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1.
Antiviral Res ; 184: 104953, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33065138

RESUMO

BACKGROUND & AIMS: Normal/mildly elevated ALT (<2 × ULN) CHB patients are potentially at risk of progression to cirrhosis and/or hepatocellular carcinoma (HCC). We aimed to assess the outcomes of anti-viral therapy for normal/mild elevation of ALT CHB patients. METHODS: CHB patients (n = 432) who have had liver biopsied were determined. It was determined that the outcomes of anti-viral therapy in CHB patients with normal/mild elevation of ALT, in response to nucleoside/nucleotide analogues (NAs) (n = 190) and pegylated interferon (PEG-IFN) (n = 30) treatment for up to 72 weeks. Non-anti-viral treated patients were used as control (n = 40). RESULTS: There was about 50% of the CHB patients showed hepatic inflammatory necrosis ≥ G2 and/or fibrosis ≥ S2 among >30-years-old. The rate of undetectable HBV DNA in NAs and PEG-IFN groups was ~50%, ~80% or ~90% at week 24, 48 or 72, respectively. HBeAg clearance rate was lower in NAs treated than that in PEG-IFN group at week 48 (6% vs 20%, P < 0.05). ALT normalization rate was increased by 1.18-fold at week 72. HBsAg decline in HBeAg+ patients treated with NAs or PEG-IFN was 0.418 or 1.217 log IU/mL (P < 0.0001) at week 48; whereas HBsAg decline was 0.176 or 0.816 log IU/mL (P < 0.001) in HBeAg- patients. HBsAg at baseline and week 24 were strong predictors of "low HBsAg at week 48". CONCLUSION: Long term anti-viral therapy inhibits HBV replication effectively in ALT<2 × ULN CHB patients. PEG-IFN therapy is recommended for HBeAg+ patients with baseline HBsAg<4.37 log IU/ml and HBeAg- patients with baseline HBsAg<2.66 log IU/ml to achieve "low HBsAg at week 48".

2.
Am J Gastroenterol ; 115(12): 2026-2035, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32858565

RESUMO

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is defined by the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) consortium and the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) as an acute deterioration of cirrhosis with multiple organ failures and high short-term mortality. However, their diagnostic criteria differ. We aimed to compare these 2 criteria in the prediction of prognosis in hospitalized cirrhosis. METHODS: This was a prospective study of nonelectively hospitalized patients with cirrhosis (N = 468) from a single tertiary hospital between 2016 and 2018. Baseline characteristics, incidence, and types of organ failure and survival data at 7, 28, and 90 days were collected. Prognostic utilities of the 2 criteria were compared. RESULTS: One hundred thirty-seven of 468 patients (29.3%) had EASL-CLIF ACLF, and 35 of 468 (7.4%) had NACSELD ACLF. The 28-day transplant-free survival of ACLF was 58.4% using EASL-CLIF and 37.1% using the NACSELD criteria. In predicting 28-day mortality, the NACSELD criteria demonstrated significantly higher overall accuracy (92.0% vs 85.3%, P < 0.01), specificity (99.7% vs 84.0%, P < 0.001), and positive predictive value (97.1% vs 50.4%, P < 0.001) but lower sensitivity (49.3% vs 92.5%, P < 0.001) and negative predictive value (91.6% vs 98.5%, P < 0.001) than those of EASL-CLIF. The results were similar in predicting 7-day outcome. However, the overall accuracy became similar between NACSELD and EASL-CLIF ACLF criteria in predicting 90-day mortality (86.3% vs 88.7%, P = 0.27) because of the decrease of sensitivity and negative predictive value of NACSELD ACLF criteria. The prognostic performance of these 2 ACLF criteria was similar when applied to patients with or without hepatitis B virus infection as an etiology of cirrhosis. DISCUSSION: There are both caveats and utilities of NACSELD and EASL-CLIF ACLF criteria in prognosis prediction in patients with cirrhosis. NACSED criteria is highly accurate in predicting morality, whereas the EASL-CLIF criteria is more sensitive to identify patients who would benefit from liver transplantation.

