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Objective To investigate the ability of combined baseline serum markers, i.e., HBV DNA, HBV RNA, HBsAg, and HBcrAg, to predict HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B (CHB) treated by nucleos(t)ide analogues. Methods A retrospective analysis was performed for 83 HBeAg-positive patients selected as subjects from the prospective CHB follow-up cohort established by Difficult & Complicated Liver Diseases and Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, from June 2007 to July 2008, and the baseline serum levels of HBV DNA, HBV RNA, HBsAg, and HBcrAg were analyzed. The t -test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The Spearman method was used for correlation analysis. A Cox regression model was established to calculate HBeAg seroconversion prediction score, and the time-dependent receiver operating characteristic curve was used to evaluate the ability of combined markers in predicting HBeAg seroconversion. The Kaplan-Meier method was used to calculate cumulative seroconversion rate in each group, and the Log-rank test was used for comparison between groups. Results For the 83 HBeAg-positive patients, the median follow-up time was 108 months, and 44.58%(37/83) of these patients achieved HBeAg seroconversion. Compared with the non-seroconversion group, the HBeAg seroconversion group had significantly lower baseline serum levels of HBV DNA [6.23(1.99-9.28) log 10 IU/mL vs 7.69(2.05-8.96) log 10 IU/mL, Z =-2.345, P =0.019] and HBV RNA [4.81(1.40-7.53) log 10 copies/mL vs 6.22(2.00-8.49) log 10 copies/mL, Z =-1.702, P =0.010], and there were no significant differences in the levels of HBsAg and HBcrAg between the two groups ( P > 0.05). The Cox regression equation constructed based on the above serum markers showed a median score of 0.95(range 0.37-3.45) for predicting HBeAg seroconversion. In the total population, the combined score was negatively correlated with HBsAg, HBV DNA, HBV RNA, and HBcrAg ( r =-0.697, -0.787, -0.990, and -0.819, all P < 0.001). Based on the median prediction score, the patients were divided into high HBeAg seroconversion group and low HBeAg seroconversion group; as for the prediction of HBeAg seroconversion rate at 36, 60, and 84 months, the high HBeAg seroconversion group had a seroconversion rate of 43.90%, 51.20%, and 63.10%, respectively, while the low HBeAg seroconversion group had a seroconversion rate of 9.60%, 17.00%, and 19.8%, respectively, and there was a significant difference between the two groups ( χ 2 =11.6, P < 0.001). Conclusion The combined prediction score based on baseline serum HBV markers can predict HBeAg seroconversion in CHB patients treated by nucleos(t)ide analogues.
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Chronic hepatitis B virus (HBV) infection is a major cause of viral hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). From chronic HBV infection to HCC, most patients go through the stages of chronic hepatitis, liver cirrhosis, and HCC. During this long process, the ongoing integration of HBV DNA into host DNA increases the risk of HCC, and the death and compensatory proliferation of hepatocytes caused by persistent liver inflammation may promote the accumulation of oncogenic mutations and finally lead to the malignant transformation of hepatocytes. Currently, nucleos(t)ide analogues are widely used anti-HBV drugs, which controls infection by inhibiting HBV replication and can thus effectively slow down disease progression and end-stage liver disease; however, anti-HBV therapy often starts late and has a relatively low treatment rate, and there is still a tendency of increase in the incidence rate of HBV-related HCC. Therefore, how to improve current antiviral strategies to further reduce the risk of HBV-related end-stage liver disease including HCC has become a hotspot in clinical practice. This article summarizes the previous studies supporting the expansion of antiviral therapy and suggests that antiviral therapy should be initiated as early as possible to inhibit viral replication and the sequential events of HBV DNA integration and ultimately reduce the risk of HCC in patients with chronic HBV infection.
