Hepatitis: Zignego AL

Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB, Anonymous00156. · Department of Internal Medicine, Medical School, Center for Research, Transfer and High Education DENOthe, Center for the Study of Systemic Manifestations of Hepatitis Viruses MaSVE, University of Florence, Florence, Italy. · Dig Liver Dis. · Pubmed #16884964 No free full text.

Abstract: Hepatitis C Virus is associated with a wide series of extrahepatic manifestations. Based on available data the link between the virus and some of these extrahepatic diseases is only suggested and needs further confirmation. Hepatitis C Virus-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinaemia, represent the most closely related extrahepatic manifestations of Hepatitis C Virus. Other Hepatitis C Virus-associated disorders include nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, porphyria cutanea tarda, lichen planus, diabetes, chronic polyarthritis, cardiopathy and atherosclerosis. A pathogenetic link between Hepatitis C Virus and some extrahepatic manifestations was confirmed by their responsiveness to antiviral therapy, which is now deemed the first therapeutic option to consider. By contrast, there are diseases where treatment with interferon was ineffective or dangerous. The aim of the present paper is to outline the most recent evidence concerning extrahepatic disorders that are possibly associated with Hepatitis C Virus infection. Special emphasis will be given to discussion of the most appropriate clinical approaches to be adopted in order to diagnose, treat (possibly prevent) and follow-up extrahepathic diseases in patients with Hepatitis C Virus infection.

Zignego AL. · No affiliation provided · J Hepatol. · Pubmed #15582141 No free full text.

This publication has no abstract.

Zignego AL, Piluso A, Giannini C. · Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Florence, Florence, Italy. · Autoimmun Rev. · Pubmed #18700171 No free full text.

Abstract: Hepatitis B (HBV) and C (HCV) viruses differ both in viral structure and in natural history of chronic infection. However, they seem to share, although to a different extent, some characteristics, like the possibility to infect not only hepatic but also lymphatic cells and to associate with some hepatic and/or extrahepatic disorders of an autoimmune and/or lymphoproliferative nature. These characteristics have been more widely studied in the case of chronic HCV infection, where they are more evident, but they have been described also in the case of HBV infection.

Zignego AL, Craxì A. · Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Internal Medicine, University of Florence, Firenze, Italy. <> · Clin Liver Dis. · Pubmed #18625431 No free full text.

Abstract: Hepatitis C virus may cause hepatic and extrahepatic diseases. Extrahepatic manifestations range from disorders for which a significant association with viral infection is supported by epidemiologic and pathogenetic data, to anecdotal observations without clear proof of causality. This article describes the diagnosis and treatment of these diseases.

Gatta A, Giannini C, Lampertico P, Pontisso P, Quarta S, Zignego AL, Atzeni F, Sarzi-Puttini P. · Clinical Medicine 5, Department of Clinical and Experimental Medicine, University of Padua, Italy. · Clin Exp Rheumatol. · Pubmed #18570752 No free full text.

Abstract: Hepatitis B virus (HBV) can be detected in peripheral blood mononuclear cells (PBMCs), mainly B lymphocytes and monocytes. The frequency of PBMC infection is higher in patients with ongoing HBV replication, but can persist for years after the complete resolution of an acute episode of hepatitis B. Infected PBMCs can act as reservoirs for the cell-to-cell transmission of the virus, and vertical transmission studies indicate that the HBV-infected PBMCs of mothers may act as a vector for intrauterine HBV infection. Recent data evaluated whether HBV occult infection could co-operate with HCV infection in the pathogenesis of mixed cryoglobulinemia (MC) and lymphoma and/or whether it may be implicated in the pathogenesis of MC and malignant diseases -B-cell non-Hodgkin's lymphoma (NHL) also independently from HCV.The treatment of chronic HBeAg-negative hepatitis B is intended to ensure the long-term suppression of HBV replication with the aim of halting the progression of liver damage and preventing the development of liver-related complications. This can be done by means of short-term "curative" treatment or long-term "suppressive" therapy. The first approach requires a 48-week course of peginterferon, which controls viral replication (HBV DNA <10.000 copies/ml) in 20-30% of patients; the second requires the long-term (possibly lifetime) administration of nucleoside and/or nucleotide analogues. As none of the currently available drugs alone suppresses viral replication (HBV DNA <200 copies/ml) for five years in all patients, some require a rescue therapy based on the addition of a non-cross-resistant drug, which should be given as early as possible ("on demand" combination therapy). However, the currently available anti-HBV analogues can easily suppress HBV replication for five years in most HBeAg-negative patients. As both strategies have their pros and cons, the best approach needs to be carefully evaluated on an individual basis.

