Chronic Hepatitis B Liver Research Articles

Efficacy and safety of Fufang Biejia Ruangan Tablets as an adjuvant treatment for chronic hepatitis B liver fibrosis: A systematic review and meta-analysis.

Meta-analysis was used to evaluate the efficacy of Fufang Biejia Ruangan Tablets in the treatment of chronic hepatitis B (CHB) liver fibrosis. Databases, including PubMed, China Knowledge Network (CNKI), China Biomedical Database (CBM), Wan Fang, VIP database, Embase, and Cochrane Library were searched. The time was searched up to May 2022. The participant intervention comparator outcomes of this study were as follows: P, patients with CHB liver fibrosis; I, Fufang Biejia Ruangan Tablets; C, pharmacological placebo; O, the efficacy rate, alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), procollagen III protein (PIIIP), hyaluronic acid (HA), laminin (LN), collagen C type IV (IV-C), portal vein diameter, spleen thickness and HBV-DNA negative conversion rate. The Cochrane Risk of Bias tool, Begg's test and Egger's test were used to evaluate the methodological quality of eligible studies. A randomized controlled trial of Fufang Biejia Ruangan Tablets was used to treat CHB liver fibrosis. Three reviewers independently selected trials, extracted data, cross-checked, and performed methodological quality assessments. Data analysis was completed by Review Manager 5.3. Twenty-six studies with 2717 patients were included in the meta-analysis. The meta-analysis showed that Fufang Biejia Ruangan Tablets was effective by increasing the efficacy. Fufang Biejia Ruangan Tablets was more efficient in improving ALT, AST, TBIL, ALB, PIIIP, HA, LN, IV-C, portal vein diameter, spleen thickness, and HBV-DNA negative conversion rate with no serious adverse reactions. It was shown that Fufang Biejia Ruangan Tablets can effectively improve liver function and relieve liver fibrosis, but future research should focus on rigorously designed, multicenter, and large randomized controlled trials.

Clinical Significance and Properties of IFN-γ+IL-17+ Th17 Cells in Liver Injury Associated with Chronic Hepatitis B Virus Infection

Introduction: Our previous study demonstrated that intrahepatic Th17 cells exacerbated the progression of chronic hepatitis B virus (HBV) infection. Meanwhile, we found a small group of IFN-γ and IL-17 double-positive Th17 cells (IFN-γ⁺IL-17⁺ Th17 cells) in liver tissues. This study aimed to investigate the clinical significance and properties of IFN-γ⁺IL-17⁺ Th17 cells in liver injury associated with chronic HBV infection. Methods: The frequencies of CD4⁺ Th cells, Tregs, and CD4⁺ T cells expressing specific chemokine receptors in the blood and liver tissues were detected using flow cytometry. The chemotaxis of C C chemokine receptor 5 (CCR5) and C-X-C chemokine receptor 3 (CXCR3) toward IFN-γ⁺IL-17⁺ Th17 cells and Tregs was evaluated by transwell chemotactic assay. Analyses of different variables were performed using GraphPad Prism v 5.01 and IBM SPSS Statistics 23.0. HBV-specific IFN-γ⁺IL-17⁺ Th17 cells were investigated using a cell stimulation assay with HBV antigens in vitro. Results: The frequencies of IFN-γ⁺IL-17⁺ Th17, Th17 cells, and Tregs in the blood were increased from normal controls to chronic hepatitis B (CHB) and acute-on-chronic liver failure (ACLF). The same trend could also be observed in CHB liver tissues compared to those in CHB blood specimens. Furthermore, the frequencies of IFN-γ⁺IL-17⁺ Th17 cells were positively associated with Th17 cells, Th17 cell-related cytokines (IL-17 and IL-6), HBV DNA load, and the levels of HBsAg, HBeAg, and ALT. The ratios of IFN-γ⁺IL-17⁺ Th17 cells to Tregs extremely decreased in ACLF blood specimens compared with those in CHB blood specimens. Additionally, CCR5 and CXCR3 were conducive to the recruitment of IFN-γ⁺IL-17⁺ Th17 cells and Tregs to liver tissue. Conclusions: IFN-γ⁺IL-17⁺ Th17 cells have Th17 cell-like properties in the progression of chronic HBV infection. CCR5 and CXCR3 facilitated the recruitment of IFN-γ⁺IL-17⁺ Th17 cells and Tregs to the liver. Importantly, the ratio of IFN-γ⁺IL-17⁺ Th17 cells to Tregs might be an effective assessment indicator of the severity of liver injury.

