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Hepatitis C Virus and Hepatocellular Carcinoma  [PDF]
Tatsuo Kanda,Osamu Yokosuka,Masao Omata
Biology , 2013, DOI: 10.3390/biology2010304
Abstract: Hepatitis C virus (HCV), a hepatotropic virus, is a single stranded-positive RNA virus of ~9,600 nt. length belonging to the Flaviviridae family. HCV infection causes acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that HCV-coding proteins interact with host-cell factors that are involved in cell cycle regulation, transcriptional regulation, cell proliferation and apoptosis. Severe inflammation and advanced liver fibrosis in the liver background are also associated with the incidence of HCV-related HCC. In this review, we discuss the mechanism of hepatocarcinogenesis in HCV-related liver diseases.
Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients  [PDF]
Sara Corchado, Luis F. López-Cortés, Antonio Rivero-Juárez, Almudena Torres-Cornejo, Antonio Rivero, Mercedes Márquez-Coello, José-Antonio Girón-González
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101760
Abstract: Objective To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism). Patients and Methods A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, ?238 TNF-α and ?592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count. Results Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of ?238 TNF-α genotype GG was detected in patients with significant liver fibrosis. Conclusions In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a ?238 TNF-α polymorphism in these patients.
Pathological Impact of Hepatitis B Virus Surface Proteins on the Liver Is Associated with the Host Genetic Background  [PDF]
Yuri Churin, Martin Roderfeld, Johannes Stiefel, Tilman Würger, Dirk Schr?der, Tomomitsu Matono, Hans-Joachim Mollenkopf, Roberta Montalbano, Malvika Pompaiah, Kurt Reifenberg, Daniel Zahner, Matthias Ocker, Wolfram Gerlich, Dieter Glebe, Elke Roeb
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090608
Abstract: Background While the immune pathogenesis caused by hepatitis B virus (HBV) infection has been studied extensively, little is known about direct pathogenic effects of HBV surface proteins. Here, we have investigated pathological cellular effects of HBV surface protein expression in the liver of transgenic mice with different genetic background. Methods The impact of HBV surface protein expression on the liver was studied in two mouse strains, BALB/c and C57BL/6. Histology and hydroxyproline assays were performed to investigate liver morphology and fibrosis. Gene expression and signaling were analyzed by microarray, qPCR and Western blotting. Results Expression of HBV surface proteins in the liver of transgenic mice induced activation of protein kinase-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (eIF2α) phosphorylation. Phosphorylation of eIF2α resulted in activation of the ER stress markers glucose regulated protein (GRP) 78 and pro-apoptotic C/EBP homologous protein (CHOP) in transgenic mice on BALB/c genetic background leading to stronger liver injury and fibrosis in comparison with transgenic mice on C57BL/6 background. Hepatic stellate cells represented the main collagen-producing liver cells in HBV transgenic mice. The key regulators of hepatocyte proliferation, transcription factors c-Jun and STAT3 were activated in HBV transgenic mice. Tumour incidence in transgenic mice was strain- and sex-dependent. Conclusions Extent of liver injury, fibrosis, and tumour development induced by hepatic HBV surface protein expression considerably depends on host genetic background.
Hepatitis C Virus, Cholesterol and Lipoproteins — Impact for the Viral Life Cycle and Pathogenesis of Liver Disease  [PDF]
Daniel J. Felmlee,Mohamed Lamine Hafirassou,Mathieu Lefevre,Thomas F. Baumert,Catherine Schuster
Viruses , 2013, DOI: 10.3390/v5051292
Abstract: Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects.
Nuevos tratamientos para la infección por virus de hepatitis C y el proceso de fibrosis hepática Novel treatments for hepatitis C viral infection and the hepatic fibrosis  [cached]
Alejandro Lugo-Baruqui,Carlos Alfredo Bautista López,Juan Armendáriz-Borunda
Revista médica de Chile , 2009,
Abstract: Hepatitis C virus (HCV) infection represents a global health problem due to its evolution to hepatic cirrhosis and hepatocellular carcinoma. The viral pathogenesis and infectious processes are not yet fully understood. The development of natural viral resistance towards the host immune system represents a mayor challenge for the design of alternative therapeutic interventions and development of viral vaccines. The molecular mechanisms of hepatic fibrosis are well described. New alternatives for the treatment of patients with HCV infection and hepatic cirrhosis are under intensive research. New drugs such as viral protease inhibitors and assembly inhibitors, as well as immune modulators have been studied in clinical trials. Additional alternatives include antifibrotic drugs, which reverse the hepatic cellular damage caused by HCV infection. This review makes reference to viral infective mechanisms, molecular pathways of liver fibrosis and overviews conventional and new treatments for HCV infection and liver fibrosis.