Craxì A, Laffi G, Zignego AL. · GI & Liver Unit, DI.BI:M.I.S., Policlinico, University of Palermo, Palermo, Italy. · Mol Aspects Med. · Pubmed #18177700 No free full text.

Abstract: Hepatitis C virus (HCV) infection is a global health problem, being the second most common chronic viral infection in the world with a global prevalence of about 3% (about 180 million people). HCV is both an hepatotropic and a lymphotropic virus; and chronic infection could cause, on one hand, chronic hepatitis, cirrhosis and hepatocellular carcinoma and on the other hand several extrahepatic diseases including, first, mixed cryoglobulinemia and lymphoma. The association between hepatic (hepatocellular carcinoma) and extrahepatic (lymphoma, thyroid cancer) malignancies has justified the inclusion of HCV among human cancer viruses. The pathogenesis of HCV-related sequelae (hepatic or extrahepatic) is not fully understood representing a challenge of prime importance in light of the optimization of clinico-therapeutic management of these patients. Combined treatment with pegylated interferon plus ribavirin is presently the first-line, gold standard treatment of most HCV-related diseases. However, mainly in the case of extrahepatic manifestations, a cautious approach to the patient, with a case to case accurate tailoring of therapy is frequently requested. The present review will outline the principal aspects of such HCV-induced systemic disease focusing on extrahepatic manifestations.

Ferri C, Antonelli A, Mascia MT, Sebastiani M, Fallahi P, Ferrari D, Giunti M, Pileri SA, Zignego AL. · Chair and Rheumatology Unit, Department of Internal Medicine, University of Modena & Reggio E., Medical School, Modena, Italy. · Autoimmun Rev. · Pubmed #18035320 No free full text.

Abstract: Mixed cryoglobulinemia (MC) is a systemic small-vessel vasculitis; B-cell expansion is the biological substrate of the disease. It can be regarded as benign lymphoproliferative condition that may evolve to frank lymphoma. HCV infection is the main causative factor of MC, as well as of other overlapping disorders, through multifactorial and multistep pathogenetic process. HCV-related B-cell proliferation represents an important model of virus-driven autoimmune/neoplastic disorder. The term HCV syndrome is referred to a wide spectrum of both hepatic and extrahepatic disorders. The present review analyzes the complex virological, clinico-pathological, and therapeutic implications of B-cell proliferation, with or without HCV infection, in MC patients.

Zignego AL, Giannini C, Monti M, Gragnani L. · Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Internal Medicine, University of Florence, Florence, Italy. · Dig Liver Dis. · Pubmed #17936221 No free full text.

Abstract: The possibility that HCV infects lymphoid cells has been widely discussed. Evidence in favor of HCV tropism for lymphoid cells derives from a series of data including: (1) the higher sensitivity of testing HCVRNA in PBMC than in serum or plasma samples, with possible detection of HCV RNA-positive PBMC in the absence of HCV viremia; (2) short-term cultures of PBMC which yield a significant increase in the amount of viral RNA on stimulation by mitogens; (3) results of "in situ" methods (i.e. in situ hybridization, immunofluorescence); (4) efficient infection of lymphoid cell lines or PBMC from normal individuals; (5) the persistence of HCV RNA in PBMC obtained from HCV-positive subjects and injected into SCID mice; (6) the long-term persistence of HCV RNA in PBMC in spite of HCV RNA negativity of serum and liver in sustained responder patients after therapy. The principal criticisms concerning effective HCV infection of lymphoid cells arise from technical difficulty in identifying HCV RNA replicative intermediate in these elements. Conflicting data may also result from differences in PBMC infection by different genotypes, samples taken at different stages in the disease process and differences in the sensitivity of detection methods, as well as low replication levels and/or proportion of infected PBMC. Interesting available data about HCV lymphotropism, which is possibly important in influencing the natural history of infection, include: (1) possible preferential viral tropism for specific PBMC subsets; (2) different lymphotropism of different viral strains; (3) selection of distinctive viral strains; (4) identification of putative HCV cell receptors; (5) association between determination of HCV lymphatic infection and t(14; 18) translocation. The clinical correlates of HCV lymphotropism are potentially very numerous, including, first, its role in determining HCV-related lymphoproliferative disorders.