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Objective To investigate the effect of cyclin D1 (with CCND1 as the gene name) on HBV replication and its potential mechanism. Methods With reference to GSE84044 dataset, the Spearman's rank correlation analysis was used to investigate the correlation between the expression levels of genes in liver tissue and serum HBV DNA load in patients with HBV-related liver fibrosis. Cyclin D1 and cyclin D1 T286A mutant were transiently expressed in the HBV cell replication model, and time-resolved immunofluorescence and quantitative real-time PCR were used to measure the levels of HBsAg/HBeAg and HBV DNA in cell culture supernatant; Western blot was used to measure the level of HBV core protein in cells; reverse-transcription quantitative real-time PCR was used to measure the level of HBV RNA in cells; dual-luciferase reporter assay was used to observe the effect of cyclin D1 on the activity of HBV basic core promoter (BCP). GSE83148 dataset was used to investigate the correlation between CCND1 and HBV-related regulatory factors. The independent samples t -test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. Results The analysis of GSE84044 data showed that 7 cell cycle genes were significantly negatively correlated with HBV DNA load in liver tissue of the patients with HBV-related liver fibrosis (all r < -0.3, all P < 0.05), which included the CCND1 gene ( r =-0.474, P < 0.001). Exogenous expression of cyclin D1 and cyclin D1 T286A mutant reduced the levels of HBsAg, HBeAg, and HBV DNA in culture supernatant of the HBV replication cell model, as well as the levels of HBV core protein and HBV RNA in cells. Exogenous expression of cyclin D1 significantly inhibited the transcriptional activity of HBV BCP. The expression level of CCND1 in liver tissue of chronic hepatitis B patients was significantly positively correlated with the expression of APOBEC3G ( r =0.575, P < 0.001), SMC5 ( r =0.341, P < 0.001), and FOXM1 ( r =0.333, P < 0.001) which inhibited HBV replication, while it was significantly negatively correlated with the expression of the HBV entry receptor NTCP ( r =-0.511, P < 0.001) and HNF1α as the transcription factor for positive regulation of HBV replication ( r =-0.430, P < 0.001). Overexpression of cyclin D1 in HepG2 cells reduced the transcriptional levels of HNF1α and NTCP. Conclusion Cyclin D1 inhibits HBV transcription and replication possibly by downregulating the expression of HNF1α and NTCP.
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Objective To investigate the consistency between Shengxiang (S) and Xinbo (X) real-time PCR methods in the quantification of HBV RNA. Methods In the prospective follow-up cohort of 108 chronic hepatitis B (CHB) patients established from July 2007 to August 2008, 20 patients with HBeAg seroconversion were selected, and 20 patients without seroconversion were selected by propensity score matching at a ratio of 1∶ 1. The two quantification methods from S and X companies were used, and a retrospective analysis was performed for HBV RNA in serum samples at baseline and weeks 12, 24, and 48. The paired t -test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data. The Pearson correlation coefficient, intraclass correlation coefficient (ICC), and the Bland-Altman method were used to evaluate the consistency of the two quantification methods. Results A total of 132 serum samples were tested by S reagent, and 154 were tested by X reagent; the detection rate of HBV RNA was 100% by both reagents. A total of 131 serum samples were tested by both reagents, with 34 samples at baseline and 29, 35, and 33 samples, respectively, at weeks 12, 24, and 48 of follow-up; at these four time points, the HBV RNA quantification data detected by X reagent were significantly higher than those detected by S reagent (5.75±1.64/5.43±1.73/5.13±1.54/4.76±1.55 log 10 copies/mL vs 4.80±1.48/4.52±1.53/4.10±1.50/3.92± 1.43 log 10 copies/mL, t =8.348, t =5.341, Z =-5.086, Z =-4.762, all P < 0.001). The correlation analysis of the two methods showed a Pearson correlation coefficient of 0.915 (95% confidence interval [ CI ]: 0.836-0.957) and an ICC of 0.771(95% CI : -0.021 to 0.931) at baseline, a Pearson correlation coefficient of 0.849(95% CI : 0.701-0.927) and an ICC of 0.733(95% CI : 0.138-0.902) at week 12, a Pearson correlation coefficient of 0.951(95% CI : 0.905-0.975) and an ICC of 0.776(95% CI : -0.058 to 0.942) at week 24, and a Pearson correlation coefficient of 0.933(95% CI : 0.867-0.967) and an ICC of 0.804(95% CI : -0.014 to 0.944) at week 48 (all P < 0.05). The Bland-Altman analysis showed that the difference of 96.18%(126/131) samples tested by the two methods was within the mean difference±1.96 standard deviation. Conclusion HBV RNA quantification by X reagent is higher than that by S reagent, while the two real-time PCR quantification methods show a good consistency in CHB patients with HBeAg seroconversion and those without seroconversion.