SIX1/EYA1 are novel liver damage biomarkers in chronic hepatitis B and other liver diseases.

BackgroundThis study aimed to investigate the clinicopathological significance of sine oculis homeobox homolog 1 (SIX1) and eyes absent 1 (EYA1) in patients with chronic hepatitis B (CHB) and other liver diseases.MethodsSIX1 and EYA1 levels were detected in human serum and liver tissues by enzyme linked immunosorbent assay (ELISA) and immunofluorescent staining method, respectively.ResultsThe serum SIX1 and EYA1 levels in 313 CHB patients were 7.24±0.11 and 25.21±0.51 ng/mL, respectively, and these values were significantly higher than those in 33 healthy controls (2.84±0.15 and 13.11±1.01 ng/mL, respectively; P<0.05). Serum SIX1 and EYA1 levels were also markedly increased in patients with numerous other liver diseases, including liver fibrosis, hepatocellular carcinoma, fatty liver disease, alcoholic liver disease, fulminant hepatic failure, autoimmune liver disease, and hepatitis C, compared to the healthy controls (P<0.05). Dynamic observation of these proteins over time in 35 selected CHB patients revealed that SIX1 and EYA1 serum levels increased over an interval. Immunofluorescent staining revealed that both SIX1 and EYA1 were only expressed in hepatic stellate cells (HSCs), and their increased expression was evident in CHB liver tissue.ConclusionsSIX1 and EYA1 are novel biomarkers of liver damage in patients of CHB and other liver diseases, with potential clinical utility.

Systematic review and Meta-analysis of efficacy and safety of Compound Glycyrrhizin Injection in improving chronic hepatitis B liver damage

To evaluate the efficacy and safety of Compound Glycyrrhizin Injection(CGI) in improving liver damage in chronic hepatitis B(CHB). PubMed, Web of Science, SinoMed, CNKI, Wanfang and VIP databases were retrieved from their inception to February 10, 2020. The randomized controlled trial(RCT) of CGI in the treatment of CHB was included. Data were independently extracted by two authors, and the methodological quality was evaluated using the Cochrane bias risk assessment tool by other two authors. Statistical analysis was performed using RevMan 5.3 software. A total of 18 two-armed RCTs were included, involving 1 915 participants. The methodological quality of all studies included was generally low. In the comparison between CGI and diammonium glycyrrhizinate, the results showed that CGI was superior to the control group in improving the overall clinical effectiveness, but there was no statistical difference between the two groups in increasing ALT normalization rate, reducing ALT and AST level. In the comparison between CGI and diammonium glycyrrhizinate+other general hepatoprotective drugs, the results showed that CGI was superior to the control group in reducing AST level, while there was no statistical difference between the two groups in reducing ALT level and increasing overall clinical effectiveness. In the comparison between CGI+other commonly used drugs(including energy mixture, glutathione, vitamins, potassium magnesium aspartate) and diammonium glycyrrhizinate+other commonly used drugs, the results showed that CGI combined with other commonly used drugs was better than the control group in reducing ALT and AST level and improving the clinical total effective rate, and there was no statistical difference between the two groups in increasing the rate of ALT normalization. In the comparison between CGI+other commonly used drugs and other commonly used drugs, the results showed that CGI combined with other commonly used drugs was superior to the control group in reducing ALT and AST level and improving the overall clinical effectiveness. In the comparison between CGI+vitamins and diammonium glycyrrhizinate+potassium magnesium aspartate+vitamins, the results showed no statistical difference between the two groups in reducing AST level. A small number of studies included reported that CGI caused mild adverse reactions when used alone or in combination with other drugs. Based on the results, CGI has a certain effect in improving CHB liver damage, but the evidence is not enough to prove that CGI would cause serious adverse events. In the future, more well-designed and strictly-enforced RCT with an adequate sample size are needed to further evaluate the effect CGI in alleviating CHB liver damage.