Ferri C, Antonelli A, Mascia MT, Sebastiani M, Fallahi P, Ferrari D, Pileri SA, Zignego AL. · Chair and Rheumatology Unit, Department of Internal Medicine, University of Modena e Reggio Emilia, Medical Sehool, Modena, Italy. · Dig Liver Dis. · Pubmed #17936215 No free full text.

Abstract: Hepatitis C virus (HCV) chronic infection may be associated with a great number of both hepatic and extrahepatic manifestations. HCV lymphotropism is responsible for poly-oligoclonal B-lymphocyte expansion, which is the common underlying alteration in a significant percentage of HCV-infected individuals. The consequent production of different autoantibodies and immune-complexes, including cryoglobulins, may lead to organ- and non-organ-specific immunological alterations. Mixed cryoglobulinemia, a small-vessel systemic vasculitis, is characterized by the coexistence of autoimmune and lymphoproliferative alterations; therefore, it represents the prototype of HCV-associated disorders. Moreover, HCV shows an oncogenic potential; several studies support its pathogenetic link with some malignancies, mainly hepatocellular carcinoma and B-cell lymphomas. On the whole, HCV-related disorders present a heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. While the majority of HCV-infected individuals is asymptomatic or may develop only liver manifestations, a significant percentage of them may develop a variable combination of autoimmune lymphoproliferative disorders. The resulting multiform clinico-pathological condition can be termed HCV syndrome. The natural history of HCV syndrome is the expression of multifactorial and multistep pathogenetic process, which usually proceeds from mild, often isolated manifestations to systemic immune-mediated disorders, and less frequently to overt malignancies.

Zignego AL, Giannini C, Ferri C. · Department of Internal Medicine, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. · World J Gastroenterol. · Pubmed #17552031 links to  free full text

Abstract: Hepatitis C virus (HCV) is a global health problem affecting 3% of the world's population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV-related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies (hepatocellular carcinoma) has justified the inclusion of HCV among human cancer viruses. HCV-associated manifestations also include porphyria cutanea tarda, lichen planus, nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, diabetes, chronic polyarthritis, sexual dysfunctions, cardiopathy/atherosclerosis, and psychopathological disorders. A pathogenetic link between HCV virus and some lymphoproliferative disorders was confirmed by their responsiveness to antiviral therapy, which is now considered the first choice treatment. The aim of the present paper is to provide an overview of extrahepatic manifestations of HCV infection with particular attention to B-cell lymphoproliferative disorders. Available pathogenetic hypotheses and suggestions about the most appropriate, currently available, therapeutic approaches will also be discussed.

Ferri C, Giuggioli D, Cazzato M, Sebastiani M, Mascia MT, Zignego AL. · Rheumatology Unit, Department of Internal Medicine, Medical School, University of Modena and Reggio Emilia, Modena, Italy. · Clin Exp Rheumatol. · Pubmed #14740431 No free full text.

Abstract: Cryoglobulinemic vasculitis (CV) is an immune-complex-mediated systemic vasculitis involving small-medium sized vessels. A causative role of hepatitis C virus (HCV) in over 4/5 patients has been definitely established on the basis of epidemiological, pathological, and laboratory studies. There is great geographical heterogeneity in the prevalence of CV as well as other HCV-related immuno-lymphoproliferative disorders. Thus, unknown environmental and/or genetic co-factors should contribute to the pathogenesis of these conditions. Due to the biological properties, HCV genomic sequences cannot be integrated into the host genome; the virus could trigger the immunological alterations only indirectly by exerting a chronic stimulus to the immune system. Recent laboratory observations gave us new important insights on the complex pathogenetic mechanism(s) of HCV-related CV. Firstly, the HCV envelop protein E2, able to bind CD81 molecule expressed on B-lymphocytes, might be involved in the first steps of HCV-driven autoimmune and lymphoproliferative phenomena. The interaction between HCV-E2 and CD81 may increase the frequency of VDJ rearrangement in antigen-reactive B-cell. One possible consequence may be the activation of anti-apoptotic Bcl-2 protoncogene that leads to extended B-cell survival. Interestingly, t(14, 18) translocation along with Bcl-2 activation have been demonstrated in B-lymphocytes of 80% HCV-related CV. The B-lymphocyte expansion is responsible for a wide autoantibody and immune-complex production, including mixed cryoglobulins. CV shows a relatively benign clinical course; however, its cumulative survival is significantly worse if compared to general population. For a correct therapeutic approach to HCV-related CV we must deal with conflicting conditions: HCV infection, autoimmune, and lymphoproliferative alterations. Therapeutic strategy of CV includes etiologic, pathogenetic, and/or symptomatic therapies, which should be tailored for the single patient according to the severity of clinical symptoms. A careful clinical monitoring of patients with HCV-related CV is mandatory in all cases, with particular attention to neoplastic complications.

