BACKGROUND/AIMS: Hepatitis-B-related acute-on-chronic liver failure has a poor prognosis. However, the advent of potent oral antiviral agents means that some patients can now recover with medical treatment. We aimed to identify the prognostic factors for hepatitis-B-related acute-on-chronic liver failure including the initial as well as the dynamically changing clinical parameters during admission. METHODS: Sixty-seven patients were retrospectively enrolled from 2003 to 2012 at Samsung Medical Center. The patients were classified into three categories: Recovery group (n=23), Liver transplantation group (n=28), and Death group (n=16). The Liver transplantation and Death groups were combined into an Unfavorable prognosis group. We analyzed the prognostic factors including the Model for End-Stage Liver Disease (MELD) scores determined at 3-day intervals. RESULTS: A multivariable analysis showed that the unfavorable prognostic factors were a high initial MELD score (> or =28) (odds ratio [OR] =6.64, p=0.015), moderate-to-severe ascites at admission (OR=6.71, P=0.012), and the aggravation of hepatic encephalopathy during hospitalization (> or =grade III) (OR=15.41, P=0.013). Compared with the baseline level, significant reductions in the MELD scores were observed on the 7th day after admission in the Recovery group (P=0.016). CONCLUSIONS: Dynamic changes in clinical parameters during admission are useful prognostic factors for hepatitis-B-related acute-on-chronic liver failure.
Acute-On-Chronic Liver Failure/*diagnosis/drug therapy/etiology ; Adult ; Aged ; Antibodies, Monoclonal, Murine-Derived/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Antiviral Agents/therapeutic use ; Cyclophosphamide/therapeutic use ; DNA, Viral/analysis ; Doxorubicin/therapeutic use ; Female ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/complications/*diagnosis/drug therapy ; Hospitalization ; Humans ; Liver Transplantation ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Prednisone/therapeutic use ; Prognosis ; Retrospective Studies ; Severity of Illness Index ; Vincristine/therapeutic use ; Young Adult

Recently, suppressor of cytokine signaling-3 (SOCS3) has been shown to be an inducible endogenous negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway which is relevant in inflammatory response, while its functions in acute liver failure and HBV-induced acute-on-chronic liver failure (HBV-ACLF) have not been fully elucidated. In this study, we explored the role of SOCS3 in the development of mouse hepatitis virus strain 3 (MHV-3)-induced acute liver failure and its expression in liver and peripheral blood mononuclear cells (PBMCs) of patients with HBV-ACLF. Inflammation-related gene expression was detected by real-time PCR, immunohistochemistry and Western blotting. The correlation between SOCS3 level and liver injury was studied. Our results showed that the SOCS3 expression was significantly elevated in both the liver tissue and PBMCs from patients with HBV-ACLF compared to mild chronic hepatitis B (CHB). Moreover, a time course study showed that SOCS3 level was increased remarkably in the liver of BALB/cJ mice at 72 h post-infection. Pro-inflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, were also increased significantly at 72 h post-infection. There was a close correlation between hepatic SOCS3 level and IL-6, and the severity of liver injury defined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respectively. These data suggested that SOCS3 may play a pivotal role in the pathogenesis of MHV-3-induced acute liver failure and HBV-ACLF.
Adult ; Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Blotting, Western ; End Stage Liver Disease ; genetics ; pathology ; virology ; Female ; Gene Expression ; Hepatitis, Viral, Animal ; genetics ; pathology ; virology ; Host-Pathogen Interactions ; Humans ; Interleukin-1beta ; genetics ; metabolism ; Interleukin-6 ; genetics ; metabolism ; Leukocytes, Mononuclear ; metabolism ; virology ; Liver Failure, Acute ; genetics ; pathology ; virology ; Male ; Mice, Inbred BALB C ; Middle Aged ; Murine hepatitis virus ; physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Severity of Illness Index ; Suppressor of Cytokine Signaling 3 Protein ; Suppressor of Cytokine Signaling Proteins ; blood ; genetics ; metabolism ; Tumor Necrosis Factor-alpha ; genetics ; metabolism ; Young Adult

