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hepatitis c virus and metabolic disorder interactions towards liver damage and atherosclerosis

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World Journal of Gastroenterology 2014年第11期20卷 2825-2838页

作者： Umberto Vespasiani-Gentilucci Paolo Gallo Antonio De Vincentis Giovanni Galati Antonio Picardi Internal Medicine and Hepatology Unit University Campus Bio-Medico of Rome00128 RomeItaly

hepatitis c virus (HcV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HcV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HcV is responsible for a “viral” steatosis which is frequently superimposed to a “metabolic” one. Several evidences suggest that HcV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HcV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HcV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.

关键词： hepatitis c virus Metabolism Insulin resistance Diabetes mellitus Steatosis Fibrosis Atherosclerosis cardiovascular risk

hepatitis c virus core antigen testing: Role in diagnosis, disease monitoring and treatment

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World Journal of Gastroenterology 2014年第22期20卷 6701-6706页

作者： Hans L Tillmann GI/Hepatology Duke Clinical Research Institute and Duke UniversityDurhamNC 27708United States

While hepatitis B virus(HBV)screening relies on hepatitis B surface antigen to confirm HBV infection since the early days of hepatitis B disease management,hepatitis c virus(HcV)infection screening is based on anti-HcV testing which does not discriminate active from past *** to confirm infection HcV RNA testing has been required;recently a HcV core antigen assay became widely commercially available which could serve to confirm *** assay is less sensitive than current HcV RNA assays,but as more than 50%of anti-HcV positive persons will be HcV core antigen positive,HcV core antigen testing can be a cost effective and reflex test to confirm HcV infection in anti-HcV positive individuals and will be easier as it can be applied on the same *** treatment monitoring,more data need to be generated,but the early data available at present suggest that HcV core antigen may be an alternative to HcV RNA *** direct antivirals,HcV core antigen could even be superior to HcV RNA testing,as direct antivirals might already prevent virus formation when HcV core antigen is still produced and thereby correlates better with eventual viral clearance.

关键词： hepatitis c virus hepatitis c Diagnostic assay Diagnostic accuracy hepatitis c virus core antigen Treatment monitoring

hepatitis c virus-associated B cell non-Hodgkin's lymphoma

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World Journal of Gastroenterology 2016年第27期22卷 6214-6223页

作者： Romeo-Gabriel Mihaila Faculty of Medicine 'Lucian Blaga' University of Sibiu 500169 Sibiu Romania Hematology Department Emergency County Clinical Hospital Sibiu 550245 Sibiu Romania

The hepatitis c virus (HcV) infected patients are prone to develop bone marrow or various tissue infiltrates with monoclonal B cells, monoclonal B lymphocytosis or different types of B cell non-Hodgkin’s lymphoma (BcNHL), of which the most common are splenic marginal zone BcNHL, diffuse large BcNHL and follicular lymphoma. The association between chronic HcV infection and non Hodgkin’s lymphoma has been observed especially in areas with high prevalence of this viral infection. Outside the limitations of some studies that have been conducted, there are also geographic, environmental, and genetic factors that contribute to the epidemiological differences. Various microenvironmental signals, such as cytokines, viral antigenic external stimulation of lymphocyte receptors by HcV antigens, and intercellular interactions contribute to B cell proliferation. HcV lymphotropism and chronic antigenic stimulation are involved in B-lymphocyte expansion, as mixted cryoglobulinemia or monoclonal gammopathy of undetermined significance, which can progress to BcNHL. HcV replication in B lymphocytes has oncogenic effect mediated by intracellular HcV proteins. It is also involved in an important induction of reactive oxygen species that can lead to permanent B lymphocyte damage, as DNA mutations, after binding to surface B-cell receptors. Post-transplant lymphoproliferative disorder could appear and it has a multiclonal potentiality that may develop into different types of lymphomas. The hematopoietic stem cell transplant made for lymphoma in HcV-infected patients can increase the risk of earlier progression to liver fibrosis and cirrhosis. HcV infected patients with indolent BcNHL who receive antiviral therapy can be potentially cured. Viral clearance was related to lymphoma response, fact that highlights the probable involvement of HcV in lymphomagenesis. Direct acting antiviral drugs could be a solution for the patients who did not tolerate or respond to interferon,

关键词： chemotherapy cryoglobulinemia Direct acting antiviral drugs hepatitis c virus Hepatocytolysis Interferon Liver transplantation Liver dysfunction Non-Hodgkin’ s lymphoma Rituximab

hepatitis c virus eradication with directly acting antivirals improves health-related quality of life and psychological symptoms

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World Journal of Gastroenterology 2019年第48期25卷 6928-6938页

作者： Silvia Nardelli Oliviero Riggio Davide Rosati Stefania Gioia Alessio Farcomeni Lorenzo Ridola Department of Translational and Precision Medicine “Sapienza”University of RomeRome 00185Italy Department of Economics&Finance University of Rome“Tor Vergata”Rome 00185Italy