3.
World J Gastroenterol ; 26(6): 645-656, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32103873

RESUMO

BACKGROUND: Reports on bacterial infection (BI) in decompensated cirrhosis (DC) is mainly from alcoholic cirrhosis. The role of BI as a trigger or complication of acute-on-chronic liver failure (ACLF) in patients with hepatitis B virus decompensated cirrhosis (HBV-DC) remains to be investigated. AIM: To investigate the impact of BI on the outcomes of the patients with HBV-DC admitted into the hospital with or without ACLF. METHODS: This retrospective study included patients with HBV-DC admitted to two tertiary centers in China. In-hospital overall survival, 90-d transplant-free survival, 5-year post-discharge survival, and cumulative incidence of ACLF were evaluated. Risk factors for death were analyzed considering liver transplantation as a competing event. RESULTS: A total of 1281 hospitalized HBV-DC patients were included; 284 had ACLF at admission. The overall prevalence of BI was 28.1%. The patients with BI had a significantly lower in-hospital survival and transplant-free 90-d survival than those without, in both the patients admitted with and without ACLF. The presence of BI significantly increased the risk of developing ACLF [sub-distribution hazard ratio (sHR) = 2.52, 95%CI: 1.75-3.61, P < 0.001] in the patients without ACLF. In the patients discharged alive, those who had an episode of BI had a significantly lower 5-year transplant-free survival. BI was an independent risk factor for death in the patients admitted without ACLF (sHR = 3.28, 95%CI: 1.93-5.57), while in ACLF admissions, the presence of pneumonia, but not other type of BI, independently increased the risk of death (sHR = 1.87, 95%CI: 1.24-2.82). CONCLUSION: BI triggers ACLF in patients with HBV-DC and significantly impairs short-term survival. HBV-DC patients should be monitored carefully for the development of BI, especially pneumonia, to avoid an adverse outcome.

4.
Liver Int ; 39(10): 1943-1953, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31206235

RESUMO

BACKGROUND: Hepatitis B virus (HBV) flare can occur in HBV patients either naïve or have interruption to treatment. Bacterial infection (BI) is a common complication of cirrhosis with potential severe outcomes. We aimed to assess the impact of HBV flare on the outcome of patients with HBV-related decompensated cirrhosis and BI. METHODS: This was a retrospective study from 2 tertiary academic hospitals in Shanghai, China of HBV patients admitted with or developed BI during admission. The characteristics of BI, prevalence of HBV flare, its impact on organ failure, acute-on-chronic liver failure (ACLF) and 90-day survival were evaluated. RESULTS: A total of 360 hospitalized patients (median age: 50 years, male: 79%, BI: at admission: 58.6%; during admission: 41.4%) were included. All patients including those with HBV flare (21%) received antiviral therapy after admission. Patients with HBV flare and BI had significantly higher percentage of liver (93.3% vs 48.8%), coagulation (64.0% vs 39.6%), cerebral (40.0% vs 21.8%) (all P < 0.01), and kidney failure (38.7% vs 26.3%, P < 0.05) compared to BI alone, associated with a higher risk of developing ACLF with a subdistribution hazard ratio (sHR) of 2.23 (95% confidence interval [CI]: 1.68-2.96). Multivariate analysis showed that ACLF development was the strongest risk factor for 90-day mortality (sHR, 95%CI: 7.36, 4.12-13.16). CONCLUSIONS: In HBV-related decompensated cirrhosis patients admitted with BI, HBV flare increased the risk of additional organ failures and ACLF, raising the risk of 90-day mortality by seven-fold. Optimization of HBV treatment in these patients should minimize the risk of HBV flare with improved outcomes.


Assuntos
Insuficiência Hepática Crônica Agudizada/mortalidade , Infecções Bacterianas/epidemiologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/complicações , Cirrose Hepática/epidemiologia , Insuficiência Hepática Crônica Agudizada/microbiologia , Insuficiência Hepática Crônica Agudizada/terapia , Adulto , Antivirais/uso terapêutico , China , DNA Viral/sangue , Feminino , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos , Insuficiência Renal/complicações , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Carga Viral
5.
Biosci Trends ; 13(2): 130-135, 2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-30930359