BACKGROUND/AIMS: The widespread use of cytotoxic chemotherapy and immunosuppressants has resulted in reactivation of hepatitis B virus (HBV) recently becoming an issue. Although rituximab (an anti-CD20 monoclonal antibody) has revolutionized the treatment of lymphoma, recent reports have suggested that rituximab therapy increases the risk of viral-mediated complications, and particularly HBV reactivation. This study analyzed real clinical practice data for rituximab-related HBV reactivation. METHODS: Between January 2005 and December 2011, 169 patients received treatment with rituximab. Screening status of the HBV infection and frequency of preemptive therapy were determined in these patients, and the clinical features of HBV reactivation were analyzed. RESULTS: Seventy-nine of the 169 patients with chronic or past HBV infection were selected for evaluation of HBV reactivation. Of the 90 patients who were excluded, 22 (13.0%) were not assessed for HBsAg and anti-HBc, and 14 (8.3%) were not assessed for anti-HBc due to seronegativity for HBsAg. The selected patients were divided into those with chronic HBV infection (n=12) and those with past HBV infection (n=67); six patients (7.6%) experienced HBV reactivation. Eight patients received preemptive therapy, but three patients (37.5%) underwent HBV reactivation. Although HBsAg seropositivity was an independent risk factor for HBV reactivation (P=0.038), of the six patients with HBV reactivation, two (33.3%) had past HBV infection and three (50%) died of liver failure. CONCLUSIONS: The findings of this study demonstrate that adherence to guidelines for screening and preemptive therapy for HBV reactivation was negligent among the included cohort. Attention should be paid to HBV reactivation in patients with past as well as chronic HBV infection during and after rituximab therapy.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies/blood ; Antibodies, Monoclonal, Murine-Derived/*adverse effects/therapeutic use ; Antineoplastic Agents/adverse effects/*therapeutic use ; Child ; Child, Preschool ; Hepatitis B/etiology/mortality/virology ; Hepatitis B Core Antigens/immunology ; Hepatitis B Surface Antigens/blood ; Hepatitis B virus/*physiology ; Humans ; Lymphoma/*drug therapy ; Middle Aged ; Odds Ratio ; Retrospective Studies ; Risk Factors ; *Virus Activation ; Young Adult

The role of hepatic CD69+ natural killer (NK) cells in virus-induced severe liver injury and subsequent hepatic failure is not well defined. In this study, a mouse model of fulminant liver failure (FHF) induced by murine hepatitis virus strain 3 (MHV-3) was used to study the role of hepatic CD69+NK cells in the development of FHF. The CD69 expression in NK cells in the liver, spleen, bone marrow and peripheral blood was detected by using flow cytometry. The correlation between the CD69 level in hepatic NK cells and liver injury was studied. The functional marker (CD107a), and activating and inhibitory receptor (NKG2D and NKG2A) expressed on CD69+NK cells and CD69-NK cells were detected by using flow cytometry. Pro-inflammatory cytokines (IL-9, IFN-γ and TNF-α) were also examined by using intracellular staining. After MHV-3 infection, the number of CD69+NK cells in the liver of BALB/cJ mice was increased markedly and peaked at 72 h post-infection. Similar changes were also observed in the spleen, bone marrow and peripheral blood. Meanwhile, the CD69 expression in hepatic NK cells was highly correlated with the serum level of ALT and AST. The expression of CD107a and NKG2D, as well as the production of TNF-α, IFN-γ and IL-9 in hepatic CD69+NK cells was all significantly up-regulated during 48-72 h post-infection. In contrast, the NKG2A expression was increased in hepatic CD69-NK cells but not in CD69+NK cells. These results suggested that hepatic CD69+NK cells play a pivotal role in the pathogenesis of FHF by enhancing degranulation and cytotoxic ability of NK cells and increasing the production of pro-inflammatory cytokines.
Animals ; Antigens, CD ; immunology ; Antigens, Differentiation, T-Lymphocyte ; immunology ; Coronavirus Infections ; immunology ; Female ; Hepatitis, Viral, Animal ; immunology ; Killer Cells, Natural ; immunology ; Lectins, C-Type ; immunology ; Mice ; Mice, Inbred BALB C ; Murine hepatitis virus ; immunology