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Hepatitis B virus (HBV) infection is the main pathogenic factor for chronic hepatitis, and if it is not treated timely and effectively, it may have the risk of developing into end-stage liver diseases such as liver cirrhosis and hepatocellular carcinoma. Neither of the two types of antiviral drugs currently used in clinical practice can completely inhibit viral replication or eliminate viral transcriptional template, which means that covalently closed circular DNA (cccDNA) exists in infected liver cells for a long time, and thus patients with chronic hepatitis B require long-term or even lifelong medication. Therefore, it is of great importance to develop novel anti-HBV drugs. Core protein allosteric modulators (CpAM) are a type of novel anti-HBV drugs and can interfere with HBV nucleocapsid assembly and inhibit the depolymerization of mature nucleocapsid, the formation of cccDNA, and the biogenesis and secretion of HBeAg. CpAM have a great potential in clinical application since they act on various links of viral replication. This article reviews the function of CpAM target protein-core protein, the classification, action targets, and anti-HBV mechanism of CpAM, and the current research status, further development, and application prospect of CpAM.
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Chronic hepatitis B virus (HBV) infection is the main cause of viral hepatitis, liver cirrhosis, and primary liver cancer. At present, nucleos(t)ide analogues (NUC) and pegylated interferon α used in clinical practice cannot directly target covalently closed circular DNA, and it is difficult to achieve clinical cure of chronic hepatitis B patients; therefore, it is urgently needed to develop direct-acting antiviral agents targeting all stages of the HBV replication cycle. Capsid assembly modulator (CpAM) targets the assembly of viral capsids through various mechanisms, thereby exerting a direct-acting antiviral effect. Its combination with NUC should have a good synergistic antiviral effect, but the results of existing clinical trials have shown that chronic hepatitis B patients who received a limited course of antiviral therapy with CpAM and NUC all experienced off-therapy viral rebound. Based on the mechanism of action of these two types of drugs, this article provides a reasonable explanation for the above clinical trial results and points out that a longer course of antiviral therapy with CpAM and NUC may be needed in the future clinical trials with safe drug withdrawal as the end point of observation, so as to deplete or silence the pool of covalently closed circular DNA and increase the possibility of safe drug withdrawal in CHB patients. In addition, further studies are needed to explore antiviral therapeutic strategies with a combination of multiple targets.
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ObjectiveTo investigate the effect of AU-rich element RNA-binding factor 1 (AUF1) on glypican 3 (GPC3) in hepatocellular carcinoma (HCC) and its possible mechanism. MethodsTCGA-HCC gene expression data were downloaded from Broad Institute Genome Data Analysis Center, and finally 371 HCC tissue samples with different etiologies and 50 adjacent tissue samples were included; LCI-HCC gene expression data were downloaded from GSE14520, and 214 patients with hepatitis B-associated HCC who had follow-up data were enrolled. A total of 35 primary liver cancer samples and corresponding adjacent tissue samples were collected from HCC patients who underwent radical surgery in Henan Provincial Cancer Hospital from 2009 to 2013. Immunohistochemistry was used to measure the protein expression of GPC3 and AUF1 in HCC tissue; Western Blot and qRT-PCR were used to measure the expression of GPC3 after AUF1 knockdown or overexpression in hepatoma cell lines; RNA-binding protein immunoprecipitation and RNA turnover assay were used to investigate the potential mechanism of AUF1 in regulating the expression of GPC3. The t-test was used for comparison of quantitative data between two groups, and the chi-square test was used for comparison of rates between two groups; the Kaplan-Meier method was used for survival analysis after surgery, and the log-rank test was used for comparison of survival rates. ResultsIn TCGA and LCI databases, the expression of GPC3 in HCC tissue was significantly higher than that in adjacent tissue (P＜0.05), and in TCGA database, the high expression of GPC3 was associated with the poor prognosis of HCC patients (P＜0.05). Immunohistochemistry showed that both GPC3 and AUF1 proteins are highly expressed in HCC tissue, with a positive expression rate of 77.1% (27/35) and 74.3% (26/35), respectively. In vitro experiment showed that AUF1 knockdown significantly reduced the expression of GPC3 in HepG2 and Huh-7 cells (P＜0.05), while AUF1 overexpression significantly increased the expression of GPC3 (P＜0.05). AUF1 protein could bind to GPC3 mRNA, and AUF1 knockdown reduced the stability of GPC3 mRNA. ConclusionAUF1 is an important post-transcriptional regulator of the GPC3 gene, and the abnormal high expression of AUF1 and GPC3 may be involved in the development and progression of HCC.
