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Viral hepatitis and hepatocellular carcinoma
Peter P Michielsen, Sven M Francque, Jurgen L van Dongen
World Journal of Surgical Oncology , 2005, DOI: 10.1186/1477-7819-3-27
Abstract: This article reviews the literature on hepatitis and hepatocellular carcinoma. The Medline search was carried out using these key words and articles were selected on epidemiology, risk factors, screening, and prevention of hepatocellular carcinoma.Screening of patients with advanced chronic hepatitis B and C with hepatic ultrasound and determination of serum alfa-fetoprotein may improve the detection of HCC, but further studies are needed whether screening improves clinical outcome.Hepatitis B and C viruses (HBV/HCV) can be implicated in the development of HCC in an indirect way, through induction of chronic inflammation, or directly by means of viral proteins or, in the case of HBV, by creation of mutations by integration into the genome of the hepatocyte.The most effective tool to prevent HCC is avoidance of the risk factors such as viral infection. For HBV, a very effective vaccine is available. Preliminary data from Taiwan indicate a protective effect of universal vaccination on the development of HCC. Vaccination against HBV should therefore be a health priority. In patients with chronic hepatitis B or C, interferon-alfa treatment in a noncirrhotic stage is protective for HCC development in responders, probably by prevention of cirrhosis development. When cirrhosis is already present, the protective effect is less clear. For cirrhosis due to hepatitis B, a protective effect was demonstrated in Oriental, but not in European patients. For cirrhosis due to hepatitis C, interferon-alfa treatment showed to be protective in some studies, especially in Japan with a high incidence of HCC in untreated patients. Virological, but also merely biochemical response, seems to be associated with a lower risk of development of HCC. As most studies are not randomized controlled trials, no definitive conclusions on the long-term effects of interferon-alfa in HBV or HCV cirrhosis can be established. Especially in hepatitis C, prospective studies should be performed using the more
Genome-Wide Association Study Confirming Association of HLA-DP with Protection against Chronic Hepatitis B and Viral Clearance in Japanese and Korean  [PDF]
Nao Nishida, Hiromi Sawai, Kentaro Matsuura, Masaya Sugiyama, Sang Hoon Ahn, Jun Yong Park, Shuhei Hige, Jong-Hon Kang, Kazuyuki Suzuki, Masayuki Kurosaki, Yasuhiro Asahina, Satoshi Mochida, Masaaki Watanabe, Eiji Tanaka, Masao Honda, Shuichi Kaneko, Etsuro Orito, Yoshito Itoh, Eiji Mita, Akihiro Tamori, Yoshikazu Murawaki, Yoichi Hiasa, Isao Sakaida, Masaaki Korenaga, Keisuke Hino, Tatsuya Ide, Minae Kawashima, Yoriko Mawatari, Megumi Sageshima, Yuko Ogasawara, Asako Koike, Namiki Izumi, Kwang-Hyub Han, Yasuhito Tanaka, Katsushi Tokunaga, Masashi Mizokami
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039175
Abstract: Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85–90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with Pmeta = 1.89×10?12 for rs3077 and Pmeta = 9.69×10?10 for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (Pmeta = 4.40×10?19 for rs3077 and Pmeta = 1.28×10?15 for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule.
Angiogenesis in chronic viral hepatitis
Micha? Kukla,Andrzej Gabriel,Marek Waluga,Rafa? Bu?dak
Polish Gastroenterology , 2009,
Abstract: It is unresolved whether angiogenesis is merely a homeostatic mechanism aimed at ensuring an adequate oxygen supply or one that exerts an additional pathogenic role leading to liver tissue damage.The development of fibrosis and the accumulation of inflammatory cells which occur in viral hepatitis may increase the resistance of liver tissue to blood flow and oxygen supply. Under these circumstances, an angiogenesis switch occurs leading to an increase in proangiogenic factors which contribute to vascular remodeling and the formation of new vessels. On the other hand, the process of chronic liver wound healing typical of fibrogenic chronic liver diseases is characterized by an over-expression of the same proangiogenic growth factors. The exact role of the virus in the pathogenesis of angiogenesis is also unclear. This review describes the pathogenesis of new blood vessel formation in chronic viral hepatitis and its potential role in disease progression. It also points to angiogenesis as a pos-sible new therapeutic target. Moreover, it summarizes recent findings concerning the pathogenic role, intrahepatic expression, and variations in the circulating levels of proangiogenic factors in patients with chronic viral hepatitis.
Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome  [PDF]
Julieta Trinks,Adrián Gadano,Pablo Argibay
Epidemiology Research International , 2012, DOI: 10.1155/2012/856810
Abstract: Hepatitis C virus (HCV) represents a major worldwide public health problem. The search for the key molecular biomarkers that may provide insight on the basis of the differences in disease progression, severity, and response to therapy is crucial for understanding the natural history of HCV, for estimating the burden of infection and for developing preventive interventions. Initially, molecular epidemiology studies have focused on studying the viral genetic diversity (genotypes, genetic variants, specific nucleotide and amino acid substitutions). However, the clinical heterogeneities of HCV infection and the imperfect predictability of the response to treatment have suggested the need to search for host genetic biomarkers. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as in treatment response and adverse effects, such as IL-28B, ITPA, and IP-10. As a consequence, nowadays the focus of molecular epidemiology studies has turned from the viral to the human genome. This paper will cover recent reports on the subject describing the most relevant viral as well as host genetic risk factors analyzed by past and current HCV molecular epidemiology studies. 1. Introduction HCV represents a major health problem with approximately 3% of the world population—that is, more than 170 million people—infected. While only 20–30% of individuals exposed to HCV recover spontaneously, the remaining 70–80% develop chronic HCV infection (CHC) [1]. Moreover, 3–11% of those people will develop liver cirrhosis (LC) within 20 years [2], with associated risks of liver failure and hepatocellular carcinoma (HCC) [3] which are the leading indications of liver transplantation in industrialized countries [4]. The socioeconomic impact of HCV infection is therefore tremendous and the burden of the disease is expected to increase around the world as the disease progresses in patients who contracted HCV years ago. Since the discovery of HCV more than 20 years ago [5], epidemiological studies have described complex patterns of infection concerning not only the worldwide prevalence of this virus but also its clinical presentation and its therapeutic response. HCV presents highly variable local prevalence rates between countries and within countries [6]; for example, in Argentina the overall prevalence of HCV infection is close to 2%, but higher rates have been reported in different small rural communities (5.7–4.9%) [7, 8]. The outcome of HCV infection is—as previously stated—heterogeneous ranging from an asymptomatic self-limiting
Correlation between pre-treatment quasispecies complexity and treatment outcome in chronic HCV genotype 3a
Isabelle Moreau, John Levis, Orla Crosbie, Elizabeth Kenny-Walsh, Liam J Fanning
Virology Journal , 2008, DOI: 10.1186/1743-422x-5-78
Abstract: The degree of sequence heterogeneity within the hypervariable region 1 was assessed by analyzing 20–30 individual clones in serial serum samples. Genetic parameters, including amino acid Shannon entropy, Hamming distance and genetic distance were calculated for each sample. Treatment outcome was divided into (1) sustained virological responders (SVR) and (2) treatment failure (TF).Our results indicate, (1) quasispecies complexity and diversity are lower in the SVR group, (2) quasispecies vary temporally and (3) genetic heterogeneity at baseline can be use to predict treatment outcome.We discuss the results from the perspective of replicative homeostasis.The Hepatitis C virus (HCV), is the causative agent of chronic hepatitis C and infects at least 170 million individuals worldwide [1-3]. The virus has been classified into six major genotypes and more than 70 subtypes based on sequence diversity [4-10]. The most important feature of HCV is that it causes chronic infection in about 50–80% of individuals [3,11-13].The HCV genome exhibits significant genetic heterogeneity due to accumulation of mutations during viral replication, attributed to a limited fidelity of the RNA dependent RNA polymerase [14,15]. This phenomenon generates a dynamic population of heterogeneous but closely related variants designated as quasispecies [14-17]. The massive genetic heterogeneity present in quasispecies has important biological consequences and enables HCV to escape immune clearance and to establish chronic infection [18-22]. Furthermore, the quasispecies distribution may influence the outcome of anti-viral therapy and be important in the development of resistance to anti-viral therapy [23-27]. It is well established that HCV genotype influences both response to therapy and disease severity as well as the viral-host interactions [19,28-30]. Patients infected with HCV genotypes 2 or 3 respond more favourably than genotype 1 to pegylated α2a-Interferon and ribavirin anti-viral therapy
Molecular characteristics and stages of chronic hepatitis B virus infection  [cached]
Ying-Hui Shi, Chang-He Shi
World Journal of Gastroenterology , 2009,
Abstract: Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Remarkable progress has been made in our understanding of the natural stages of chronic HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. Knowledge of the HBV genome organization and replication cycle can unravel HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. Most HBV infections are spontaneously resolved in immunocompetent adults, whereas they become chronic in most neonates and infants at a great risk of developing complications such as cirrhosis and hepatocellular carcinoma (HCC). Those with chronic HBV infection may present in one of the four phases of infection: immune tolerance, immune clearance [hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB)], inactive carrier state, and reactivation (HBeAg-negative CHB). Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers. Long-term monitoring and optimal timing of antiviral therapy for chronic HBV infection help to prevent progression of HBV-related liver disease to its later stage, particularly in patients with higher risk markers of HCC, such as serum DNA concentration, HBeAg status, serum aminotransferase, HBV genotypes, and pre-core or core mutants.