Recently, the Th17 cells and IL-17 have been shown to play a critical role in the immune-mediated liver injury in hepatitis B, while their functions in acute liver failure have not been well elucidated yet. In this study, we primarily investigated the role of IL-17 in the development of mouse hepatitis virus strain 3 (MHV-3)-induced acute liver failure. IL-17 mRNA levels in liver tissue were quantified by using quantitative real-time polymerase chain reaction, and cytokine IL-17 levels in liver tissue and serum were determined by using ELISA in MHV-3-induced murine fulminant hepatitis model. The IL-17 expression levels on CD4(+)T and CD8(+)T cells were determined by using flow cytometry. The correlation between IL-17 level and liver injury was studied. Th17 associated cytokines were also investigated by intracellular staining. Our results showed that the IL-17 expression was significantly elevated in the liver and serum of BALB/cJ mice infected with MHV-3. Moreover, a time course study showed that the percentage of both IL-17-producing CD4(+)T cells and IL-17-producing CD8(+)T cells was increased remarkably in the liver starting from 48 h and peaked at 72 h post-infection. There was a close correlation between hepatic or serum IL-17 concentration and the severity of liver injury defined by ALT level, respectively. Th17 associated cytokines, IL-6, IL-21 and IL-22, were also increased significantly at 72 h post-infection. It was concluded that IL-17 may contribute to the pathogenesis of MHV-3-induced acute liver failure.
Animals ; Female ; Hepatitis, Viral, Animal ; metabolism ; Interleukin-17 ; metabolism ; Liver Failure, Acute ; metabolism ; virology ; Mice ; Mice, Inbred BALB C ; Murine hepatitis virus ; metabolism

OBJECTIVETo establish a animal model of hepatic steatosis induced by chronic viral hepatitis in C(57)BL/6 mice.

METHODSC(57)BL/6 mice were randomly assigned to control group, high-fat diet group, mouse hepatitis virus strain A59 (MHV-A59) virus infection group, and high-fat diet plus virus infection group. At 13 weeks of the experiment, serum samples were collected to detect MHV antibodies and transaminase and lipid levels. The hepatic pathologies of the mice were examined with Oil red O staining of the frozen sections the and HE staining of paraffin-embedded sections.

RESULTSThe mice in the two virus infection groups showed strong positivity of MHV antibodies in the serum. Compared with the control group, the mice in high-fat diet group and the two virus infection groups had significantly increased AST and ALT levels with also elevated TC and LDL-C levels. The two virus infection groups both exhibited obvious pathologies in the liver characteristic of chronic viral hepatitis with increased lipid accumulation in the hepatocytes.

CONCLUSIONWe have successfully established a mouse model of hepatic steatosis induced by chronic viral hepatitis, which provides the basis for further study of the disease mechanism.

Animals ; Antibodies, Viral ; blood ; Chronic Disease ; Diet, High-Fat ; Disease Models, Animal ; Fatty Liver ; virology ; Hepatitis, Chronic ; virology ; Mice ; Mice, Inbred C57BL ; Murine hepatitis virus

Many studies have recently reported reactivation in hepatitis B surface antigen (HBsAg)-negative subjects with the use of biologic agents such as rituximab. However, occult hepatitis B virus infection itself has little clinical impact. We experienced a case of acute exacerbation caused by occult hepatitis B infection without HBsAg seroconversion. No mutation was found on the major hydrophilic loop of the S protein. The patient recovered from acute exacerbation after antiviral therapy. In conclusion, acute exacerbation can be induced by occult hepatitis B virus infection itself without reactivation. In such a case, antiviral therapy should be considered.
Antibodies, Monoclonal, Murine-Derived ; Hepatitis ; Hepatitis B ; Hepatitis B Surface Antigens ; Hepatitis B virus ; Humans ; Rituximab

OBJECTIVETo explore the mechanisms of a novel potassium channel gene named KCTD9 (potassium channel tetramerization domain containing 9) in model of fulminant viral hepatitis induced by murine hepatitis virus 3 (MHV-3).

METHODS78 BALB/cJ mice(6 male) were randomly and equally assigned to two groups, model group of fulminant viral hepatitis induced by MHV3 and its control. 75 C3H/HeJ female mice were done into two groups, 39 for model group of chronic hepatitis induced by MHV3, 36 for control. Various samples including spleen, liver and lymphocytes from mice of two model groups and the controls were examined for KCTD9 expression by real time quantitative PCR and Immunohistochemistry. Independent-samples T test or one-way ANOVA were carried out in different groups.