Ferri C, Zignego AL, Giuggioli D, Sebastiani M, Cazzato M, Antonelli A, La Civita L, Fadda P, Longombardo G, Pileri S. · Dipartimento di Medicina Interna, Reumatologia, Università di Pisa, Italy. · Cleve Clin J Med. · Pubmed #12086259 links to  free full text

This publication has no abstract.

Ferri C, Zignego AL, Pileri SA. · Dipartimento di Medicina Interna, Università di Pisa, Pisa 56126, Italy. · J Clin Pathol. · Pubmed #11825916 links to  free full text

Abstract: Serum cryoglobulins are found in a wide spectrum of disorders but are often transient and without clinical implications. Monoclonal cryoglobulins are usually associated with haematological disorders, whereas mixed cryoglobulins are found in many infectious and systemic disorders. So called essential mixed cryoglobulinaemia shows a striking association with hepatitis C virus (HCV) infection (> 90%). It is a systemic vasculitis (leucocytoclastic vasculitis) with cutaneous and multiple visceral organ involvement. Chronic HCV infection can lead to a constellation of autoimmune and neoplastic disorders. In this review, the aetiology, diagnosis, disease heterogeneity, and treatment of cryoglobulinaemia are discussed.

Ferri C, Zignego AL. · Dipartimento Medicina Interna, Rheumatology Unit, University of Pisa, Italy. · Curr Opin Rheumatol. · Pubmed #10647955 No free full text.

Abstract: Mixed cryoglobulinemia (MC) is a systemic vasculitis of small to medium-sized vessels due to the vascular deposition of circulating immune-complexes (CIC) and complement. A leukocytoclastic vasculitis is the histologic hallmark of cutaneous manifestations of the disease, while a clonal B lymphocyte expansion in blood, bone marrow, liver, and spleen represents the underlying pathologic alteration responsible for the production of cryo-CIC and non-cryo CIC with rheumatoid factor activity. A causative role of hepatitis C virus (HCV) infection has been demonstrated in the large majority of MC patients. Hepatitis C virus is both a hepatotropic and a lymphotropic virus; due to this latter biological peculiarity, HCV may trigger a constellation of autoimmune-lymphoproliferative disorders. Besides MC, other important HCV-related diseases are porphyria cutanea tarda, autoimmune hepatitis, membranoproliferative glomerulonephritis, and B cell neoplasias. Hepatitis C virus-related MC represents a link between autoimmune and lymphoproliferative disorders; moreover, MC is an important model to study the complex relation between infections and immune system alterations in humans. During the last years many other autoimmune manifestations have been correlated with HCV infection; namely, sicca syndrome, chronic polyarthritis, polydermatomyositis, fibromyalgia, autoimmune thyroiditis, lung fibrosis, and diabetes mellitus. It is often difficult to verify whether the above associations are coincidental or a pathogenetic link actually exists. At least for particular patients' subsets and in some geographic areas, a causative role of HCV seems to be likely. The geographically heterogeneous distribution of HCV-related autoimmune diseases suggests the contribution of important environmental and genetic factors in the pathogenesis of such conditions. In clinical practice, patients with recent-onset, atypical rheumatic and autoimmune disorders should be carefully investigated for possible HCV infection; this is particularly advisable for correct diagnosis and adequate therapeutic strategy.

Zignego AL, Bréchot C. · Department of Internal Medicine, University of Florence, Italy. · J Hepatol. · Pubmed #10453955 No free full text.

This publication has no abstract.

Taliani G, Gemignani G, Ferrari C, Aceti A, Bartolozzi D, Blanc PL, Capanni M, Esperti F, Forte P, Guadagnino V, Mari T, Marino N, Milani S, Pasquazzi C, Rosina F, Tacconi D, Toti M, Zignego AL, Messerini L, Stroffolini T, Anonymous00210. · Department of Infectious and Tropical Diseases, La Sapienza University, Rome, Italy. · Gastroenterology. · Pubmed #16618404 No free full text.