BAcKGROUND Alterations in health-related quality of life(HRQoL)and neuropsychological disorders were described in the hepatitis c virus(HcV)*** several studies investigated the modifications of HRQoL after HcV eradication,no data exists on the modifications of neuropsychological *** To investigate the effect of directly acting antivirals(DAAs)treatment on HRQoL and neuropsychological *** Thirty nine patients with HcV infection underwent a neuropsychological assessment,including Zung-Self Depression-Rating-Scale,Spielberg State-Trait Anxiety Inventory Y1-Y2 and the Toronto-Alexithymia Scale-20 items before and after DAAs *** was detected by Short-Form-36(SF-36).RESULTS All HRQoL domains,but role limitation physical and bodily pain,significantly improved after ***,after DAAs treatment,all domains of HRQoL returned similar to those of *** neuropsychological test significantly improved after HcV eradication.A significant correlation was observed among each psychological test and the summary components of *** multiple linear regression analysis including each psychological test as possible covariates,Zung-Self Depression Rating Scale(Zung-SDS)score was independently and significantly related to summary components of the SF-36 in the basal state and the difference between Zung-SDS score before and after treatment was the only variable significantly and independently related to the modification of HRQoL induced by the *** Neuropsychological symptoms strongly influenced HRQoL in HcV patients and there was a significant improvement of neuropsychological tests and HRQoL after DAAs treatment.

关键词： hepatitis c virus Health related quality of life Depression State and trait anxiety Alexithymia Directly acting antivirals

hepatitis c virus-associated pruritus: Etiopathogenesis and therapeutic strategies

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World Journal of Gastroenterology 2017年第5期23卷 743-750页

作者： Youssef Alhmada Denis Selimovic Fadi Murad Sarah-Lilly Hassan Youssef Haikel Mossaad Megahed Matthias Hannig Mohamed Hassan Department of Pathology University of Mississippi Medical Center Graduate School of Dental Medicine Depart-ment of Restorative DentistryDivision of Oral Health ScienceHokkaido University clinic of Operative Dentistry Periodontology and Preventive DentistrySaarland University Department of Surgery Tulane University School of Medicine clinic of Dermatology University Hospital of Aachen Institut National de la Santéet de la RecherchéMédicale Department of Operative Dentistry and Endodontics Dental FacultyUniversity of Strasbourg

In addition to its contributing role in the development of chronic liver diseases, chronic hepatitis c virus (HcV) infection is associated with extrahepatic manifestations, particularly, cutaneous-based disorders including those with pruritus as a symptom. Pruritus is frequently associated with the development of chronic liver diseases such as cholestasis and chronic viral infection, and the accumulation of bile acids in patients’ sera and tissues as a consequence of liver damage is considered the main cause of pruritus. In addition to their role in dietary lipid absorption, bile acids can trigger the activation of specific receptors, such as the G protein-coupled bile acid receptor (GPBA/ TGR5). These types of receptors are known to play a crucial role in the modulation of the systemic actions of bile acids. TGR5 expression in primary sensory neurons triggers the activation of the transient receptor potential vanilloid 1 (TRPV1) leading to the induction of pruritus by an unknown mechanism. Although the pathologic phenomenon of pruritus is common, there is no uniformly effective therapy available. Understanding the mechanisms regulating the occurrence of pruritus together with the conduction of large-scale clinical and evidence-based studies, may help to create a standard treatment protocol. This review focuses on the etiopathogenesis and treatment strategies of pruritus associated with chronic HcV infection.

关键词： hepatitis c virus Pruritus cholestasis Autotoxin Lysophosphatidic acid PI3 kinase

hepatitis c virus NS5A inhibitors and drug resistance mutations

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World Journal of Gastroenterology 2014年第11期20卷 2902-2912页

作者： Shingo Nakamoto Tatsuo Kanda Shuang Wu Hiroshi Shirasawa Osamu Yokosuka Department of Molecular Virology Graduate School of MedicineChiba UniversityChiba 260-8677Japan Department of Gastroenterology and Nephrology Graduate School of MedicineChiba UniversityChiba 260-8677Japan

Some direct-acting antiviral agents for hepatitis c virus (HcV), such as telaprevir and boceprevir have been available since 2011. It was reported that HcV NS5A is associated with interferon signaling related to HcV replication and hepatocarcinogenesis. HcV NS5A inhibitors efficiently inhibited HcV replication in vitro. Human studies showed that dual, triple and quad regimens with HcV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HcV with or without peginterferon/ribavirin, could efficiently inhibit HcV replication according to HcV genotypes. These combinations might be a powerful tool for “difficult-to-treat” HcV-infected patients. “First generation” HcV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. “Second generation” NS5A inhibitors such as GS-5816, AcH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HcV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HcV NS5A inhibitors should be used with HcV NS3/4A inhibitors, HcV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HcV NS5A inhibitor resistance mutations and recommends that HcV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.