Nuevos tratamientos para la infección por virus de hepatitis C y el proceso de fibrosis hepática
Lugo-Baruqui,Alejandro; Bautista López,Carlos Alfredo; Armendáriz-Borunda,Juan;
Revista médica de Chile , 2009, DOI: 10.4067/S0034-98872009000200015
Abstract: hepatitis c virus (hcv) infection represents a global health problem due to its evolution to hepatic cirrhosis and hepatocellular carcinoma. the viral pathogenesis and infectious processes are not yet fully understood. the development of natural viral resistance towards the host immune system represents a mayor challenge for the design of alternative therapeutic interventions and development of viral vaccines. the molecular mechanisms of hepatic fibrosis are well described. new alternatives for the treatment of patients with hcv infection and hepatic cirrhosis are under intensive research. new drugs such as viral protease inhibitors and assembly inhibitors, as well as immune modulators have been studied in clinical trials. additional alternatives include antifibrotic drugs, which reverse the hepatic cellular damage caused by hcv infection. this review makes reference to viral infective mechanisms, molecular pathways of liver fibrosis and overviews conventional and new treatments for hcv infection and liver fibrosis.
Impact of IL12B Gene rs 3212227 Polymorphism on Fibrosis, Liver Inflammation, and Response to Treatment in Genotype 4 Egyptian Hepatitis C Patients  [PDF]
Samar Samir Youssef,Asmaa Mostafa Abd El-Aal,Amr Saad,Moataza Hassan Omran,Taher El Zanaty,Sameh Mohamed Seif
Disease Markers , 2013, DOI: 10.1155/2013/627589
Abstract: Introduction. Hepatitis C virus (HCV) infection affects almost 3% of the world's population with the highest prevalence in Egypt (15%). The standard therapy; pegylated interferon (PEG-IFN) and ribavirin, is effective in only 60% of Egyptian patients; moreover it is costly, prolonged, and has severe side effects, so prediction of response is essential to reduce burden of unfavorable treatment. Several viral and host factors have been proved to affect response to the treatment PEG-IFN and ribavirin; the strongest of them is polymorphisms near IL28B; nonetheless, nonresponse in patients with favorable IL28B is still unexplained, which implies the importance of studying other immunological factors that may correlate with response. Interleukin 12 (IL-12) is one of the most important proinflammatory cytokine presented with the initiation of immune response, determining Th1 and Th2 differentiation. A functional single nucleotide polymorphism (A/C) at the 3′ untranslated region (3′UTR) at position 1188 (NCBI SNP database no 3212227) was reported to be associated with responding more efficiently to antiviral combination therapy in HCV genotype 1 infected patients. The present study aims to evaluate association between this polymorphism with fibrosis stages, necroinflammation activity, response to the combined therapy, and gender in Egyptian HCV genotype 4. Material and Methods. A total of 133 Egyptian chronic HCV (CHCV) patients were treated with IFN/RBV and were followed up. IL12B 1188 A/C genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PRC-RFLP) analysis. Results. A nonsignificant trend for higher sustained virological response (SVR) was observed in patients homozygote for IL12B 1188 A/C SNP CC genotype (69% SVR versus 30.8% NR) only but not in AC and AA genotypes. No association was detected between IL12B 1188 A/C polymorphism and less severe fibrosis or less liver activity. By stratification of response according to gender genotype, a significant difference in response between males and females was seen among AA genotype carriers only due to high number of non responder females. Conclusion. IL12B CC genotype appears to have some influence on SVR achievement but not on severe fibrosis and severe necroinflamation activity. Females carrying A/A genotype of IL12B 1188 A/C SNP achieve less SVR than those carrying AC and CC genotypes. 1. Introduction Hepatitis C “The Silent Killer” is a liver disease which means inflammation of the liver caused by the hepatitis C virus (HCV). It is suspected that there are, at
Circulating Cytokines and Histological Liver Damage in Chronic Hepatitis B Infection  [PDF]
Kittiyod Poovorawan,Pisit Tangkijvanich,Chintana Chirathaworn,Naruemon Wisedopas,Sombat Treeprasertsuk,Piyawat Komolmit,Yong Poovorawan
Hepatitis Research and Treatment , 2013, DOI: 10.1155/2013/757246
Abstract: Each phase of hepatitis B infection stimulates distinct viral kinetics and host immune responses resulting in liver damage and hepatic fibrosis. Our objective has been to correlate host inflammatory immune response including circulating Th1 and Th2 cytokines in patients with chronic hepatitis B infection with liver histopathology. Sixty-four patients with chronic hepatitis B without previous treatment were recruited. The liver histology and histological activity index were assessed for various degrees of necroinflammation and hepatic fibrosis. We determined circulating levels of the Th1 and Th2 cytokines. Forty-six males and 18 females at a median age of 34.5 years were studied. HBeAg was present in 28/64 (43.75%) of the patients. In patients negative for HBeAg, IL-10 and IFN-gamma were significantly correlated with degrees of necroinflammation ( , , resp.; ). Moreover, TNF-alpha was significantly correlated with degrees of fibrosis ( ; ), and IL-10 and TNF-alpha were significantly correlated with significant fibrosis ( , , resp.; ). These correlations were found in the HBeAg negative group as opposed to the HBeAg positive group. In HBeAg negative patients, circulating cytokines IL-10 and IFN-gamma were correlated with degrees of necroinflammation, whereas IL-10 and TNF-alpha were correlated with significant fibrosis. 