Relation between serum levels of high mobility group box 1 and hepatitis B virus-related acute-on-chronic liver failure / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To evaluate the levels of high mobility group box 1 protein (HMGB1) in serum of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) and investigate its potential relation to the clinical features of these patients.</p><p><b>METHODS</b>Sixty patients with HBV-related ACLF, 30 patients with chronic hepatitis B (CHB), and 24 healthy individuals (controls) were enrolled in the study. Markers of liver function, such as aspartate aminotransferase (AST), were measured by routine biochemical methods. Imaging studies, such as abdominal computed tomography or magnetic resonance imaging, were used for disease staging. Serum levels of HMGB1 were measured by ELISA. Deaths within the 2-month follow-up after serum collection were used for the survival analysis. Patients who developed peritonitis, pneumonia, or other bacterial and fungal infections during the 2-month follow-up after serum collection were classified as the infected group. Pairwise comparisons were carried out by t-test, and multiple comparisons were carried out by analysis of variance.</p><p><b>RESULTS</b>Patients with HBV-related ACLF had significantly higher serum levels of HMGB1 than CHB patients or controls (P = 0.003). Among the patients with HBV-related ACLF, those in the late stage (n = 20) had significantly higher levels of HMGB1 than those in the early stage (n = 20) (P = 0.005). The serum levels of HMGB1 correlated well with AST level in patients with HBV-related ACLF (P = 0.006). In addition, patients with HBV-related ACLF who developed infection or died during follow-up also had significantly higher levels of HMGB1 (P = 0.028 or P = 0.017, respectively).</p><p><b>CONCLUSION</b>Enhanced serum level of HMGB1 is associated with development of HBV-related ACLF in CHB patients. The strong correlation between HMGB1 and AST levels suggest that HMGB1 may be useful as a prognostic marker for development of ACLF.</p>

The study on frequency distribution of regulatory T cells and its functional markers in peripheral blood of chronic hepatitis B / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To explore the role of treg cells and its functional markers in pathogenesis of chronic hepatitis B, and the correlation with disease progression.</p><p><b>METHODS</b>20 cases of healthy control people,53 cases of chronic hepatitis B patients and 24 cases of liver cirrhosis patients were enrolled into the groups. Detecting the frequencies of CD4+ CD25+ Fox3+ cells, CD4+ CD25+ CD127(low) cells, CD39+ treg cells and CTLA-4+ treg cells in treg cells by flow cytometry. Clinical parameters were investigated in the same time.</p><p><b>RESULTS</b>The frequencies of treg cells, CD4+ CD25+ CD127(low) cells and CD39+ treg cells were significant different among healthy control group, CHB group and LC group (P < 0.01). The frequencies of treg cells, CD4+ CD25+ CD127(low) cells and CD39+ treg cells were significantly different in moderate-severe CHB group compared with mild CHB group (P < 0.05, P < 0.05, P < 0.01). In CHB group the frequencies of CD4+ CD25+ Foxp3+ cells were positively correlated with ALT (r = 0. 289, P < 0.05) and AST (r = 0.302, P < 0.05), the frequencies of CD4+ CD25+ Foxp3+ cells had a significant positive correlation with the frequencies of CD4+ CD25+ CD127(low) cells (r = 0.478, P < 0.01).</p><p><b>CONCLUSION</b>The frequencies of treg cells and its functional markers probably had a dynamic tendency in the process of chronic hepatitis B and were closely related with the change of liver function parameters. CD39+ treg cells may be a group of functional treg cells, which indicated that CD39 be a sensitive marker to react treg cells function. In some sense, CD4+ CD25+ CD127(low) cells frequency could represent treg cell frequency.</p>