Abstract: BACKGROUND & AIMS: Inadequate data are available about retreatment of nonresponders to interferon (IFN) and ribavirin. Thus, this study evaluated the efficacy and tolerability of a 48-week therapy with pegylated IFN-alpha-2b plus high-dose ribavirin in patients who have failed to respond to the combination. Treatment up to 48 weeks also in patients who have failed to clear hepatitis C virus (HCV) RNA by week 24 was also evaluated. METHODS: One hundred forty-one patients who previously did not respond to IFN and ribavirin, 86% with genotype 1 or 4 infection, 52% with high viral load (>800.000 IU/mL), 22% with cirrhosis, were retreated with pegylated IFN-alpha-2b 1.5 microg/kg per week and ribavirin 1000-1200 mg/day for 48 weeks and followed up for 24 weeks. RESULTS: By intent-to-treat analysis, 20% of patients achieved a sustained virologic response (SVR). SVR of genotype 1 patients was 19%. Independent predictors of SVR were low gamma-glutamyltransferase levels (OR, 22.9; 95% CI: 6.6-79.6) and low viral load (OR, 3.8; 95% CI: 1.1-12.6). Twelve (23%) out of 51 patients who were HCV RNA positive after 24 weeks of therapy achieved a late virologic response (after week 24) and 5 (10%) of them, all with genotype 1, achieved an SVR. Genotype was not associated with response (P = .2) or with early response (P = .3). CONCLUSIONS: Retreatment with pegylated IFN-alpha-2b and ribavirin of multi-experienced and "difficult to treat" nonresponder patients produced a very promising SVR. Accurate selection of patients, such as those with low viral load and low gamma-glutamyltransferase levels, and prolongation of therapy beyond 24 weeks also in HCV RNA-positive patients may further increase the rate of SVR.

Giannelli F, Moscarella S, Giannini C, Caini P, Monti M, Gragnani L, Romanelli RG, Solazzo V, Laffi G, La Villa G, Gentilini P, Zignego AL. · Department of Internal Medicine, University of Florence, School of Medicine, Italy. · Blood. · Pubmed #12689948 links to  free full text

Abstract: Hepatitis C virus (HCV) may be associated with the mixed cryoglobulinemia syndrome and other B-cell lymphoproliferative disorders (LPDs). The t(14;18) translocation may play a pathogenetic role. Limited data are available regarding the effects of antiviral therapy on rearranged B-cell clones. We evaluated the effects of interferon and ribavirin on serum, B-lymphocyte HCV RNA, and t(14; 18) in 30 HCV+, t(14;18)+ patients without either mixed cryoglobulinemia syndrome or other LPDs. The t(14;18) translocation was analyzed by both bcl-2/JH polymerase chain reaction and bcl-2/JH junction sequencing in peripheral blood mononuclear cells in all patients. Fifteen untreated patients with comparable characteristics served as controls. Throughout the study, the presence or absence of both t(14;18) and HCV RNA sequences were, in most cases, associated in the same cell samples. At the end of treatment, t(14;18) was no longer detected in 15 patients (50%) with complete or partial virologic response, whereas it was persistently detected in nonresponders (P <.05), as well as in 14 of 15 control patients. In 4 responder patients, t(14;18) and HCV RNA sequences were no longer detected in blood cells after treatment, but were again detected after viral relapse; the same B-cell clones were involved in the pretreatment and posttreatment periods. In conclusion, this study suggests that antiviral therapy may induce regression of t(14;18)-bearing B-cell clones in HCV+ patients and that this phenomenon may be related, at least in part, to the antiviral effect of therapy. This in turn suggests that antiviral treatment may help prevent or treat HCV-related LPDs.

Battaglia S, Benzoubir N, Nobilet S, Charneau P, Samuel D, Zignego AL, Atfi A, Bréchot C, Bourgeade MF. · Inserm, Unité 785, Villejuif, France. · PLoS One. · Pubmed #19190755 links to  free full text

Abstract: BACKGROUND: Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. PRINCIPAL FINDINGS: We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. CONCLUSION/SIGNIFICANCE: Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.

Antonelli A, Ferri C, Fallahi P, Ferrari SM, Frascerra S, Franzoni F, Galetta F, Zignego AL, Ferrannini E. · Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy. · Dig Liver Dis. · Pubmed #18760981 No free full text.