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ObjectiveTo investigate the serological markers associated with posthepatectomy recurrence in patients with hepatocellular carcinoma, and to establish a prognostic model to evaluate whether palliative hepatectomy is suitable for such patients. MethodsA total of 111 patients with hepatocellular carcinoma who underwent hepatectomy in the Affiliated Cancer Hospital of Zhengzhou University from February 2009 to July 2013 and received follow-up were enrolled. Basic clinical data were collected and the patients were divided into recurrence group and non-recurrence group according to whether recurrence was observed during follow-up. The t-test was used for comparison of normally distributed continuous data between two groups and the Wilcoxon rank sum test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. Survival curves were plotted using the Kaplan-Meier method, and survival differences were analyzed using the log-rank test. A Cox regression analysis was used to perform univariate and multivariate analyses, and the area under the ROC curve (AUC) was used to evaluate prediction efficiency. ResultsThe Kaplan-Meier survival curves showed that the patients with low alpha-fetoprotein (AFP), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and fibrinogen and high CXCL13 had a longer median time to recurrence (P＜0.05). AFP (hazard ratio ［HR］［95%CI］=1.69(1.03~2.79), P=0.039), GGT (HR［95%CI］=1.89(1.14~3.14), P=0.014), and CXCL13 (HR［95%CI］=0.54(0.33~0.89), P=0.015) were independent factors associated with posthepatectomy recurrence. The prognostic index PI=0.526×AFP+0.637×GGT-0.616×CXCL13 established based on these factors had an AUC of 0.87, a sensitivity of 93.75%, and a specificity of 63.64% in predicting recurrence within 0-3 months after palliative hepatectomy, with a significant reduction in prediction efficiency for recurrence within 0-6 months (AUC=0.68) or a longer period of time. The recurrence prediction efficiency of this model for palliative hepatectomy was significantly higher than that for radical resection. ConclusionThe prognostic model established based on CXCL13, AFP, and GGT can be used to evaluate the risk of early recurrence after palliative hepatectomy and thus helps clinicians to make diagnosis and treatment decisions based on patients’ benefits.
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There is still a large number of patients with chronic hepatitis B virus (HBV) infection in China, which greatly affects the health of Chinese people. With the change in lifestyle, the incidence rate of nonalcoholic fatty liver disease (NAFLD) is increasing year by year in China. Some clinical studies have shown that there is a relatively low incidence rate of chronic HBV infection with NAFLD, while there are still reports on NAFLD in promoting the progression of chronic hepatitis B-related diseases. Based on literature search and review, this article attempts to investigate the interaction between HBV replication, abnormal lipid metabolism, and fatty liver disease in patients with chronic hepatitis B and NAFLD, in order to provide ideas for HBV antiviral treatment and prevention of NAFLD.
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Objective@#To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP).@*Methods@#The correlation between ALT, AST and other liver enzyme changes condition and NCP patients’ disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. t-test or Spearman rank correlation analysis was used for statistical analysis.@*Results@#ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of ACE2 (r > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells.@*Conclusion@#We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.
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Objective@#To establish and evaluate diagnostic efficacy and applicability of serum Golgi protein (GP) 73 based non-invasive diagnostic model with other conventional serological indicators for compensated stage hepatitis B cirrhosis.@*Methods@#666 cases with chronic hepatitis B (CHB) who had visited to the Fifth Medical Center of People’s Liberation Army General Hospital from January 2010 to December 2017 were selected as the study subjects, and were classified according to compensated stage cirrhosis into clinical and pathological diagnosis group based on whether or not the liver histological examination was performed. A diagnostic model of compensated stage hepatitis B cirrhosis in the clinical diagnosis group was established. The current clinically used diagnostic model of liver cirrhosis, aspartate aminotransferase/platelet ratio index (APRI), fibrosis index (FIB)-4 and liver stiffness measurement (LSM) were compared. Eventually, the diagnostic model was verified step by step by pathological diagnosis group.@*Results@#The area under the receiver operating characteristic curve (AUC) of GP73 and APRI, FIB-4, and LSM for cirrhosis patients in the clinical diagnosis group were 0.842, 0.857, 0.864, and 0.832, respectively. The diagnostic efficiency of the four indicators were of similar (P value > 0.05). A diagnostic model of compensated stage hepatitis B cirrhosis (GAPA) using logistic regression analysis was established: LogitP = 1/ [1 + exp (1.614-0.054 × GP73-0.045 × Age + 0.030 × PLT-0.015 × ALP)]. The AUC of the model was as high as 0.940 and the optimal cut-off value were 0.41. The corresponding diagnostic sensitivity and specificity were 0.92 and 0.82, respectively. The diagnostic efficiency was better than that of APRI, FIB-4, LSM and GP73 alone (P < 0.05). The AUC of GAPA was 0.877 in the pathological diagnosis group, which was similar to the diagnostic efficacy of LSM (0.891) and FIB-4 (0.847) (P > 0.1), but still superior to that of APRI (0.811) and GP73 alone (0.780) (P < 0.001).@*Conclusion@#GAPA, a diagnostic model for compensated stage hepatitis B cirrhosis established in this study, has a good diagnostic efficacy in both the clinical and pathological diagnosis group, and has certain auxiliary diagnostic value in the areas where resources are relatively scarce or where LSM has not been developed.