Association between HBV genotype and chronic/severe liver disease with HBV infection in Chinese patients / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To explore the association between HBV genotype and chronic/severe liver disease with HBV infection in Chinese patients.</p><p><b>METHODS</b>Serum samples were collected from 2922 patients with HBV infection. HBV genotyping was performed with type-specific primers polymerase chain reaction, and the virological and biochemical markers were detected, which differences in the genotypes between various clinical types of HBV infection and liver function and virological markers between various HBV genotyping were analyzed.</p><p><b>RESULTS</b>The genotype B, C, BC combinations, D of 2922 patients with HBV infection accounted for 15.9%, 83.5%, 0.41%, 0.21% respectively. The ratio of genotype B in acute hepatitis group was higher (P = 0.003), which the ratio of genotype C in the cirrhosis group and the hepatocellular carcinoma group was higher (P = 0.000, 0.000). The difference in ratio of genotype C was not statistically significant between acute-on-chronic liver failure group and chronic hepatitis group. HBeAg-positive rate, viral load and liver function markers of B, C genotype group in acute hepatitis group and chronic hepatitis group were not significant different. HBeAg-positive rates of genotype C in acute-on-chronic liver failure group, cirrhosis group, hepatocellular carcinoma group were higher than that of genotype B (P = 0.000, 0.024, 0.003). Viral load of genotype C in hepatocellular carcinoma group was higher than that of genotype B (P = 0.025). Cholinesterase levels of genotype C in the acute-on-chronic liver failure group and the hepatocellular carcinoma group was lower than that of genotype B (P = 0.0004, 0.02).</p><p><b>CONCLUSION</b>There were HBV genotype B, C, B/C combinations and D in Chinese patients with HBV infection, with genotype B and C being the major ones. Compared with HBV genotype B, genotype C in Chinese patients with HBV infection was more likely to chronic infection, evolved to cirrhosis and hepatocellular carcinoma, but genotype difference was not observed in occurrence of acute-on-chronic liver failure. Genotype was not significant effect in acute and chronic hepatitis B, but HBeAg-positive rate/viral load was higher and liver damage was more severe in severe and end-stage genotype C HBV infection patients.</p>

Lamivudine and entecavir significantly improved the prognosis of early-to-mid stage hepatitis B related acute on chronic liver failure / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To clinically study the antiviral effects of lamivudine and entecavir on patients with early-to-mid stage Hepatitis B related acute on chronic liver failure (HBV-ACLF). METHODS; A prospective, randomized, open and parallel controlled clinical trial was designed to observe the antiviral effects of nucleoside analogues on patients with early-to-mid stage HBV-ACLF. Three groups were set for controlled study, i. e. basic treatment group, lamivudine plus basic treatment group and entecavir plus basic treatment group.</p><p><b>RESULTS</b>One month after treatment, the improvement rates of lamivudine group and entecavir group were 58.85% and 59.15% respectively, significantly higher than that of basic treatment group which was 34.84% (Chi(2) = 9.8323, P = 0.043). By the end of six months, the cumulative survival rates of patients with the antiviral treatments, i.e., lamivudine, entecavir, were 65.8%, 60.1%, significantly higher than that (42%) without the antiviral treatment (P = 0.045, P = 0.04 respectively). The cumulative survival rate in patients with a MELD score < 30 was higher than that with a MELD score over 30 (Chi(2) = 3.920, P = 0.048). For the patients with pretreatment HBV DNA > or = 10(7), the cumulative survival rate in patients with entecavir treatments group was higher than that of patients in basic treatment group (Chi(2) = 5. 014 P= 0.025). According to the Ordinal Regression analysis, antiviral therapy by using either lamivudine or entecavia could significantly increase the improvement rate of patients with early-to-mid stage HBV-ACLF. But severe complications, including hepatorenal syndrome, electrolyte imbalance and hepatic encephalopathy, medical history of liver cirrhosis, and pretreatment HBV DNA > or = 10(7) had significant impacts on prognosis of this group patients.</p><p><b>CONCLUSIONS</b>Antiviral therapy by using either lamivudine or entecavia could significantly increase the survival rate of patients with early-to-mid stage HBV-ACLF.</p>

Rescue of dendritic cells malfunction and loading with HBV proteins in patients with chronic hepatitis B in vitro / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To investigate dendritic cell (DC) malfunctions in patients with chronic hepatitis B (CHB) and try some means to restore the function in vitro.</p><p><b>METHODS</b>Twelve CHB patients and 10 healthy people were enrolled in the study. Phenotype analysis and allogeneic mixed lymphocyte reaction (AMLR) assay of DC from these subjects were made. Enzyme-linked ELISpot method for detecting IFN-gamma-producing CD8 (+) T cells were used to evaluate the efficacy of DC loaded in vitro with HBsAg or HBcAg.</p><p><b>RESULTS</b>DC from patients had a lower expression of co-stimulatory molecules and impaired AMLR capacity, but was restored partially by cytokine cocktail in vitro. Mature DC loaded with HBsAg or HBcAg showed a greater capacity for IFN-gamma-production than immature DC.</p><p><b>CONCLUSION</b>Malfunction of DC from CHB patients may be rescued by a cocktail of cytokines, and therapeutic DC vaccines loaded with HBV protein might be helpful to treat CHB patients.</p>