Chronic hepatitis B: The interplay between intrahepatic lymphocyte population and viral antigens in relation to liver damage.

In Chronic hepatitis B (CHB) infection, virus and immune response interplay is thought to be responsible for pathogenesis. Yet, the impact of each immune cell population and viral protein expression in liver damage is still unknown. Our aim was to study the interplay between intrahepatic immune response and viral activity in relation to CHB liver damage. Immunostaining was performed in 29 liver biopsies from untreated CHB patients to characterize liver infiltrate [Th (CD4+), CTL (CD8+), Treg (FoxP3+), Th17 (IL-17A+) and Th1 (T-bet+)] and viral antigen expression (HBsAg and HBcAg). Inflammatory activity and fibrosis were assessed using the HAI and METAVIR scoring system. All studied populations were identified in the portal-periportal (P-P) areas with a CD4+ lymphocyte predominance, while only CD8+ and FoxP3+ cells were observed in the intralobular area. Both P-P CD4+ and intralobular CD8+ cell frequencies were increased among severe hepatitis cases. Concerning HBsAg and HBcAg expression, a mutually exclusive pattern was observed. HBcAg was mainly detected among HBeAg-positive patients and was associated with hepatitis severity and higher frequency of P-P FoxP3+, intralobular CD8+ and FoxP3+ cells. HBsAg was identified among HBeAg-negative cases with less severe hepatitis grade and lower frequency of P-P CD4+ and intralobular FoxP3+ lymphocytes. In conclusion, the HBV antigen profile expression seen during CHB infection may be reflecting different stages of viral replication which impacts the host immune response and liver damage process. While HBcAg might be an inducer of a regulatory microenvironment, the intralobular CTL population seemed to have a key role in hepatitis severity.

Clinical significance of decoy receptor 3 upregulation in patients with hepatitis B and liver fibrosis.

Decoy receptor 3 (DcR3) is a tumor necrosis factor receptor, which may inhibit apoptosis. The aim of the present study was to investigate the clinical significance of DcR3 upregulation in patients with chronic hepatitis B (CHB) and hepatic fibrosis. A total of 128 patients with a clinical diagnosis of CHB who underwent liver biopsy were included in the present study. The expression levels of DcR3, hyaluronic acid (HA), type III procollagen, type IV collagen (IV-C) and laminin protein were assessed. The diagnostic value of DcR3 in patients with CHB with hepatic fibrosis was determined using receiver operating characteristic (ROC) curve analysis. DcR3 was significantly upregulated in patients with CHB, particularly in patients with active CHB. The expression of DcR3 was significantly increased in patients with CHB with liver fibrosis and liver cirrhosis, compared with patients with CHB without liver fibrosis. The area under the ROC curve for the diagnosis of CHB liver fibrosis based on DcR3 or DcR3 combined with IV-C/HA was 0.807 or 0.869, with a sensitivity and specificity of 76.9 and 77.8% or 84.6 and 81.2%, respectively. DcR3 is a marker for liver fibrosis in patients with hepatitis B infection. The use of DcR3 in combination with IV-C and HA may further increase its diagnostic value for liver fibrosis.

Diagnostic value of γ-glutamyl transpeptidase-to-platelet ratio index for hepatic fibrosis in patients with chronic hepatitis B