RESULTSIncreased expressions of KCTD9 mRNA was observed in livers of both model mice of fulminant viral hepatitis and chronic hepatitis. Compared with the control mice, the expressions of KCTD9 mRNA were up-regulated by 577.1-, 8.8-, 59.4- and 10.8-fold in hepatic NK cells, CD4+ T cells, CD8+ T cells and splenic NK cells respectively in model mice of fulminant viral hepatitis 48 hr post MHV-3 infection, whereas down-regulation by 43% and 69% in splenic CD4 + T cells and CD8+ T cells were found respectively. In contrast, in model mice of chronic viral hepatitis the expressions of KCTD9 mRNA were down-regulated by 71% and 51% in hepatic CD4+ T cells and NK cells, respectively. The expression of KCTD9 protein was mainly evidenced in infiltrative mononuclear cells of liver as shown by immunohistochemistry. Basal expression was also investigated and showed constitutive expression of KCTD9 in brain, thymus and other organs in BALB/cJ mice.

CONCLUSIONA novel potassium channel gene KCTD9 was highly expressed in hepatic NK cells and T cells of fulminant hepatitis mice induced by MHV-3.

Animals ; CD4-Positive T-Lymphocytes ; immunology ; metabolism ; Female ; Hepatitis, Viral, Animal ; immunology ; metabolism ; virology ; Killer Cells, Natural ; immunology ; metabolism ; Liver ; metabolism ; virology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Murine hepatitis virus ; Potassium Channels ; genetics ; metabolism

In order to assess the microbiological contamination of laboratory mice and rats in Korea over the 2-year period from 2007 to 2008, we monitored animals housed in mouse and rat facilities equipped with barrier systems. In a barrier animal facility in Korea, the most important viruses in the identified pathogen were the mouse hepatitis virus (MHV) and Pasteurella (Pa.) pneumotropica, and Staphylococcus aureus was identified as the most common bacterial pathogen in Korea. The most commonly detected parasite in the identified pathogen was Trichomonas spp. in the mouse facilities and Entamoeba spp. in the rat facilities. In many cases, these pathogen-contaminated animals were genetically modified animals obtained from the university. Currently, consistent with the increased transfer of genetically modified animals between domestic and foreign animal facilities, the Pa. pneumotropica and parasites infection rates were shown to have increased as compared to those of the 2004-2006 period. Indeed, the MHV infection rate has been maintained at almost 20% in Korean animal facilities over the past 10 years. These results showed that effective quarantine programs for contaminated genetically engineered mutant mice and the monitoring of regular or irregular MHV monitoring in animal colonies should help to reduce pathogen contamination in Korean animal facilities.
Animals ; Animals, Genetically Modified ; Entamoeba ; Korea ; Mice ; Murine hepatitis virus ; Parasites ; Pasteurella ; Quarantine ; Rats ; Sendai virus ; Staphylococcus aureus ; Trichomonas

In order to assess the microbiological contamination of laboratory mice and rats in Korea over the 2-year period from 2007 to 2008, we monitored animals housed in mouse and rat facilities equipped with barrier systems. In a barrier animal facility in Korea, the most important viruses in the identified pathogen were the mouse hepatitis virus (MHV) and Pasteurella (Pa.) pneumotropica, and Staphylococcus aureus was identified as the most common bacterial pathogen in Korea. The most commonly detected parasite in the identified pathogen was Trichomonas spp. in the mouse facilities and Entamoeba spp. in the rat facilities. In many cases, these pathogen-contaminated animals were genetically modified animals obtained from the university. Currently, consistent with the increased transfer of genetically modified animals between domestic and foreign animal facilities, the Pa. pneumotropica and parasites infection rates were shown to have increased as compared to those of the 2004-2006 period. Indeed, the MHV infection rate has been maintained at almost 20% in Korean animal facilities over the past 10 years. These results showed that effective quarantine programs for contaminated genetically engineered mutant mice and the monitoring of regular or irregular MHV monitoring in animal colonies should help to reduce pathogen contamination in Korean animal facilities.
Animals ; Animals, Genetically Modified ; Entamoeba ; Korea ; Mice ; Murine hepatitis virus ; Parasites ; Pasteurella ; Quarantine ; Rats ; Sendai virus ; Staphylococcus aureus ; Trichomonas