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Objective:To investigate the relationship between the down-regulation expression of sodium taurocholate cotransporting polypeptide (NTCP) in proliferating hepatocytes and the response to antiviral therapy of chronic hepatitis B (CHB) patients.Methods:Sixty-eight hepatitis B e antigen (HBeAg)-positive CHB patients admitted to the Fifth Medical Center of PLA General Hospital from January 2011 to March 2015 were included. Basic information and laboratory data were collected. Based on the baseline (before antiviral treatment) inflammatory activity (G), the patients were divided into ≤G2 group and >G2 group. Twelve liver puncture tissue samples were selected from each group for NTCP and Ki67 immunofluorescence staining.The proportion of Ki67-positive cells was calculated, and the staining of NTCP was scored. Five pairs of tissue specimens of patients who had hepatitis B virus (HBV) infection were diagnosed with focal nodular hyperplasia (FNH) and underwent nodular resection surgery from March 2014 to March 2017 were collected.Immunohistochemical staining was used to detect the expressions of Ki67, NTCP and hepatitis B surface antigen (HBsAg) in each tissue specimen, and the proportion of staining positive cells or the staining intensity was calculated. Statistical analysis was performed by Mann-Whitney U test, chi-square test or Spearman correlation analysis. Results:The proportion of Ki67-positive cells (6.75%(6.20%, 8.16%))in five liver FNH tissues with HBV infection was significantly higher than that in adjacent non-FNH tissues (0.75%(0.66%, 1.20%)), while the immunohistochemical scores of NTCP and HBsAg (3.00 (1.00, 3.00) and 2.00 (1.00, 2.00), respectively) were both significantly lower than those in adjacent non-FNH tissues (8.00 (8.00, 9.00) and 8.00 (6.00, 8.00), respectively), the differences were all statistically significant ( Z=-2.611, -2.424 and -2.635, respectively, P=0.009, 0.015 and 0.008, respectively). There were 37 patients in >G2 group, and 31 patients in ≤G2 group. After six months of antiviral treatment, CHB patients with persistent inflammation in >G2 group obtained a better virological response, with serum HBV DNA and HBeAg showing a greater decline ((0.71±0.14) lg IU/mL and (0.92±0.13) lg IU/mL, respectively) than those in ≤G2 group ((0.54±0.30) lg IU/mL and (0.49±0.65) lg IU/mL, respectively) ( Z=-3.048 and -2.666, respectively, P=0.002 and 0.008, respectively). The proportion of Ki67-positive cells in the specimens of >G2 group (4.34%(1.84%, 8.77%)) was significantly higher than that of ≤G2 group (0.34%(0, 0.80%)) ( Z=-3.640, P<0.01), and the immunohistochemical staining score of NTCP (1.00 (0, 3.25)) was significantly lower than that of ≤G2 group (6.00 (4.00, 8.00)) ( Z=-3.012, P=0.003). Spearman correlation analysis showed that the NTCP immunohistochemical score was negatively correlated with the proportion of Ki67-positive cells ( r=-0.512, P=0.01). Conclusions:CHB patients with persistent inflammationare often accompanied by more active hepatocyte proliferation and low membrane NTCP expression, which is not conducive to HBV reinfection. It may facilitate these patients to obtain better virological response.