Abstract: BACKGROUND: No study evaluates serum levels of CXCL10 and CCL2 chemokines in patients with hepatitis C associated mixed cryoglobulinaemia. AIMS: To measure circulating CXCL10 and CCL2 in cryoglobulinaemic patients. PATIENTS AND METHODS: Serum CXCL10 and CCL2 were assayed in 70 consecutive cryoglobulinaemic patients, and in 2 control groups (1:1, gender- and age-matched) of healthy (controls), or of chronic hepatitis C subjects without cryoglobulinaemia. RESULTS: Cryoglobulinaemic patients showed higher CXCL10 serum levels than controls (p<0.0001), or hepatitis C patients (p=0.001) (389 +/- 141, 91 +/- 51, 311 +/- 142 pg/ml, respectively). By defining a "high CXCL10" as a value at least 2 S.D. above the mean value of the control group (>193 pg/ml), 79% of cryoglobulinaemic patients, 5% of the controls and 69% of hepatitis C patients had high CXCL10 (p<0.0001). CXCL10 levels were (p<0.01) increased in cryoglobulinaemic patients with active vasculitis, with respect to those without (445+/-108, 339 +/- 161 pg/ml, respectively). Cryoglobulinaemic patients showed significantly higher CCL2 serum level than controls (p<0.01), but not than hepatitis C patients (541 +/- 493, 387 +/- 173 and 451 +/- 281 pg/ml, respectively). CONCLUSION: Our study first demonstrates high serum levels of CXCL10 and CCL2 chemokines in cryoglobulinaemic patients. Circulating CXCL10 is higher overall in cryoglobulinaemic patients with active vasculitis, suggesting a prevalence of the Th1 immune response in this phase.

Libra M, Gloghini A, Malaponte G, Gangemi P, De Re V, Cacopardo B, Spandidos DA, Nicoletti F, Stivala F, Zignego AL, Carbone A. · Department of Biomedical Sciences, University of Catania, Via Androne, 83-95124 Catania, Italy. · J Hepatol. · Pubmed #18538438 No free full text.

Abstract: BACKGROUND/AIMS: The gastrointestinal tract is the most common site of mucosa-associated lymphoid tissue (MALT) lymphoma development. Among the several genetic abnormalities involved in MALT development, the impact of t(14;18)-(IgH;Bcl-2) translocation has only been marginally analyzed. To this end, a consecutive series of gastrointestinal MALT lymphomas were analyzed. METHODS: t(14;18)-(IgH;Bcl-2) translocation, at the major break point region (MBR) and minor cluster region (mcr), were assessed by the polymerase chain reaction (PCR) in tumour DNA obtained from 40 consecutive gastrointestinal MALT lymphoma patients. Five out of the 40 patients studied were positive for hepatitis C virus (HCV) infection. RESULTS: Two out of 40 cases analyzed turned out to carry this chromosome aberration. Interestingly, both lymphomas bearing t(14;18) translocation derived from patients with chronic HCV infection. Nucleotide sequence analysis confirmed that Bcl-2 was joined to JH6 in both MALT lymphomas. Moreover, the heavy chain gene combinations detected in both MALT lymphomas were those usually found in the HCV-associated lymphomas. CONCLUSIONS: Our data support the notion that among gastrointestinal MALT lymphomas, t(14;18)-(IgH;Bcl-2) translocation clusters in HCV-positive patients sustaining the role of HCV infection in the lymphoma development.

Guerra CT, Caini P, Giannini C, Giannelli F, Gragnani L, Petrarca A, Solazzo V, Monti M, Laffi G, Zignego AL. · Department of Internal Medicine, Center for the Study of Systemic Manifestations of Hepatitis Viruses MaSVE, University of Florence, Florence, Italy. · Dig Liver Dis. · Pubmed #17936229 No free full text.