1. Introduction Chronic hepatitis B infection is a major cause of chronic liver disease worldwide. Each phase of hepatitis B infection stimulates distinct viral kinetics and host immune responses resulting in liver damage and hepatic fibrosis [1]. Vaccine induced immune response in humans has provided excellent long term protection and result decline prevalence of hepatitis B virus (HBV) infection in long term [2, 3]. In contrast to host immune response in chronic hepatitis B infection, due to immune tolerance, only a small proportion of chronic hepatitis B (CHB) patients could clear the infection [4]. Histological damage and risk of HCC in CHB patients depend on various parameters such as duration of infection, coinfection with other hepatitis viruses, and alcohol consumption [5]. Cytokines are known to play a significant role in host immune responses. In chronic hepatitis B patients, the concentration of circulating Th17 cells (producing IL-17) increased with disease progression from CHB (mean, 4.34%) to acute-on-chronic liver failure (mean, 5.62%) patients as compared to healthy controls (mean, 2.42%) [6]. Furthermore, higher serum levels of IL-10 and IL-12 in HBeAg positive patients are correlated with early, spontaneous HBeAg
Markers of Inflammation and Fibrosis in Alcoholic Hepatitis and Viral Hepatitis C  [PDF]
Manuela G. Neuman,Hemda Schmilovitz-Weiss,Nir Hilzenrat,Marc Bourliere,Patrick Marcellin,Cristhian Trepo,Tony Mazulli,George Moussa,Ankit Patel,Asad A. Baig,Lawrence Cohen
International Journal of Hepatology , 2012, DOI: 10.1155/2012/231210
Abstract: High levels of profibrinogenic cytokine transforming factor beta (TGF-β), metalloprotease (MMP2), and tissue inhibitor of matrix metalloprotease 1 (TIMP1) contribute to fibrogenesis in hepatitis C virus (HCV) infection and in alcohol-induced liver disease (ALD). The aim of our study was to correlate noninvasive serum markers in ALD and HCV patients with various degrees of inflammation and fibrosis in their biopsies. Methods. Serum cytokines levels in HCV-infected individuals in the presence or absence of ALD were measured. Student's-t-test with Bonferroni correction determined the significance between the groups. Results. Both tumor-necrosis-factor- (TNF)-α and TGF-β levels increased significantly with the severity of inflammation and fibrosis. TGF-β levels increased significantly in ALD patients versus the HCV patients. Proinflammatory cytokines’ responses to viral and/or toxic injury differed with the severity of liver inflammation. A combination of these markers was useful in predicting and diagnosing the stages of inflammation and fibrosis in HCV and ALD. Conclusion. Therapeutic monitoring of TGF-β and metalloproteases provides important insights into fibrosis. 1. Introduction Alcohol-induced liver disease (ALD) encompasses a spectrum of hepatic injury, ranging from simple steatosis to cirrhosis. Alcohol ethylic (ethanol), a hepatotoxin, produces the oldest form of liver injury known to humankind [1–4]. In addition, ethanol-inducible cytochrome P-450 (CYP2E1) increases vulnerability of the heavy drinker to commonly prescribed drugs [5–7]. Moreover, dysregulated cytokines, including TNF-α and downstream cytokines, play a pivotal role in the pathophysiology of ALD [8, 9]. In addition, Th1 cells produce interleukin (IL)-2, interferon (IFN)-γ, and TNF-α, that promote inflammation and cell-mediated immunity in an attempt to control infection [10–12]. Th2 cells produce IL-10 [10] and IL-4, inducing fibrogenesis [13–17]. In HCV, an impaired HCV-specific CD4+ T-cell response can lead to persistence of the virus characterized by inflammation [18–22]. The expression of suppressor of cytokine signaling (SOCS) proteins permits the host to better respond to therapies [23]. The initial liver histological changes are characterized by accumulation of inflammatory cells and matrix deposition around the portal vein [24–26]. In liver disease, including ALD and HCV, liver fibrosis is defined as the abnormal accumulation of extracellular matrix (ECM) [26–33]. In all cases, inflammation plays a crucial role [24, 34]. TGF-β mediates the effects through signal mothers
Hyper-Activated Pro-Inflammatory CD16+ Monocytes Correlate with the Severity of Liver Injury and Fibrosis in Patients with Chronic Hepatitis B  [PDF]
Ji-Yuan Zhang,Zheng-Sheng Zou,Ang Huang,Zheng Zhang,Jun-Liang Fu,Xiang-Sheng Xu,Li-Ming Chen,Bao-Sen Li,Fu-Sheng Wang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017484
Abstract: Extensive mononuclear cell infiltration is strongly correlated with liver damage in patients with chronic hepatitis B virus (CHB) infection. Macrophages and infiltrating monocytes also participate in the development of liver damage and fibrosis in animal models. However, little is known regarding the immunopathogenic role of peripheral blood monocytes and intrahepatic macrophages.
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