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Objective@#To determine whether single-stranded guided RNA (gRNA) and Cas9 protein exist in the exosome secreted by cells transfected with CRISPR/Cas9 expression plasmid. Furthermore, to explore whether CRISPR/Cas9 system can edit target genes of peripheral cells through the intercellular transmission of exosomes.@*Methods@#(1) The CRISPR/Cas9 expression plasmid was transfected into HuH7 cells. The supernatant was collected and the exosomes were concentrated and purified by differential centrifugation. The morphology and particle size of exosomes were determined by electronic microscopy and Malvern laser scatter granulometry. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the levels of gRNA and Cas9 protein. (2) HuH7 cells transfected with pBB4.5 1.2×HBV and HBV specific CRISPR/Cas9 expression plasmids were co-cultured. After 2 days, HBV DNA was extracted and sequenced by PCR.@*Results@#There were not only full-length gRNA and Cas9 protein in the exosomes of Huh7 cells transfected with CRISPR / Cas9 expression plasmid. In addition, gene-editing functions were delivered between the cells to achieve the destruction of HBV genome of surrounding cells.@*Conclusion@#The CRISPR-Cas9 gene-editing system has the potential to deliver exosomes between cells via carrying functional gRNA and Cas9 proteins. This phenomenon hints that we are in the process of using the CRISPR/Cas9 system for gene therapy. Therefore, it is necessary to consider the potential effects of exosomes-carried gRNA and Cas9 proteins on the surrounding cells of the distal tubules.
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Hepatitis B virus (HBV) infection remains to be a serious public health problem in China. There used to be a high prevalence of HBV infection in China, which resulted in a large number of HBV susceptible and post-infected population. Single anti-HBc positive usually indicates post HBV infection and its prevalence is particularly high among people over 40 years old, some of whom may be occult hepatitis B virus infection (OBI). The clinical diagnosis of OBI is difficult and easily missed. Since OBI may cause chronic liver disease progression and even lead to cirrhosis and hepatocellular carcinoma eventually, and more importantly, patients with OBI may leed to HBV reactivation when the immune function decreases or immunosuppressive therapy is performed, the accurate identify of OBI is of particular importance. Moreover, OBI is the potential source of HBV infection, which may transmit through blood transfusion, organ transplantation and mother-to-child transmission. In view of this situation, we reviewed the mechanism, prevalence and definition of OBI, and proposed a determination system for replication-competent HBV DNA based on our understanding of the updated OBI definition. It is expected to be beneficial for OBI diagnosis, treatment and management.
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Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and most of the patients have a background of chronic HBV infection. Nucleos(t)ide drugs (NAs) are currently recommended by major guidelines as a first-line treatments for chronic hepatitis B. However, it is still clinically possible to observe that some patients who have acquired virological response (HBV DNA below the lower detection limit) after NAS treatment progress to HCC, and its mechanism of development is still unclear. In this review, the mechanism relevant to HCC progression in treatment of chronic hepatitis B patients with NAs is analyzed mainly from the aspects of gene integration and persistent inflammatory injury.
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Hepatitis B virus (HBV) infection is the main cause of chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. HBV covalently closed circular DNA (cccDNA) is the template for HBV replication and exists stably in hepatocytes, which is the main factor for persistent infection. However, existing antiviral drugs including nucleos(t)ide analogues and interferons do not directly target cccDNA, and thus it is difficult to achieve the clinical cure of CHB. With the progress in biotechnology and in-depth understanding of the features of HBV cccDNA, more and more studies have been conducted on antiviral therapies targeting cccDNA, but there is still a long way before clinical application. This article briefly reviews related research advances.
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Viral hepatitis, liver cirrhosis, and hepatocellular carcinoma caused by hepatitis B virus (HBV) infection still threaten the health of people in China. Efficient antiviral therapy can significantly prevent the progression of liver diseases and reduce the incidence rate of end-stage liver disease, but it is very difficult to achieve clinical cure by current drugs, and nucleos(t)ide analogues may require long-term medication. New serological markers can be used for further optimization of antiviral regimens, among which serum HBV RNA is transcribed from covalently closed circular DNA (cccDNA) and is mainly derived from pregenomic RNA and its splice variants with no or partial reverse transcription. This article summarizes the sources and existing forms of serum HBV RNA, the influencing factors for serum HBV RNA level, the correlation between serum HBV RNA and other serum virological markers, and the correlation between serum HBV RNA and cccDNA in liver tissue, as well as the clinical significance of serum HBV RNA in monitoring antiviral efficacy and predicting the risk of viral rebound after drug withdrawal.