Abstract: BACKGROUND: Platelet-activating factor (PAF), a powerful phospholipid mediator of inflammation, is degraded by plasma PAF-acetyl-hydxolase (pPAF-AH), an enzyme which circulates in serum mainly in a complex with lipoproteins that confer its biological activity. Hepatitis C virus (HCV) is linked to lipoproteins in serum too. Reduced pPAF-AH activity was observed in several diseases, including systemic vasculitis. AIM: To evaluate if chronic HCV infection could alter pPAF-AH physiological functions. SUBJECTS: 145 subjects were studied: 56 HCV- and 52 HBV-infected patients (pathologic controls); 37 healthy subjects (healthy controls). METHODS: pPAF-AH activity, PAF and Apo B100 titers were determined in plasma; enzyme expression levels were evaluated in monocyte-derived macrophages. HCV-RNA was detected in plasma, peripheral blood mononuclear cells and liver samples. RESULTS: HCV-infected patients showed an increase of PAF levels following a significant decrease of pPAF-AH activity. A recovery of pPAF-AH activity occurs only in patients who clear HCV after the antiviral treatment. Expression levels of pPAF-AH mRNA and Apo B100 titers were not modified in HCV patients in comparison to controls. CONCLUSION: In light of these results, it is tempting to hypothesize that during chronic HCV infection, the PAF/pPAF-AH system may be altered and this condition may contribute to HCV-related vascular damage.

Alisi A, Giannini C, Spaziani A, Anticoli S, Caini P, Zignego AL, Balsano C. · Laboratory of Molecular Virology and Oncology, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome, Italy. · Dig Liver Dis. · Pubmed #17936228 No free full text.

Abstract: HCV chronic infection leads to liver diseases and also to a wide range of extrahepatic disorders including benign, but pre-lymphomatous forms (mixed cryoglobulinemia) to frank hematological neoplasia (non-Hodgkin's lymphoma). Recent data showed the involvement of p53 superfamily members in the pathogenesis of different lymphatic malignancies. In fact, tymomas and a subset of non-Hodgkin's lymphomas (NHLs) express high levels of p63. Thus, we analyzed whether alterations in p53 superfamily gene expression are observable in B lymphocytes isolated from HCV-infected patients with and without lymphoproliferative disorders. We showed, by real-time PCR, a significant induction of DNp63 mRNAs in B lymphocytes obtained from HCV-positive low grade non-Hodgkin's lymphoma patients. Since our current understanding of HCV proteins emphasizes the ability of the HCV core protein to deregulate the expression and activity of p53-related proteins, we established different B lymphocyte cell lines (Wil2-ns, Daudi and Ramos) stably expressing HCV core protein, in order to investigate the possible involvement of the viral protein in the upregulation of DNp63 in B lymphocytes. The analysis of p63 family transcripts showed no transcriptional changes for the p63 TA isoforms, whereas an increase (>5 times) of DNp63 mRNA occurred. In all cell lines, this abnormal expression was associated with a significant increase of cell proliferation that was specifically inhibited by silencing DNp63 mRNA. These findings suggest a pathogenetic role of the HCV core in HCV-related lymphomagenesis, through the induction of DNp63's pro-proliferative effects.

De Re V, Caggiari L, De Vita S, Mazzaro C, Lenzi M, Galli M, Monti G, Ferri C, Zignego AL, Gabrielli A, Sansonno D, Dammacco F, Libra M, Sacchi N, Talamini R, Spina M, Cannizzaro R, Guidoboni M, Dolcetti R. · CRO-IRCCS, Aviano National Cancer Institute, Pordenone, Italy. · Dig Liver Dis. · Pubmed #17936227 No free full text.

Abstract: The ability of the immune system to distinguish between self and non-self is critical to the functioning of the immune response. A breakdown in these mechanisms can lead to the onset of autoimmune disease. Clinical and molecular data suggest that shared immunogenetic mechanisms lead to the autoimmune process. The most studied part of the autoimmune process is the human leukocyte antigen (HLA) region. Recently, progress has been made in narrowing down HLA cluster classifications based on structural and functional features of HLA alleles. Using this approach we have investigated 175 patients with hepatitis C virus (HCV)-induced type II cryoglobulinemia (MC), and compared them to a control group of 14,923 bone marrow donors. Additionally, we investigated the frequency of HLA homozygosity in the same groups of subjects. Our results provide evidence of a role for DR5 and DQ3 HLA class II clusters and a higher frequency of HLA homozygous leading to the clinical outcome of type II mixed cryoglobulinemic autoimmune disease. The DR5 cluster is characterized by a Glu in beta 9 and its polymorphism is connected with preferred anchors at beta 9 of the binding peptide, while the DQ3 cluster is characterized by Glu B86 and Leu B87, which allows the binding of large hydrophobic amino acids at p1 of the binding peptide. The mechanisms by which variations in HLA lead to autoimmunity remain unknown, although they are likely to be mediated by continuous presentation of HCV epitopes to T cells and a genetic background that limits the effective clearance of HCV. The results presented in this paper have increased our knowledge of the mechanism of autoimmune disease and B-cell lymphoproliferation during HCV infection. The work was performed in accordance with the principles of the 1983 Declaration of Helsinki. There is no conflict of interest.