RESUMO

Single nucleotide polymorphisms (SNP) influence the outcome of antiviral therapy in chronic hepatitis B patients. Interferon ß promoter stimulator 1 polymorphisms (IPS-1) regulate interferon (IFN) mediated viral clearance in hepatitis B virus (HBV) infection. In our study, HepG2 and HepG2.2.15 were transfected with different SNP genotype expression vectors of IPS-1 (wild-type, rs17857295, rs7262903 and rs7269320). The production of IPS-1 and IFN were evaluated in these transfected cells. IPS-1 in the HepG2.2.15 cells transfected with rs17857295 or rs7262903 was 37% or 31% lower than that with wild-type transfection (p < 0.001). IFN-ß in rs17857295 or rs7262903 transfected HepG2.2.15 cells was 5.4 or 3.7 fold higher than that of wild-type transfection (p < 0.0001). IPS-1 in rs7269320 SNP transfected HepG2.2.15 cells was 40% lower than that of wild-type transfection (p < 0.0001); no significantly different IFN-ß was observed between rs7269320 SNP and wild-type transfections. IFN-ß expression was > 2 fold higher in rs17857295 transfected HepG2.2.15 cells than HepG2 cells (p < 0.001). The data suggests that host HBV viral clearance is stronger in IPS-1 rs17857295 or rs7262903 SNP genotype patients than wild-type patients. Relatively weak inducible IFN-ß production in HBV infected patients with IPS-1 rs7269320 SNP or wild-type may contribute to chronic virus infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Hepatite B/genética , Interferon beta/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Vetores Genéticos/metabolismo , Genótipo , Células HEK293 , Células Hep G2 , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
6.
Cell Biosci ; 8: 14, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29484170

RESUMO

Background: Chronic hepatitis B (CHB) remains a global health dilemma with high morbidity and mortality. Human males absent on the first (hMOF) (a histone acetyltransferase) is responsible for DNA damage repair, tumorigenesis and cell cycle regulation. Persistence of HBV DNA contributes to cirrhosis and hepatocellular carcinoma (HCC) in CHB patients. Histone acetyltransferase enhances HBV replication, however the precise underlying mechanism of hMOF in HBV replication in CHB patients remains to be explored. This study aims to investigate the correlation between hepatic hMOF and HBV DNA replication in CHB patients, and may provide new insights towards the treatment of CHB patients. Methods: hMOF in liver biopsy (CHB, n = 33 HBeAg+; n = 20 HBeAg-, and three healthy controls) was determined, using immunohistochemistry, qPCR and Western blot. The correlation between hMOF and HBsAg, as well as, HBeAg were determined. Results: A positive correlation between hMOF and HBV DNA in overall CHB patients was observed. A distinct positive correlation between hMOF and HBsAg and/or HBeAg in HBeAg+ CHB patients was also detected, however not observed between hMOF and HBsAg in HBeAg- CHB patients. No correlation was observed between hMOF and hepatic inflammation severity and fibrotic stage in CHB patients. Conclusions: Hepatic hMOF might contribute to host HBV clearance in CHB patients and possible pathogenesis.

7.
Oncotarget ; 8(62): 105407-105424, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29285260

RESUMO

Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p<0.001; 0.34(0.21-0.55), p=0.001; or 0.46(0.25-0.83), p=0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p=0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p=0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p=0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC.

8.
Liver Int ; 37(11): 1612-1621, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28772348

RESUMO

BACKGROUND & AIMS: Serum Golgi protein 73 (GP73) is a potential biomarker for fibrosis assessment. We aimed to develop an algorithm based on GP73 and liver stiffness (LS) for further improvement of accuracy for significant fibrosis in patients with antiviral-naïve chronic hepatitis B virus (HBV) infection. METHODS: Diagnostic accuracy evaluation of GP73 and development of GP73-LS algorithm was performed in training cohort (n = 267) with an independent cohort (n = 133) for validation. RESULTS: A stepwise increasing pattern of serum GP73 was observed across fibrosis stages in patients with antiviral-naïve chronic HBV infection. Serum GP73 significantly correlated (rho = 0.48, P < .001) with fibrosis stage and was an independent predictor for the presence of significant fibrosis (OR, 95%CI: 1.02, 1.01-1.03, per increase in 1 ng/mL, P < .001). Both LS (AUROC, 95%CI: 0.82, 0.77-0.87, accuracy: 74.7%) and GP73 (AUROC, 95%CI: 0.76, 0.71-0.82, accuracy: 71.5%) well-predicted significant fibrosis and outperformed APRI (AUROC, 95%CI: 0.69, 0.63-0.76, accuracy: 66%) and FIB-4 (AUROC, 95%CI: 0.66, 0.60-0.73, accuracy: 63.6%). Using GP73-LS algorithm, GP73 < 63 in agreement with LS < 8.5 provided accuracy of 81.7% to excluded significant fibrosis. GP73 ≥ 63 in agreement with LS ≥ 8.5 provided accuracy of 93.3% to confirm significant fibrosis. Almost 64% or 68% of patients in the training or validation cohort could be accurately classified. CONCLUSIONS: Serum GP73 is a robust biomarker for significant fibrosis diagnosis. GP73-LS algorithm provided better diagnostic accuracy than currently available approaches. More than 60% antiviral naïve CHB patients could use this algorithm without resorting to liver biopsy.