A multicenter retrospective analysis of diagnosis and treatment of 72 hemophagocytic syndrome patients / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore early diagnosis of hemophagocytic syndrome (HPS) and effective treatment.</p><p><b>METHODS</b>A multicenter retrospective study was carried out to analyze the causes, clinical features, laboratory findings, treatment and clinical outcomes of 72 patients with HPS.</p><p><b>RESULTS</b>Among the 72 patients, EBV infection and T lymphoma were the most common initiating diseases. The most common clinical features were persistent fever (100%) and splenomegaly (83.3%). The diagnostic sensitivity was persistent fever (100%), peripheral cytopenia in two or more lineages (97.2%), high concentration of serum soluble CD25 (93.1%) and low NK cell activity (94.4%). The median percentage of serum glycosylated ferritin was significantly lower in patients in HPS group \[(17.4 +/- 16.0)%\] than in control group \[(53.6 +/- 13.3)%\] (P < 0.01). And the median level of serum TNF-alpha was significantly higher in patients group \[(143.2 +/- 64.8) microg/L\] than in controls \[(66.9 +/- 19.4) microg/L\] (P < 0.01). Hepatic dysfunction was seen in most patients (83.6%) mainly manifested as elevated liver enzymes and hypoalbuminemia. The 15-week total survival rate was 46.8% in 47 treated patients, and was 63% in 27 treated with fludarabine in combination with high dose methylprednisolone. The platelet count and fibrinogen level were significantly lower in death group than in survival group.</p><p><b>CONCLUSIONS</b>The diagnostic sensitivities of presistent fever, peripheral cytopenia in two or more lineages, high concentration of serum soluble CD25 and low NK cell activity are relatively high and lacking hemophagocytosis does not exclude the diagnosis. Low percentage of glycosylated ferritin and high concentration of TNF-alpha would be helpful to the diagnosis. High dose methylprednisolone combined with fludarabine is an effective therapy. Platelet count and fibrinogen level are poor prognostic factors for HPS.</p>

Clinical profiles of circulating dendritic cell phenotype and lymphocyte subsets in patients chronically infected with HBV during lamivudine treatment / 中华实验和临床病毒学杂志

<p><b>BACKGROUND</b>To investigate the changes of circulating dendritic cell (DC) and lymphocytes subsets in chronic hepatitis B patients treated with lamivudine.</p><p><b>METHODS</b>Sixteen chronic hepatitis B patients treated with lamivudine were included and followed up for 48 weeks in this study. Before and during lamivudine treatment, DC collected from peripheral blood sample was cultured in vitro and surface markers of DC and lymphocytes subsets were detected by flow cytometry simultaneously.</p><p><b>RESULTS</b>Of the 16 patients, 11 were consistently HBV DNA negative in serum and HBV DNA YMDD variants appeared in 5 cases. In the consistent responder group, HLA-DR level of DC decreased transiently in 12 weeks and recovered in 48 weeks (P<0.05). At 48 weeks CD80, CD40 and CD1a were improved compared with baseline level (P<0.05). In the YMDD variant group, CD83 and HLA-DR level of DC decreased at 12 weeks treatment (P<0.05) and HLA-DR was still lower compared with baseline (P<0.05). In the consistent responder group, no significant changes occurred in lymphocyte subsets number at 12 weeks treatment, but CD4 + T cell was improved and NK cell dropped at 48 weeks compared with baseline level (P<0.05). In the YMDD variant group lymphocyte subsets had no statistically significant change.</p><p><b>CONCLUSION</b>In the consistent responder group, the expression of surface costimulatory molecules of DC, such as CD80 and CD40,was partly recovered after the virus of hepatitis B had been inhibited efficiently, HLA-DR levels of DC decreased transiently at 12 weeks and recovered in 48 weeks and CD4+ T cell improved and NK cell dropped at 48 weeks. In the YMDD variant group, HLA-DR levels of DC were lower consistently during treatment compared with baseline level.</p>