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Liver cirrhosis is the end-stage change of chronic liver diseases with various causative factors. The accurate diagnosis of liver cirrhosis in an early stage is very important for the timely treatment and prognosis of patients. A liver biopsy test is the gold standard for the diagnosis of liver cirrhosis; but its use is limited in clinical practices due to its invasive nature. The conventional non-invasive measures (APRI, FIB-4 and LSM) for diagnosis of liver cirrhosis could not fulfill the needs. Therefore, finding a new serological marker of liver cirrhosis has become a research hotspot. Based on literature review and our own results, we suggest that serum GP73 as the most potential serum marker for liver cirrhosis diagnosis. This review briefly introduces the application of serum GP73 in the diagnosis of liver cirrhosis and the potential mechanism relevant to its involvement in the development of liver cirrhosis.
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Objective@#To investigate the prognostic value of albumin/globulin ratio on postoperative survival outcomes in patients with hepatocellular carcinoma.@*Methods@#Data of 630 patients with HCC, who underwent surgical resection from February 2009 to July 2013, were retrospectively analyzed. Patients were divided into low-value group (A/G < 1.5, defined as L group) and high-value group (A/G≥1.5, defined as H group), and their distribution characteristics were observed with the normal A/G threshold value. Independent risk factors’ affecting survival and prognosis was analyzed with univariate and multivariate Cox’s regression model. Survival trend of all patients with low-value and high-value groups in A, B and C of Barcelona stage (BCLC stage) were analyzed using the Kaplan-Meier method.@*Results@#Multivariate analysis showed that preoperative A/G ratio (P = 0.007), alpha-fetoprotein (P < 0.001), gamma-glutamyltransferase (P = 0.006), RBC (P = 0.014), international normalized ratio (P = 0.009), preoperative BCLC staging (P < 0.001) and number of tumors (P = 0.003), and intraoperative blood transfusion (P < 0.001) were independent prognostic factors affecting long-term survival in HCC patients. The median overall survival time in-group L was 15 months, significantly lower than that in group H of 42 months (P < 0.001). Stratified analysis showed that the short-term survival advantage of patients with high A / G value was limited to those with Barcelona stage A (P < 0.001), and disappeared in patients with Barcelona stage B and C (P > 0.05). The long-term survival advantage existed in patients with Barcelona stage A (P < 0.001), B (P < 0.05), and disappeared in C (P > 0.05).@*Conclusion@#Preoperative albumin/globulin ratio can predict postoperative prognosis and survival, and direct towards the treatment for early stage of HCC and thus representing as an indicator of high clinical value.
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Objective: To investigate the effect of macrophage-capping protein (CapG) on migration and proliferation of human gastric cancer cell line.Methods: Real-time PCR method was used to detect the expression of CapG gene in four gastric cancer cell lines, and AGS cells with low expression and transfection were selected as the research objects.Specific primers were designed for CapG and recombinant plasmids synthesized.A lentivirus packaging system which could express CapG was constructed, and a cell line stably expressing CapG was established by infecting human gastric cancer cell line AGS cells.The effect of overexpression of CapG gene on the growth and proliferation of AGS cells was analyzed by CCK8 assay.Cells cratch and Transwell assay were used to analyze the effect of overexpression of CapG gene on AGS cell migration.Results: After the overexpression of CapG, the growth rate of AGS cells was slightly lower than that of the control group, but there was no significant difference between the two groups (t=2.424, P=0.073).Scratch test showed that the average narrowing distance of the scratches in the CapG experimental group was significantly reduced compared with the control group, the average narrowing distance of the CapG experimental group and the control group was 336.99 μm and 45.54 μm, the difference was statistically significant (t=14.97, P=0.004).The average number of cell penetra-ting membrane in the CapG experimental group and the eGFP control group was 176 and 70, the number of the cells in the CapG experimental group was significantly higher than that of the control group (t=40.00, P<0.001).Conclusion: The overexpression of CapG gene has no significant effect on the growth and proliferation of AGS cells of gastric cancer cell line.Overexpression of CapG gene can promote the migration of AGS cells of gastric cancer cell lines.