Assuntos
Hepatite B Crônica/complicações , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Fígado/fisiopatologia , Proteínas de Membrana/sangue , Adulto , Algoritmos , Biomarcadores/sangue , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade
9.
J Med Virol ; 89(11): 1973-1980, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28671305

RESUMO

The diversity of HCV genotypes is ever-evolving and requires continuous surveillance. The aim of this study was to investigate the dynamics of HCV genotypes, and their associated demographic and clinical patterns in China. By searching computerized hospital information system, a total of 1155 HCV-positive patients eligible for analysis were retrospectively identified from 12 380 consecutive in-patients in the Department of Infectious Diseases, Ruijin Hospital in China between 2009 and 2014. The percentages of HCV genotype 1, 2, 3, or 6 were 61.3%, 12.8%, 18.5%, or 7.4%, respectively. The number of patients hospitalized for HCV infection increased gradually over the study period, particularly those infected by genotype 3 HCV. Patients of genotype 1, 2, 3, or 6 were significantly different. Genotype 1 or two patients were much older, with higher proportion of blood transfusion history. In contrast, genotype 3 or six patients were younger, predominantly male, with more exposure to intravenous drug use. The cirrhosis incidence was higher in genotype 1 or two patients, followed by genotype 3 and six patients. Strikingly, genotype 3 cirrhotic patients were younger, and their estimated infection durations were also shorter, suggestive of a faster disease progression in genotype 3 patients. Multivariate analysis demonstrated that presence of HBcAb was an independent predictor of cirrhosis (OR 2.19, 95%CI 1.27-3.42; P = 0.004). The leading increase and the younger trend of cirrhosis incidence in genotype 3 patients argue for a higher priority to manage the infection in this highly at-risk population.


Assuntos
Hepacivirus/genética , Hepatite C Crônica/epidemiologia , Hepatite C/epidemiologia , Cirrose Hepática/epidemiologia , Adulto , Fatores Etários , Idoso , China/epidemiologia , Progressão da Doença , Feminino , Genótipo , Hepacivirus/imunologia , Antígenos de Superfície da Hepatite B/sangue , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Hospitalização , Humanos , Incidência , Cirrose Hepática/sangue , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Abuso de Substâncias por Via Intravenosa/complicações , Adulto Jovem
10.
J Gastroenterol Hepatol ; 32(3): 677-686, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27548078

RESUMO

BACKGROUND AND AIM: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is an acute deterioration of liver function on chronic liver disease with immune disorder. Th22 cells and IL-22 were correlated with inflammatory and autoimmune diseases. However, Th22 cells and IL-22 in the pathogenesis of HBV-ACLF remains to be elucidated. It was investigated the correlation between Th22 and prognosis in HBV-ACLF. METHODS: Seventy-one HBV-ACLF and 65 chronic hepatitis B patients were recruited. The peripheral frequencies of Th22, Th17 and Th1, or IL-22 and IL-17 were determined, using flow cytometry or ELISA, respectively. It was further analyzed the correlation between Th22 mediated circulating IL-22 and survival rate of HBV-ACLF patients. RESULTS: It was upregulated that the peripheral frequencies of Th22/Th17 cells as well as plasma IL-22 and IL-17 in HBV-ACLF patients, but the frequency of Th1 cells was decreased, compared with health controls. Elevated Th22 cells and IL-22 were correlated with HBV-ACLF disease severity. Elevated plasma IL-22 level (>29.5 pg/ml) was correlated with poor survival rate of HBV-ACLF patients at baseline, using Kaplan-Meier analysis. CONCLUSIONS: Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-ACLF. Th22 cells/IL-22 might be served as biomarkers for evaluating the prognosis of HBV-ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada/etiologia , Hepatite B Crônica/complicações , Interleucinas/sangue , Linfócitos T Auxiliares-Indutores , Insuficiência Hepática Crônica Agudizada/mortalidade , Adulto , Biomarcadores/sangue , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/mortalidade , Humanos , Interleucinas/imunologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Linfócitos T Auxiliares-Indutores/imunologia , Adulto Jovem
11.
Cell Biosci ; 5: 66, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26640654