Boddi M, Abbate R, Chellini B, Giusti B, Solazzo V, Soft F, Pratesi G, Pratesi C, Gensini G, Zignego AL. · Clinica Medica Generale e Cardiologia, Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy. · Dig Liver Dis. · Pubmed #17936225 No free full text.

Abstract: BACKGROUND: Clinical and experimental evidence suggests that hepatitis C virus (HCV) infection shows peculiar characteristics that strongly support a role in the development of atherosclerosis. We aimed to investigate whether (a) HCV infection can facilitate asymptomatic carotid lesions and (b) the presence of HCV RNA sequences can be shown in plaque tissues. METHODS: The status of carotid arteries, studied as intima-media thickness (IMT) in carotid bifurcation and prevalence and severity of plaques in internal carotid artery, was investigated by high-resolution B-mode ultrasonography in 31 HCV seropositive (HCV+) and in 120 age-matched HCV seronegative (HCV-) subjects evaluated for cardiovascular risk factors. The atherosclerotic risk profile, inflammation markers and main liver function tests were also studied in all patients. HCV RNA sequences were investigated by highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) in plaque tissues and serum of 2 HCV+ patients who underwent carotid revascularization. RESULTS: Genomic and antigenomic HCV RNA strands were evidenced within both the carotid plaque tissues examined. The prevalence of an IMT > 1 mm, but not the prevalence and severity of internal carotid plaques, was significantly higher (P < 0.001) in HCV+ than in HCV patients. The atherosclerotic risk profile for traditional and inflammatory factors did not differ between the HCV+ and HCV- groups. Main liver function tests did not differ between the two groups. HCV positivity was significantly associated with >1 mm IMT (P < 0.01) according to univariate analysis, and this association remained significant in multivariate regression analysis. CONCLUSIONS: The novel finding of HCV RNA sequences within carotid plaques suggests a local pro-atherogenetic action of the virus inside the plaque. On the whole our data strongly support that HCV infection facilitates the occurrence of carotid atherosclerotic lesions.

Petrarca A, Rigacci L, Monti M, Giannini C, Bernardi F, Caini P, Colagrande S, Bosi A, Laffi G, Zignego AL. · Department of Internal Medicine, Center for the Study of Systemic Manifestations of Hepatitis Viruses (MASVE), University of Florence, Florence, Italy. · Dig Liver Dis. · Pubmed #17936214 No free full text.

Abstract: Mixed cryoglobulinemia (MC) is the most strictly virus-related extrahepatic HCV disease. Antiviral therapy is considered the first therapeutic option; however, MC patients are frequently excluded from treatment due to contraindications. The effectiveness of B-cell depletion by anti-CD20 monoclonal antibody (rituximab) has recently been described, but the possibility of an immunodepression- related increase in viral replication and aminotransferase values limits its use in patients with advanced liver disease. Unfortunately, MC patients frequently also have cirrhosis. To our knowledge, no data are available regarding the effect of rituximab therapy in patients with decompensated cirrhosis. We report the successful treatment with rituximab (4 weekly infusions of 375 mg/m 2) of two patients (a 58-year-old man, and a 65-year-old woman) with HCV-related MC syndrome and decompensated liver cirrhosis. These patients underwent at least 6 months of post-treatment follow-up. In both cases a consistent improvement of MC syndrome was evident after treatment. In addition, improvement of liver protidosynthetic activity, increased prothrombin time, impressive reduction or disappearance of ascites and encephalopathy were also observed, in spite of some increase in viral titers or in ALT values. The Child-Pugh score improved from B8 to A6 and from Cll to B7, respectively. Pre- and post-treatment transjugular liver biopsies were available in 1 patient, showing disappearance of lymphocytic infiltration after treatment. These case reports show the effectiveness and safety of rituximab in patients with HCV-related MC and advanced cirrhosis, and strongly suggest that the depletion of CD20+ B-cells induced by rituximab treatment may be responsible for liver function improvement. The mechanisms involved are unknown. Interesting working hypotheses may implicate a role played by B-cell infiltrates in conditioning liver damage. The improvement of Kupffer cell function due to the cryocrit value reduction might also play a role.