patients, ISG15 mRNA expression was increased in HBV compared to non-HBV infection (P = 0.016). The ISG15 rs1921 variant and ISG15 expression are associated with HBV-related liver diseases. Taken together, ISG15 appears to be a proviral factor involved in HBV replication and triggering progression of HBV-related liver diseases.

Genetic variants of mannose-binding lectin 2 gene influence progression and prognosis of patients with hepatitis B virus infection in China

Mannose-binding lectin (MBL) is a member of the calcium-dependent collectin family involved in the innate immune system that mediates phagocytosis and activates complement by binding to carbohydrate motifs. We studied allele and haplotype frequencies of -221C/G and codon 54G/A in MBL2 gene to reveal their relationship with the developing and progression of hepatitis B virus (HBV)-related liver diseases. This study was performed in 171 healthy controls, 133 chronic hepatitis B (CHB) patients, 97 patients with HBV-related liver cirrhosis (LC) and 334 HBV-related hepatocellular carcinoma (HCC) patients. The genotypes of these two polymorphisms in these subjects were detected using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. Stratification analyses by clinical characteristics and survival analysis of HCC patients were also performed according to their genotypes. The genotype and allele frequencies at codon 54 manifested a significant difference between healthy controls and patients with progressive HBV-related liver diseases, especially liver cirrhosis. Allele A appeared to have protective effect from developing LC and HCC compared with G allele. The percentages of the patients with G allele at -221C/G increased in HBV-related disease groups. When combined together as a haplotype, lower haplotype AC frequency was associated with a decreased risk for the progression of HBV-related liver diseases and HCC developing. Furthermore, HCC patients with G allele at codon 54 showed to have better survival than those with A allele. These results indicated that polymorphisms in MBL2 gene may influence susceptibility, progression and prognosis of HBV-related liver diseases.

FRI-245 - Functional Variants and Aberrant Methylation in the SOCS3 Promoter Region Influence the Progression of HBV-Related Liver Diseases

FRI-245 - Functional Variants and Aberrant Methylation in the SOCS3 Promoter Region Influence the Progression of HBV-Related Liver Diseases

Hepatitis E Virus Superinfection and Clinical Progression in Hepatitis B Patients

Hepatitis E virus (HEV) infection may cause acute hepatitis and lead to hepatic failure in developing and developed countries. We studied HEV seroprevalences in patients with hepatitis B virus (HBV) infection to understand the consequences of HEV superinfection in a Vietnamese population. This cross-sectional study was conducted from 2012 to 2013 and included 1318 Vietnamese patients with HBV-related liver diseases and 340 healthy controls. The case group included patients with acute (n = 26) and chronic hepatitis B (n = 744), liver cirrhosis (n = 160), hepatocellular carcinoma (n = 166) and patients with both liver cirrhosis and hepatocellular carcinoma (n = 222). Anti-HEV IgG and IgM antibodies were assessed in patients and controls by ELISA. HEV-RNA was identified by PCR assays and sequencing. Seroprevalences of anti-HEV IgG among hepatitis B patients and controls were 45% and 31%, respectively (adjusted P = 0.034). Anti-HEV IgM seroprevalences were 11.6% and 4.7% in patients and controls, respectively (adjusted P = 0.005). Seroprevalences were higher among the elder individuals. When stratifying for patient groups, those with liver cirrhosis had the highest anti-HEV IgG (52%) and anti-HEV IgM (19%) seroprevalences. Hepatitis B patients with current HEV infection had abnormal liver function tests compared to patients with past or without HEV infection. One HEV isolate was retrieved from a patient with both liver cirrhosis and hepatocellular carcinoma and identified as HEV genotype 3. This study indicates high prevalences of HEV infection in Vietnamese HBV patients and among healthy individuals and shows that HEV superinfection may influence the outcome and progression of HBV-related liver disease.

Hepatitis B: 50 years after the discovery of Australia antigen.

It is an honour to be invited to recount the progress in our understanding and management of hepatitis B 50 years after the discovery of Australia antigen (Au Ag). During this half century, we have gone from identifying the causative agent--hepatitis B virus (HBV), understanding its biology and the disease it causes, to having vaccines that can prevent HBV infection and antiviral therapy that can suppress HBV replication and prevent progression of HBV-related liver disease. As a result of the progress, prevalence of HBV infection and morbidity and mortality from chronic HBV infection has declined.

Soluble MICB protein levels and platelet counts during hepatitis B virus infection and response to hepatocellular carcinoma treatment.

BackgroundThe human major histocompatibility complex class I polypeptide-related sequence B (MICB) is a protein that modulates the NK and T cell activation through the NKG2D receptor and is related to several diseases including cancer.MethodsThe study investigated the prognostic role of soluble MICB (sMICB) protein in the progression of HBV-related liver diseases and to HBV-related HCC treatment. The sMICB serum levels were measured in 266 chronic HBV-infected Vietnamese patients and in healthy controls, and correlated with clinical and laboratory parameters and with therapeutic interventions for HBV-related HCC.ResultsSignificant differences in both clinical and laboratory parameters were observed among the patient groups with different stages of hepatitis. The platelet counts were significantly decreased with disease progression (P < 0.001). The sMICB serum levels were significantly increased in HBV patients compared to healthy controls (P < 0.0001). Among the patients with different stages of hepatitis, asymptomatic individuals (ASYM) revealed higher sMICB serum levels while liver cirrhosis (LC) patients revealed lower sMICB serum levels (P < 0.0001) compared to other patient groups. Notably, the sMICB serum levels were decreased in treated HCC patient group compared to not-treated HCC patient group (P = 0.05). Additionally, the sMICB levels were significantly correlated with platelet counts in ASYM and HCC patients (r = −0.37, P = 0.009; and r = 0.22, P = 0.025, respectively).ConclusionsOur results demonstrate a potential role of sMICB serum levels and platelet counts during immune response to the HBV infection, liver disease progression and response to the HCC treatment.