RESUMO

BACKGROUND: The initiation of hepatitis B virus (HBV) replication involves the formation of covalently closed circular DNA (cccDNA) and its transcription into pregenomic RNA (pgRNA) in hepatocyte nuclei. The regulatory mechanism of HBV replication by acetyltransferase is thus far not well understood, but human acetyltransferase has been reported as being involved in the regulation of HBV replication. RESULTS: Depletion of KAT8 or HAT1 via RNA interference (RNAi) markedly down-regulated HBV-DNA and pgRNA levels in HepG2.2.15 cells, with KAT8 knockdown reducing both HBsAg and HBeAg more than HAT1 knockdown. Consistent with these observations, HBV replication regulators hepatocyte nuclear factor-4-α (HNF4α) and peroxisome proliferator-activated receptor gamma coactivator- (PPARGC-) 1-α were decreased following knockdown of HAT1 or KAT8. CONCLUSIONS: These data suggest that KAT8 or HAT1 regulate HBV replication and may be potential drug targets of anti-HBV therapy.

12.
Zhonghua Gan Zang Bing Za Zhi ; 23(1): 34-9, 2015 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-25751384

RESUMO

OBJECTIVE: To investigate the changes in circulating plasmacytoid dendritic cells (pDCs) in patients with chronic hepatitis B (CHB) during the course of treatment with pegylated-interferon alfa-2s (peg-IFNa-2a) and to determine the correlations with therapeutic response. METHODS: Forty-one patients with CHB who were receiving peg-IFNa-2a antiviral treatment for 48 weeks were enrolled in the study.Expression of the Toll-like receptor 9 (TLR9) on and frequency and functionality of the pDCs were analyzed at treatment weeks 0, 2, 12, 24, 36 and 48. RESULTS: All patients exhibited an initially rapid decrease in the numbers of circulating pDCs and showed CpG-induced endogenous IFNa production within the first 2 weeks of treatment.Subsequently, all responders displayed a continuous increase in pDC numbers as well as functionality, both of which peaked around week 12 of treatment; in addition, these treatment responses were accompanied by significantly increased levels of type 1 T helper cytokines (P less than 0.05), which did not occur in the non-responders. CONCLUSION: pDCs are involved in the initial therapeutic immune response stimulated by peg-IFNa-2a treatment.Recovery of blood pDC number and functionality may represent a predictor of favorable response to peg-IFNa-2a antiviral treatment in patients with CHB.


Assuntos
Células Dendríticas , Hepatite B Crônica , Antivirais , Humanos , Interferon-alfa , Polietilenoglicóis , Proteínas Recombinantes , Receptor Toll-Like 9 , Resultado do Tratamento
13.
Infect Genet Evol ; 31: 161-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25640825

RESUMO

AIMS: To investigate whether IPS1 polymorphisms affect peginterferon alpha (PEG-IFN) efficacy in chronic hepatitis B (CHB) patients using a tag- single nucleotide polymorphism (SNP) approach. METHODS: A total of 212 hepatitis B e antigen (HBeAg)-positive patients treated with a 48weeks of PEG-IFN monotherapy were enrolled initially and 127 patients were followed for 48weeks posttreatment. Genotype analysis was performed for 10 tag-SNPs in IPS1. RESULTS: The end of virological response (EVR) rate was 45.8% (97/212) and the sustained virological response (SVR) rate was 45.7% (58/127). Meanwhile, 35.4% (75/212) achieved HBeAg seroconversion at the end of treatment. In a multivariate analysis, the rs2464 CC genotype was independently associated with EVR (OR 2.21, 95% CI 1.23-3.98, P=0.008) and SVR (OR 2.34, 95% CI 1.05-5.20, P=0.037) after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. Meanwhile, rs2464 CC genotype were also independently associated with decline of HBsAg levels below 1500IU/mL at 12weeks of treatment (OR 2.52, 95% CI 1.01-6.29, P=0.047). Furthermore, three SNPs were found to be independently associated with HBeAg seroconversion at the end of treatment. (1) The rs2326369 CC genotype was independently associated with no HBeAg seroconversion (OR 0.52, 95% CI 0.29-0.95, P=0.034); (2) The rs6515831 TT genotype was independently associated with HBeAg seroconversion (OR 2.11, 95% CI 1.14-3.90, P=0.017); (3) The rs2464 CC genotype was independently associated with HBeAg seroconversion (OR 2.36, 95% CI 1.26-4.42, P=0.007). CONCLUSIONS: Polymorphisms in IPS1 are independently associated with treatment response to PEG-IFN among Chinese HBeAg-positive CHB patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antivirais/uso terapêutico , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Polimorfismo Genético , Adulto , Biomarcadores/sangue , China , Feminino , Genótipo , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Desequilíbrio de Ligação , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Adulto Jovem
14.
J Hepatol ; 63(1): 148-55, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25681556