Complete hepatitis B virus genome analysis in HBsAg positive mothers and their infants with fulminant hepatitis B
Michael Friedt, Patrick Gerner, Philip Wintermeyer, Stefan Wirth
BMC Gastroenterology , 2004, DOI: 10.1186/1471-230x-4-11
Abstract: The complete HBV-genomes of five mothers and their infants with fulminant hepatitis were isolated from the sera, amplified and directly sequenced.Between 6 and 43 base pair exchanges between the HBV genomes of the infants and their mothers were identified. The mutations spread over the entire virus genome. Nucleotide exchanges in the basic core promotor and precore region were identified in all cases. A heterogeneous virus population was detected in four mothers.Many new mutations were proved to emerge during fulminant hepatitis B in infants, who had been perinatally infected. HBeAg negative variants were the predominant population in all children, whereas these mutants could only be detected as subpopulations in four mothers. The data suggest that the selection of a specific HBeAg negative viral strain may be associated with the development of fulminant hepatitis B in children.To date, the pathogenic mechanism leading to the different clinical courses of hepatitis B in early childhood is largely unknown. Without immunization, 90% of the babies born to HBeAg-positive mothers develop a chronic carrier status. On the other side children of anti-HBe positive mothers become less frequently infected, but are at considerable risk to develop fulminant hepatitis B (FHB). The clinical outcome is poor and without liver transplantation most of these patients die at the age of 3–5 months. Both, host and virus specific factors are considered to have an important impact on the clinical course.FHB in adults has been associated with mutations in the basic core promotor BCP (1762 A to T and 1764 G to A) [1] and the precore region (1896 G to A) [2,3]. A number of additional changes have been identified in cis acting regulatory elements and the four open reading frames including mutations of the pre-S2 start codon. It was suggested that these mutations may influence viral replication and alter the HBV-protein expression [4-6]. In a study from Sterneck et al. the full length genome ana
Cytokines: their pathogenic and therapeutic role in chronic viral hepatitis
Larrubia,J. R.; Benito-Martínez,S.; Miquel-Plaza,J.; Sanz-de-Villalobos,E.; González-Mateos,F.; Parra,T.;
Revista Espa?ola de Enfermedades Digestivas , 2009, DOI: 10.4321/S1130-01082009000500006
Abstract: cytokines make up a network of molecules involved in the regulation of immune response and organ functional homeostasis. cytokines coordinate both physiological and pathological processes occurring in the liver during viral infection, including infection control, inflammation, regeneration, and fibrosis. hepatitis b and hepatitis c viruses interfere with the complex cytokine network brought about by the immune system and liver cells in order to prevent an effective immune response, capable of viral control. this situation leads to intrahepatic sequestration of nonspecific inflammatory infiltrates that release proinflammatory cytokines, which in turn favor chronic inflammation and fibrosis. the therapeutical administration of cytokines such as interferon alpha may result in viral clearance during persistent infection, and revert this process.
Nucleos(t)ide analogues treatment outcome in genotype B and C chronic hepatitis B
Myo Nyein Aung,Wattana Leowattana,Noppadon Tangpukdee,Chatporn Kittitrakul
North American Journal of Medical Sciences , 2010,
Abstract: Background: Hepatitis B genotypes influence the course and severity of the disease. Aim: To compare the treatment outcome of chronic hepatitis B genotype B and C patients after treating with nucleos(t)ide analogues for six months. Patients and Methods: Forty chronic hepatitis B patients attending the liver clinic of Hospital for Tropical diseases, Bangkok, were studied in retrospective cohort design. Six genotype B patients (15%) and thirty-four genotype C patients (85%) were treated. Serum hepatitis B viral load , serum alanine amino transferase level, HBeAg status and alpha-feto protein level were measured at the time of starting nucleos(t) analogues therapy, and six months later. Besides, achievement of undetectable viral load was assessed in patients with normal serum alanine amino transferase compared to patients with high serum alanine amino transferase level. Results: After six months of nucleos (t) analogues treatment, achievement of undetectable hepatitis B viral load was higher in genotype B patients (66.7%) than in genotype C patients (42.4%) (Relative Risk=1.57, 0.79-3.14). Biochemical remission, HBeAg seroconversion and tumor marker levels between the two groups were not significantly different. Moreover, achievement of undetectable hepatitis B viral load was significantly higher in normal alanine amino transferase level (75%) than in patients with high serum alanine amino transferase level (33.3%) on nucleos(t)ide analogue treatment (Relative Risk=2.25, 1.20- 4.20). Conclusion: Chronic hepatitis B treatment outcome between genotype B and C were not significantly different. Patients with normalized serum alanine amino transferase level tend to achieve undetectable viral load after nucleoside analogues treatment.
Cytokine Estimation in Chronic Viral Hepatitis with Autoimmune Impairments
Umida Nabieva,Adolat Ismailova
International Journal of Public Health Science , 2013, DOI: 10.11591/ijphs.v2i2.2438
Abstract: The pattern of autoimmune impairments was studied in patients with chronic viral hepatitis in association with the level of inflammatory cytokines and interferon status. Study was conducted in groups of patients with various levels of the detected autoantibodies to ssDNA. Autoantibodies to ssDNA were found in 37,7% of patients with HCV. In the group of HCV patients with autoimmune disorders, the levels of the cytokines and interferon levels were considerably higher than those in the group of patients without associated autoimmune diseases
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