Objective To compare the diagnostic values of γ-glutamyl transpeptidase-to-platelet ratio index (GPRI), aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on the four factors (Fib-4) for chronic hepatitis B(CHB) fibrosis and cirrhosis. Methods According to the Metavir score, 262 CHB patients were divided into F0—F1 group (n=131), F2—F3 group (n=102) and F4 group (n=29). The age, gender, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidas (γ-GT) and platelet count were recorded. GPRI, APRI, Fib-4 scores were calculated separately. Statistical analysis was performed by t test, Kruskal-Wallis H test, and χ2 test. The correlations between serum models and liver fibrosis stages were analyzed using the Spearman test. Results The scores of GPRI in F0—F1 group, F2—F3 group and F4 group were 0.39 (0.21, 0.95), 1.05 (0.38, 2.39) and 2.11 (1.12, 3.33), respectively. The difference was statistically significant (χ2=40.645, P<0.01). APRI scores in the three groups were 0.49 (0.32, 0.97), 0.77 (0.52, 1.52) and 1.12 (0.77, 2.50), respectively. The difference was statistically significant (χ2=32.636, P<0.01). Fib-4 scores in the three groups were 1.36 (0.92, 2.05), 2.34 (1.28, 4.35) and 3.86 (3.03, 8.99), respectively. The difference was statistically significant (χ2=48.943, P<0.01). Age, γ-GT, AST and liver fibrosis were all positively correlated with liver fibrosis (r=0.322, 0.301 and 0.199, respectively, all P<0.05). Platelet was negatively correlated with liver fibrosis (r=—0.455, P<0.05), while ALT was not significantly associated with hepatic fibrosis (r=0.111, P=0.073). GPRI, APRI and Fib-4 were positively correlated with liver fibrosis (r=0.625, 0.417 and 0.399, respectively, all P<0.05). The areas under the operating characteristic curve of GPRI for significant hepatic fibrosis, advanced liver fibrosis and cirrhosis were 0.818, 0.864 and 0.837, respectively. APRI for significant hepatic fibrosis, advanced liver fibrosis and cirrhosis were 0.694, 0.766 and 0.722, respectively, while Fib-4 were 0.696, 0.770 and 0.724, respectively. The low cutoff values of GPRI for various stages of liver fibrosis were 0.99, 1.04 and 1.06, respectively, and the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were all higher than those of APRI and Fib-4. The high cutoff values of GPRI for liver fibrosis at each stage were 2.49, 3.69 and 6.77, respectively, and the sensitivity, specificity, PPV and NPV of the diagnosis were all higher than those of APRI and Fib-4. Conclusion The diagnostic value of GPRI for CHB liver fibrosis is higher than those of APRI and Fib-4. Key words: Hepatitis B, chronic; Liver fibrosis; γ-glutamyl transpeptidase; Platelets; Prognosis

Development and validation of a model for staging hepatic fibrosis for chronic hepatitis B patients with E antigen-positive.

BackgroundInterest is growing in the use of non-invasive techniques for complementing liver biopsy for liver fibrosis assessment. We aimed to prospectively evaluate liver histology in chronic hepatitis B (CHB) patients with e-antigen positivity, and develop and validate a novel scoring system—e-antigen-positive CHB liver fibrosis (EPLF) score—for noninvasively predicting the fibrosis stages.MethodsWe identified the baseline variables associated with fibrosis stage (MATAVIR score, F0–F4) in 212 CHB patients with e-antigen positivity. These significant variables were used to develop the EPLF scoring system. The EPLF score equation was developed based on the prediction of fibrosis stages via multivariate ordered logistic regression analysis. The diagnostic powers of the EPLF score and several non-invasive markers were assessed through an area under the receiver operating characteristic curve (AUROC) analyses. This EPLF score model was validated in another set of 208 similar patients.ResultsThe natural logarithms of serum albumin, HBeAg, and HBsAg levels were selected as significant independent variables for the EPLF score equation. The EPLF score had good diagnostic power (AUROC, 0.72–0.90, p<0.001) and good diagnostic accuracy (72–85%), with a high positive predictive value (80.8–92.8%) for each fibrosis stage in the test group. Similar results were observed in the validation group (AUROC, 0.73–0.89, p<0.001). The EPLF score exhibited a strong correlation with fibrosis stage (r=0.67, p<0.001), and was the preferable non-invasive marker for staging liver fibrosis.ConclusionIn e-antigen-positive patients with CHB, the EPLF score could serve as a potential non-invasive marker of liver fibrosis stage.

Key elements of the RNAi pathway are regulated by hepatitis B virus replication and HBx acts as a viral suppressor of RNA silencing.