RESUMO

BACKGROUND & AIMS: Th22 cells regulate host immunity against pathogenic invasion, including protecting host against chronic hepatitis B; however, the relationship between drug induced liver injury (DILI) and Th22/Th17 cells is still unclear. We investigated the role of Th22 cells in DILI development. METHODS: The frequencies of peripheral Th22/Th17/Th1 cells and intrahepatic IL-22/IL-17 production from DILI, non-DILI liver diseases, and healthy controls were examined. Plasma IL-22/IL-17 and the related cytokines were determined in DILI patients at week 0 (defined as the occurrence of liver injury within 7days), 4 and 24. Multivariable stepwise logistic regression was applied to explore the associations between various factors and recovery of DILI. RESULTS: The frequencies of Th22/Th17 cells were significantly higher in DILI onset patients than HC. Significant increase of Th22 cells and the related cytokines levels was observed in DILI with hepatocellular injury type. There was a positive correlation between intrahepatic IL-22 level and liver regeneration. Plasma IL-22 level was higher in DILI patients with improved liver function than unimproved function. Multivariable analysis showed that the odds ratio (OR) of plasma IL-22 at 4weeks was 1.054 [95% confidence interval (CI), 1.012, 1.124]. CONCLUSIONS: Increased peripheral and intrahepatic IL-22-secreting cells are detected in DILI. Th22 and its related cytokines might be hepato-protective, which might provide new perspective for understanding the immunopathogenesis of DILI. Plasma IL-22 might be a reliable indicator to evaluate the prognosis of DILI and provide a novel therapeutic target for DILI treatment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Interleucinas/metabolismo , Fígado/metabolismo , Células Th17/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Seguimentos , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Células Th17/metabolismo
15.
Liver Int ; 35(2): 473-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24517415

RESUMO

AIMS: To investigate whether IL28B polymorphisms could affect the treatment response to peginterferon alpha (PEG-IFN) in chronic hepatitis B (CHB) patients in the Chinese Han population. METHODS: A total of 212 hepatitis B e antigen (HBeAg)-positive patients treated with PEG-IFN monotherapy were enrolled in this study. Genotype analysis was performed for IL28B rs12980275, rs12979860 and rs8099917 using the MassArray system. Response was defined as cases showing normal aminotransferase (ALT) levels, HBV DNA level < 200 IU/ml and HBeAg seroconversion after 48 weeks of PEG-IFN therapy. RESULTS: The patients were infected with hepatitis B virus (HBV) genotype B (44.8%) and C (55.2%) with a total response rate of 34.9%. For the three SNPs, there were significant differences between the response (R) and non-response (NR) groups both in allele frequencies and genotype distributions. IL28B genotype was independently associated with R for AA vs. N-AA (OR 2.70, 95% CL 1.21-6.01; P = 0.015) at rs12980275 after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. There were similar results for rs12979860 CC vs. N-CC (OR 2.56, 95% CL 1.15-5.67; P = 0.021) and rs8099917 TT vs. N-TT (OR 2.80, 95% CL 1.23-6.39; P = 0.015) respectively. Furthermore, one block formed by rs12980275 and rs12979860 was identified in this study. In multivariate analyses, the most common haplotype A-C was independently associated with high rates of R (OR 2.53, 95% CL 1.20-5.34; P = 0.015). CONCLUSIONS: Our study suggested that genetic variations in IL28B may play a critical role in PEG-IFN efficacy in HBeAg-positive CHB patients in Han Chinese.