Hepatitis B virus genotypes and alanine aminotransferase levels in HBeAg negative patients with chronic hepatitis B and liver cirrhosis / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate genotypes of the hepatitis B virus (HBV) and alanine aminotransferase (ALT) levels of HBeAg negative patients with chronic hepatitis B and liver cirrhosis.</p><p><b>METHODS</b>HBV serological markers and ALT levels were detected in 62 patients with chronic hepatitis B and 41 cases with liver cirrhosis, using enzyme linked absorbent immunoassays and an enzyme method, respectively. A polymerase chain reaction of S region was used for HBV genotyping.</p><p><b>RESULTS</b>Of the 62 patients with chronic hepatitis B, 21 (33.9%) were HBeAg negative, and 41 (66.1%) HBeAg positive. Among 41 cases with liver cirrhosis, 28 (68.3%) were HBeAg negative, and 13 (31.7%) HBeAg positive. Of these 62 patients with chronic hepatitis B, 53 (85.5%) were infected with HBV genotype C, and 9 (14.5%) with genotype B. Thirty-nine (95.1%) of the 41 patients with liver cirrhosis were infected with genotype C, and 2 (4.9%) with genotype B. The proportion of HBeAg negative chronic hepatitis B patients with ALT level > 40 U/L was lower than that of the HBeAg positive group (47.6% and 85.4%, respectively) (P < 0.01). The percentage of ALT levels > 40 U/L of the negative patients with liver cirrhosis was also lower as compared to that of the HBeAg positive patients, but there was no statistical difference between the two groups, because of the small sample size (P > 0.05).</p><p><b>CONCLUSION</b>The proportion of HBeAg negative patients is high in the group of chronic hepatitis B and liver cirrhosis. These patients have relatively low ALT levels, and mainly have HBV genotype C infection.</p>

Frequency and function decrease of circulating type 2 pre-dendritic cells (pDC2) and its clinical significance in liver cirrhotic patients with chronic HBV infection / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To identify the frequency and interferon (IFN)-alpha-producing ability of circulating type 2 pre-dendritic cells (pDC2) and evaluate its role in liver cirrhotic patients with chronic HBV infection.</p><p><b>METHODS</b>27 liver cirrhotic patients were included in our study and 25 patients with chronic hepatitis B and 25 healthy individuals were enrolled as controls. The numbers of circulating pDC2 and lymphocytes including CD4+ T cells, CD8+ T cells, NK cells as well as B cells were analyzed by flow cytometry. The IFN-alpha-producing function of peripheral blood mononuclear cells (PBMCs) representing the circulating pDC2 was determined by ELISA assay after stimulated by ultraviolet-inactivated herpes simplex virus-1 (UV-HSV-1).</p><p><b>RESULTS</b>The number of pDC2 were (7.21+/-2.38)*10(6)/L, (4.49+/-3.08) *10(6)/L and (2.89+/-1.17) *10(6)/L for healthy control, chronic hepatitis B and cirrhotic patients respectively. Both the number and IFN-alpha-producing function of circulating pDC2 in liver cirrhotic patients significantly lower than that in healthy subjects. There was a correlated simultaneous decrease numbers of circulating CD8+ T cells, NK cells in HBV-infected cirrhotic patients. Furthermore, cirrhotic patients with opportunistic infections have lower numbers of pDC2, CD8+ T cells and NK cells compared to those without opportunistic infections.</p><p><b>CONCLUSIONS</b>Liver cirrhotic patients with chronic HBV infection have a significant decrease of circulating pDC2 level and IFN-alpha-producing function. The decreased number and function of pDC2, together with the lower number of CD8+ T cells and NK cells may result in the decline of host immune response, which may partially contribute to the disease progression of HBV infection and opportunistic infections.</p>

Correlation of clinical features with pathology in chronic viral hepatitis / 中华实验和临床病毒学杂志

<p><b>BACKGROUND</b>To investigate the correlation of clinical features with pathology in chronic viral hepatitis (CH).</p><p><b>METHODS</b>Analyses of single factor and multiple factors of serum biochemical indices, imaging examination results, symptoms and signs with degree of pathological lesion of hepatic tissue in 973 cases of CH were conducted. Meanwhile, the hepatic functional index (AAPEA index) was used to investigate the role of serum biochemical indices in diagnosis of CH.</p><p><b>RESULTS</b>In these patients with CH,the severity of hepatic lesion was closely correlated to symptoms and signs, biochemical indices such as PTA, ALT, TBIL, ALB, A/G, gamma-globulin (gamma-G) by electrophoresis, AST and cholinesterase (CHE) as well as splenic thickness. AST was superior to ALT in reflecting degree of hepatic inflammatory activity. The total mistaken judgment rate of multiple factor analysis was 28.1%. The correlation coefficient of AAPEA index to degrees of hepatic inflammatory activity, fibrosis and pathological grading was 0.559, 0.545 and 0.529, respectively (P<0.000 1)</p><p><b>CONCLUSIONS</b>The biochemical indices such as PTA, ALT, TBIL, ALB, A/G, gammaG, AST, CHE and the determination of splenic thickness by ultrasonography B could reflect hepatic pathological changes to certain extent. AST was superior to ALT in reflecting degree of hepatic inflammatory activity. Incorrect judgment rate was high in determination of moderate and severe CH by multiple factor analysis. Conformity rate between AAPEA index and pathological diagnosis was better than any of them alone in diagnosing CH.</p>