Efficacy and safety of long-term therapy with Entecavir (ETV) or Tenofovir (TDF) in patients with HBV-related cirrhosis

Background: In virological suppressed patients the goal of therapy is the prevention of liver disease progression, hepatic decompensation, HCC development and need for OLT. Aims: To assess the impact of long-term ETV or TDF therapy on the progression of HBV-related liver disease and verify the safety profile in cirrhotic patients. Patients and methods: 48 patients with HBV-related liver cirrhosis Child A, HBeAg-negative, treated with ETV (25 patients) or TDF (23 patients) for a median of 34 months (range 1–78) were enrolled. Nine patients had HBV/HDV coinfection. The patients were subjected to periodicmonitoring of liver and kidney function, and surveillance forHCC. At the time of therapy initiation and every 2–3 years, patients performed esophagogastroduodenoscopy. In TDF patients, bone densitometry was performed at baseline and after 2 years. Results: All patients had virological response after 12 months of treatment. No patient had ascitic decompensation, except 3 HDV-positive patients. At baseline, in the TDF group, 9 patients had esophageal varices (6 = F1, F2 =2, F3 =1); at the end of FU, 5 remained stable, 2 improved and 2 worsened. In the ETV group, 3 patients had esophageal varices F1 that remained stable. At the time of TDF therapy initiation, 5 patients already had a HCC. During FU, 4/5 patients recurred and 3 of these died for HCC. A new diagnosis of HCC was reported in 6 cases (4 TDF, 2 ETV). ETV or TDF therapy was well tolerated, only 1 patient showed reduction eGFR <50ml/min and reduced TDF dose. After at least 2 years of therapy, 19/23 TDF patients repeated MOC, which remained stable in 13 cases, worsened in 3 and improved in 3 cases. Conclusions: Antiviral treatment has a favorable impact on the natural history of HBV-related cirrhosis,while not reducing the risk of HCC.

Role of IFN-ks, IFN-ks related genes and the DEPDC5 gene in Hepatitis B virus-related liver disease.

Recent studies have associated genetic variation near the interleukin 28B (IL28B/IFN-λ3) gene with natural clearance of the hepatitis C virus (HCV) infection, and a common variant in the DEP domain containing 5 (DEPDC5) locus on chromosome 22 has been shown to affect susceptibility to hepatocellular carcinoma (HCC) in Japanese individuals with chronic HCV infection. This study was conducted to determine whether polymorphisms near or in interferon-lambda (IFN-λs) genes and their receptor genes such as interleukin 28 receptor, alpha (IL28RA) and interleukin 10 receptor, beta (IL10RB) as well as p21-activated kinases 4 (PAK4) and iron/zinc purple acid phosphatase-like protein (PAPL), which are locate upstream of IFN-λs, and lastly the DEPDC5 gene are associated with hepatitis B virus-related liver disease in Han Chinese. The study subjects included 507 normal healthy controls, 350 individuals with natural clearance of HBV and 792 HBV-infected patients. The patients were categorized into 157 inactive carriers (Case I), 216 active carriers (Case II), 111 cirrhotics (Case III) and 308 HCC patients (Case IV) subgroups. Seven single nucleotide polymorphisms (SNPs) were genotyped using the Matrix-assisted Laser Desorption/Ionisation mass spectrometric (MALDI-TOF MS) SNP genotyping assay. Rs423058 upstream of PAPL, rs2834167 in IL10RB and rs1012068 in DEPDC5 were associated with chronic HBV status, HBV natural clearance and the presence of HCC (P = 0.0004–0.024), respectively. PAPL, IL10RB and DEPDC5 polymorphisms have an impact on progression of HBV-related liver disease. However, IFN-λs genes as a tool to differentiate between different clinical courses of HBV infection were not useful in the Han Chinese population.

Molecular characteristics and stages of chronic hepatitis B virus infection

Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Remarkable progress has been made in our understanding of the natural stages of chronic HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. Knowledge of the HBV genome organization and replication cycle can unravel HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. Most HBV infections are spontaneously resolved in immunocompetent adults, whereas they become chronic in most neonates and infants at a great risk of developing complications such as cirrhosis and hepatocellular carcinoma (HCC). Those with chronic HBV infection may present in one of the four phases of infection: immune tolerance, immune clearance [hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB)], inactive carrier state, and reactivation (HBeAg-negative CHB). Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers. Long-term monitoring and optimal timing of antiviral therapy for chronic HBV infection help to prevent progression of HBV-related liver disease to its later stage, particularly in patients with higher risk markers of HCC, such as serum DNA concentration, HBeAg status, serum aminotransferase, HBV genotypes, and pre-core or core mutants.