Assuntos
Grupo com Ancestrais do Continente Asiático , Hepatite B Crônica/virologia , Interferon-alfa/uso terapêutico , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Alanina Transaminase/sangue , Frequência do Gene , Estudos de Associação Genética , Genótipo , Antígenos E da Hepatite B/metabolismo , Humanos , Interferons , Análise Multivariada , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
16.
Zhonghua Gan Zang Bing Za Zhi ; 22(11): 806-11, 2014 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-25531375

RESUMO

OBJECTIVE: To evaluate the efficacy of nucleos(t)ide analogues (NA) treatment and to assess the long-term outcomes, including survival, liver function improvement and virologic response, in patients with decompensated cirrhosis due to hepatitis B virus (HBV) infection. METHODS: Patients with Child-Turcotte-Pugh (CTP) scores more than or equal to 7, who had been treated with either lamivudine or other agents, but who were free of co-infection with other hepatitis virus were enrolled between January 2005 and December 2009. The study participants were subgrouped according to the antiviral drugs received or model for endstage liver disease (MELD) score for comparative analyses.Additionally, the 19 patients who were treated with NA for more than 5 years were investigated for changes in biochemical and virological indices, before and after the antiviral treatment. RESULTS: A total of 166 patients (125 males; 89 e-negative) and 52 untreated healthy patients (as control) were analyzed.The cohort of patients receiving antiviral therapy had significantly better 5-year actuarial survival than the untreated patients (74.1% vs.34.9%, P less than 0.001). For patients with MELD score more than or equal to 18, actuarial survival was not significantly different between the two groups (P=0.073). CONCLUSION: Antiviral therapy significantly increases survival and improves the clinical long-term outcome of patients with HBV-induced decompensated cirrhosis.Antiviral treatment should be initiated at an early stage to maximize benefit in the improvement of clinical status.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/etiologia , Administração Oral , Antivirais/administração & dosagem , Estudos de Coortes , Coinfecção , Feminino , Vírus da Hepatite B , Hepatite B Crônica/complicações , Humanos , Lamivudina , Masculino , Estudos Retrospectivos , Resultado do Tratamento
17.
PLoS One ; 8(7): e68757, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874752

RESUMO

BACKGROUND: Acute-on-chronic liver failure (ACLF) is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor)/TNFR (tumor necrosis factor receptor) 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc]) prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55) pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF. METHODOLOGY: Chronic liver disease (liver fibrosis/cirrhosis) was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA), and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN)/lipopolysaccharide (LPS) i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations. PRINCIPAL FINDINGS: Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL)-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA). This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats. CONCLUSIONS: sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.


Assuntos
Falência Hepática Aguda/tratamento farmacológico , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores Chamariz do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores Chamariz do Fator de Necrose Tumoral/metabolismo , Animais , Galactosamina/farmacologia , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Lipopolissacarídeos/farmacologia , Fígado , Falência Hepática , Ratos , Ratos Wistar , Receptores do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/imunologia , Albumina Sérica/farmacologia
18.
Int J Mol Med ; 30(6): 1498-504, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22992810

RESUMO

Chronic hepatitis B (CHB) virus infection is caused by compromised host immunity, but the precise underlying mechanism remains unclear. Retinoic acid-inducible gene I (RIG-I) triggers antiviral immunity by inducing interferon-ß (IFN-ß) production following viral infection. To investigate the role of the RIG-I-IFN-ß signaling pathway in monocyte-derived dendritic cells (moDCs) during CHB infection, moDCs were generated by stimulating CD14+ monocytes in vitro. MoDCs from patients with CHB, acute hepatitis B (AHB) and healthy controls (HCs) were challenged with vesicular stomatitis virus (VSV) and the levels of RIG-I, IFN-ß promoter stimulator 1 (IPS-1) and IFN-ß in the stimulated moDCs were determined. Following 16 h of VSV stimulation, RIG-I expression was reduced by 50% in moDCs from CHB patients and by 70% in moDCs from AHB patients relative to HC moDCs, concomitant with a 20% decrease in IFN-ß expression in CHB patients relative to AHB patients and HCs. Additionally, a significant correlation between the RIG-I/IPS-1 ratio and alanine aminotransferase (ALT) level was observed. To further investigate the function of RIG-I in chronic hepatitis B virus (HBV) infection, HepG2 or HepG2.2.15 (HBV-transformed) cell lines were challenged with VSV following RIG-1 transfection. IFN-ß induction was suppressed in HepG2.2.15 cells, but was restored following RIG-I transfection. Taken together, these data indicate that compromised moDC function in CHB patients is attributable to an impaired RIG-I-IFN-ß signaling pathway, which results in compromised host viral clearance and HBV persistence in a susceptible population.