关键词： AcH-3102 Direct-acting antiviral agents Daclatasvir hepatitis c virus Ledipasvir

hepatitis c virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment

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World Journal of Gastroenterology 2014年第32期20卷 11054-11061页

作者： carlo Visco Silvia Finotto Department of Hematology and cell Therapy San Bortolo Hospital

A significant association between hepatitis c virus (HcV) infection and B-cell lymphoma has been reported by epidemiological studies, most of them describing a strong relationship between indolent lymphomas and HcV. Furthermore, the curative potential of antiviral therapy on HcV related indolent lymphomas supports a specific role for the virus in lymphomagenesis. These observations are reinforced by numerous laboratory experiments that led to several hypothetical models of B-cell transformation by HcV. Diffuse large B-cell lymphoma (DLBcL), the most common lymphoma subtype in the western countries, has been associated to HcV infection despite its aggressive nature. This association seems particularly prominent in some geographical areas. clinical presentation of HcV-associated DLBcL has consistently been reported to differ from the HcV-negative counterpart. Nevertheless, histopathology, tolerance to standard-of-care chemo-immunotherapy (R-cHOP or cHOP-like regimens) and final outcome of HcV-positive DLBcL patients is still matter of debate. Addition of rituximab has been described to enhance viral replication but the probability of severe hepatic complications remains low, with some exceptions (i.e., hepatitis B virus or immune immunodeficiency virus co-infected patients, presence of grade > 2 transaminases elevation, cirrhosis or hepatocarcinoma). HcV viral load in this setting is not necessarily directly associated with liver damage. Overall, treatment of HcV associated DLBcL should be performed in an interdisciplinary approach with hepatologists and hematologists with close monitoring of liver function. Available reports reveal that the final outcome of HcV-positive DLBcL that receive standard immunochemotherapy is not inferior to their HcV-negative counterpart. This review summarizes data on epidemiology, pathogenesis and therapeutic approach on HcV-associated DLBcL. Several issues that are matter of debate like clinical management of patients with trans

关键词： hepatitis c virus Non-Hodgkin lymphoma Liver Toxicity Diffuse large B-cell lymphoma Rituximab cyclophosphamide Hydroxydaunorubicin Vincristine Prednisolone Immuno-chemotherapy Antiviral treatment

hepatitis c virus reinfection after liver transplantation: Is there a role for direct antiviral agents?

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World Journal of Gastroenterology 2014年第28期20卷 9253-9260页

作者： Marco Dall’Agata Annagiulia Gramenzi Maurizio Biselli Mauro Bernardi Semeiotica Medica - Policlinico S.Orsola-Malpighi Dipartimento di Scienze Mediche e ChirurgicheUniversity of Bologna

Recurrence of hepatitis c virus(HcV)infection following liver transplantation(LT)is almost universal and can accelerate graft cirrhosis in up to 30%of *** development of effective strategies to treat or prevent HcV recurrence after LT remains a major challenge,considering the shortage of donor organs and the accelerated progression of HcV in LT *** antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HcV LT recipients,even though the combination is not as effective as it is in immunocompetent patients.A sustained virological response in the setting of LT improves patient and graft survival,but this is only achieved in 30%-45%of patients and the treatment is poorly *** improve the efficacy of pre-and post-transplant antiviral therapy,a new class of potent direct-acting antiviral agents (DAAs)has been *** aim of this review is to summarize the use of DAAs in LT HcV ***,cochrane Library,MEDLINE,EMBASE,Web of Science and clinical trial databases were searched for this *** date,only three clinical studies on the topic have been published and most of the available data are in abstract *** a moderately successful early virological response has been reported,DAA treatment regimens were associated with severe toxicity mitigating their potential ***,the ongoing nature of data,the lack of randomized studies,the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and *** conclusion,large welldesigned clinical studies on DAAs in HcV LT patients are required before these drugs can be recommended after transplantation.

关键词： hepatitis c virus Liver transplantation Direct antiviral agents Peginterferon/ribavirin Immunosuppressive agents

hepatitis c virus,mitochondria and auto/mitophagy:Exploiting a host defense mechanism

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World Journal of Gastroenterology 2014年第10期20卷 2624-2633页

作者： Vitalba Ruggieri carmela Mazzoccoli Valerio Pazienza Angelo Andriulli Nazzareno capitanio claudia Piccoli Laboratory of Preclinical and Translational Research IRCCS Referral Cancer Center of Basilicata 85028 Rionero in Vulture (PZ) Italy Gastroenterology Unit IRCCS "Casa Sollievo della Sofferenza" Hospital 71013 Foggia Italy Department of Medical and Experimental Medicine University of Foggia 71122 Foggia Italy

hepatitis c virus(HcV)is the major reason for liver transplantation and the main cause of liver-related morbidity and mortality in a great number of *** for the other viruses,this pathogen interferes in more than one process and in more than one way with host cell biology.A mounting body of evidence points,in particular,toward the drastic alterations of mitochondrial physiology and functions that virus is able to induce,albeit the mechanisms have partly remained *** of the mitochondria in immunity and in quality control systems,as autophagy,as well as the strategies that HcV has evolved to evade and even to manipulate mitochondrial surveillance for its benefit,highlights the importance of deepening the mechanisms that modulate this virus-mitochondrion interaction,not only to intensify our knowledge of the HcV infection pathogenesis but also to design efficient antiviral strategies.

关键词： hepatitis c virus Mitochondrial dysfunctions Immunity Autophagy Mitophagy