The host-mediated RNAi pathways restrict replication of viruses in plant, invertebrate and vertebrate systems. However, comparatively little is known about the interplay between RNAi and various viral infections in mammalian hosts. We show in the present study that the siRNA-mediated silencing of Drosha, Dicer and Ago2 [argonaute RISC (RNA-induced silencing complex) catalytic component 2] transcripts in Huh7 cells resulted in elevated levels of HBV (hepatitis B virus)-specific RNAs and, conversely, we observed a decrease in mRNA and protein levels of same RNAi components in HepG2 cells infected with HBV. Similar reductions were also detectable in CHB (chronic hepatitis B) patients. Analysis of CHB liver biopsy samples, with high serum HBV DNA load (>log108 IU/ml), revealed a reduced mRNA and protein levels of Drosha, Dicer and Ago2. The low expression levels of key RNAi pathway components in CHB patient samples as well as hepatic cells established a link between HBV replication and RNAi components. The HBV proteins were also examined for RSS (RNA-silencing suppressor) properties. Using GFP-based reversion of silencing assays, in the present study we found that HBx is an RSS protein. Through a series of deletions and substitution mutants, we found that the full-length HBx protein is required for optimum RSS activity. The in vitro dicing assays revealed that the HBx protein inhibited the human Dicer-mediated processing of dsRNAs into siRNAs. Together, our results suggest that the HBx protein might function as RSS to manipulate host RNAi defence, in particular by abrogating the function of Dicer. The present study may have implications in the development of newer strategies to combat HBV infection.

IL‐22 and non‐ELR‐CXC chemokine expression in chronic hepatitis B virus‐infected liver

Hepatitis B virus infection is still a major global health problem, despite decades of research. Interleukin (IL)-22 induces acute phase reactants and chemokines, favors anti-microbial defence and protects tissues from damage. IL-22 is important in chronic skin inflammation, but its role in chronic hepatitis B (CHB) is unclear. This study explores the association between intra-hepatic IL-22 expression, its relevant associated cytokines and the severity of liver inflammation/fibrosis in CHB patients. IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines (CXCL-9, CXCL-10, CXCL-11), fibroblast growth factors and Kupffer cell (KC) numbers were measured in patients with CHB (n=65), acute hepatitis B (AHB; n=4), chronic hepatitis C (CHC; n=14) and non-viral hepatitis (n=23), using immunohistochemistry. Expression of IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines and number of KCs in liver tissues were substantially higher in AHB patients than others. In CHB patients, the expression of IL-22, IL-6, CXCL-9 and CXCL-10 were significantly higher with alanine aminotransferase (ALT) levels ≤ twice the upper limit of normal (ULN), compared with those with ALT levels >twice the ULN, whereas IL-10 and IL-17 showed a reverse pattern. IL-22 was inversely (P<0.01), but IL-17 was positively (P<0.05), correlated with the histological activity index) in these patients, and a significant negative correlation between the fibrosis stage and IL-22 or non-ELR-CXC chemokines was observed. Furthermore, immunofluorescent labeling demonstrated a close spatial association of IL-22, CXCL-9, -10 or -11 in the CHB liver. We speculate that IL-22 and non-ELR-CXC chemokines synergistically may provide protection in liver inflammation/fibrosis during CHB infection.

Hepatocyte apoptosis in the patients with chronic hepatitis B

To investigate the relationship between hepatocyte apoptosis and the level of inducible nitric oxide synthase (iNOS) in hepatic tissue in the patients with chronic hepatitis B(Ct-IB). We observed 37 cases with CHB and 10 normal controls. Transferase-mediated-UTP-biotin nick-end labling (TUNEL) technique was used to detect apoptosis cells and immunohistochemical staining were also performed to investigate the expression of inducible nitric oxide synthase (iNOS) in biopsy samples. The serum level of ALT, HBV DNA, grading of necroinflammatory activity and staging of fibrosis were also assessed. Hepatocytes in all CHB liver tissues were positively stained by TUNEL in various degree. In contrast, control tissues did not show DNA fragmentation. A significant correlation was seen between apoptosis index (AI) and necroinflammatory grading (r = 0.404, P = 0.015) and serum iNOS level (r = 0.465, P = 0.004). It did not correlate with fibrosis stage and serum alanine aminotransferase level. The oxidative stress in patients with CHB may reflected the apoptosis of hepatocyte. Apoptosis involves in liver injury of CHB, but with no significant correlation to serum level of ALT.