Assuntos
RNA Helicases DEAD-box/metabolismo , Hepatite B Crônica/metabolismo , Interferon beta/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Estudos de Casos e Controles , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Feminino , Células Hep G2 , Vírus da Hepatite B/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Interferon beta/genética , Masculino , Ativação Transcricional , Vesiculovirus/fisiologia
19.
Zhonghua Gan Zang Bing Za Zhi ; 20(3): 185-9, 2012 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-22475136

RESUMO

OBJECTIVE: To explore the categories of drugs causing hepatotoxicity and analyze the clinical and histological features of the corresponding drug-induced liver injury (DILI), in order to gain insights into potential diagnostic factors for DILI. METHODS: A total of 138 DILI patients treated at our hospital from April 2008 to April 2010 were retrospectively analyzed. The responsible drug for each DILI case was recorded. The Roussel Uclaf Causality Assessment Method (RUCAM) had been used to diagnose DILI. Only cases that had scored as highly probable or probable (more than or equal to 6 points by RUCAM) were included in this study. The patients' general condition, clinical manifestations, and serum biochemical and immunological parameters were assessed. Sixty-six of the patients underwent liver biopsy, and were assessed for liver pathological changes. Clinical and laboratory test data were collected and used to classify the total 138 cases as hepatocellular injury, cholestatic, or mixed hepatocellular-cholestatic types. RESULTS: Within our patient population, the leading cause of DILI was Chinese herb medicine, accounting for 53.62% of cases. Antibiotics were implicated in 7.97% of cases, and dietary supplement in 6.52% of cases. Correlation between the clinical features and histological injury pattern was stronger at the time of biopsy (more than or equal to 3 days after laboratory results) (kappa = 0.63, P less than 0.05) than at the onset of DILI (kappa = 0.25, P less than 0.05). All modified hepatic activity index (HAI) necroinflammatory scores and fibrosis scores were more severe in the cholestatic and mixed injury types than in the hepatocellular injury type (P less than 0.01 and P less than 0.05, respectively). CONCLUSION: Chinese herbal medicine, dietary supplements and antibiotics were the main causes of DILI in our patient population. The clinical and histological features correlated well, especially at later stages of DILI. The degree of inflammation and fibrosis was significantly higher in cholestatic and mixed hepatocellular-cholestatic injury types than in the hepatocellular injury type. Assessment of both clinical and pathological features may represent a more accurate diagnostic method for DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Medicamentos de Ervas Chinesas/efeitos adversos , Fígado/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/efeitos adversos , Anti-Infecciosos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Apoptosis ; 17(7): 702-16, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22374434

RESUMO

Acute liver failure (ALF) still has an unacceptable high mortality rate, despite substantial improvements with multidisciplinary care. The precise underlying mechanism of ALF remains to be explored. It has been reported that microRNAs (miRNAs) are novel regulators in a number of liver diseases, but the role of miRNAs in the development of ALF is not fully understood. An ALF murine model was generated by ip injection of D: -GalN/LPS, which was confirmed with histopathology and biochemistry. The hepatic miRNA expression profile in ALF was determined by microarray and verified by qRT-PCR. The functions and signal pathways of the targeted genes of these deregulated miRNAs were predicted, using bioinformatics analysis. The possible underlying mechanism was investigated by exploring the relationship between miRNA modification and hepatocyte apoptosis. There were a total of 95 significantly changed miRNAs in ALF compared to mock-treated (P < 0.01). Among these 95 miRNAs, 20 were up-regulated and 26 were down-regulated at both 5 and 7 h time points. Bioinformatics analysis predicted that some of these 46 miRNAs were involved in apoptosis. Among the up-regulated miRNAs involved in apoptosis, miR-15b and miR-16 showed the highest enrichment and targeted the common anti-apoptotic gene, BCL2. Our in vitro data demonstrated that miR-15b and/or miR-16 regulated BCL2 at the protein level. Inhibition of miR-15b and/or miR-16 reduced hepatic apoptosis and TNF production. These data suggest that miR-15b and miR-16 regulate TNF mediated hepatic apoptosis via BCL2 during ALF, and may shed light on the development of a therapeutic strategy for treatment of ALF.


Assuntos
Apoptose/genética , Hepatócitos/metabolismo , Falência Hepática Aguda/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Biologia Computacional , Regulação para Baixo/genética , Citometria de Fluxo , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Hepatócitos/patologia , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/genética
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