Hepatitis: Caini P

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.

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.

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.

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.

Alisi A, Giannini C, Spaziani A, Caini P, Zignego AL, Balsano C. · Laboratory of Molecular Virology and Oncology, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome, Italy. · J Cell Physiol. · Pubmed #17654494 No free full text.

Abstract: Hepatitis C virus (HCV) core protein has been shown to deregulate cell growth and programmed cell death in hepatoma cells, but only minimal informations are available about its possible role on B-lymphoproliferative disorders (LPDs). The aim of our work was to analyze the biological activity of HCV core protein on B-cell proliferation. We established Wil2-ns and Ramos B-cell lines that stably expressed the HCV core protein. Growth curve, thymidine incorporation analysis, as well as the expression of PCNA and activated-ERKs demonstrated that HCV core protein induced an increased growth in both cell lines. Interestingly, the HCV core protein expression determined, in our model, a downregulation of DNp73 and an upregulation of DNp63, which was essential for the maintenance of viral-dependent effects on cell growth. Finally, we have identified phosphoinositide 3-kinase (PI3K) as mediator of HCV core-dependent transcriptional increase of DNp63, which in turn correlated with the increasing of lymphocyte proliferation. In primary B-lymphocytes, derived from HCV-related low-grade non-Hodgkin's lymphoma patients, consistent results were obtained. These findings provide evidence for a possible pathogenetic role played by HCV core protein in HCV-related lymphomagenesis; it could occur through the deregulation of PI3K activity, consequent activation of Akt and overexpression of DNp63.

Caini P, Guerra CT, 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 and Higher Education Research and Transfer Center DENOTHE, University of Florence, Florence, Italy. · J Viral Hepat. · Pubmed #17212640 No free full text.

Abstract: Hepatitis C virus (HCV) chronically infects about 200 million individuals worldwide and leads to severe liver and lymphatic diseases. HCV circulates in the serum, associated with apoB-containing lipoproteins. Platelet-activating factor (PAF), a pro-inflammatory mediator, is mainly modulated by plasma PAF-acetylhydrolase (pPAF-AH), associated with ApoB100-containing low-density lipoproteins (LDL). The aim of the study was to evaluate the potential effects of chronic HCV infection on the PAF/pPAF-AH system. HCV-RNA was detected in plasma, peripheral blood mononuclear cells (PBMC) and liver samples. Plasma PAF levels, pPAF-AH activity, ApoB100 serum titres and pPAF-AH mRNA levels in cultured macrophages were determined. Plasma PAF levels were significantly higher and pPAF-AH activity was significantly lower in HCV patients than in controls. No significant modifications of pPAF-AH mRNA in macrophages or in ApoB100 values were observed in HCV patients compared with controls. Patients who cleared HCV after antiviral treatment showed a complete restoration of pPAF-AH activity and significant decrease of PAF levels during the follow-up. No data exist about the PAF/pPAF-AH system behaviour during HCV infection. This study shows that in HCV patients modifications of pPAF-AH activity/PAF levels take place and that HCV clearance restored pPAF-AH activity. This suggests that circulating viral particles play a role in PAF/pPAF-AH system modifications and such an alteration could be involved in HCV-related damage.

Zignego AL, Ferri C, Giannelli F, Giannini C, Caini P, Monti M, Marrocchi ME, Di Pietro E, La Villa G, Laffi G, Gentilini P. · Department of Internal Medicine, University of Florence, School of Medicine, Viale Morgagni, 85, 50134 Florence, Italy. · Ann Intern Med. · Pubmed #12353944 links to  free full text

Abstract: BACKGROUND: Hepatitis C virus (HCV) infection is strictly associated with mixed cryoglobulinemia, a benign B-cell lymphoproliferative disorder that may evolve to lymphoma. An increased prevalence of bcl-2 rearrangement (the t(14;18) translocation) has been shown in patients infected with HCV. OBJECTIVE: To evaluate the prevalence of bcl-2 rearrangement in patients with HCV-related mixed cryoglobulinemia and patients with chronic hepatitis but no cryoglobulinemia. DESIGN: Prospective study. SETTING: Two university hospitals. PATIENTS: 37 consecutively recruited patients with HCV-related mixed cryoglobulinemia and 101 patients with chronic HCV infection but without mixed cryoglobulinemia. MEASUREMENTS: Clinical and serologic characteristics; liver biopsy; bcl-2 rearrangement, Bcl-2 expression, and the ratio of Bcl-2 to Bax in total peripheral blood mononuclear cells and cell subgroups; and sequence analysis of the junction of bcl-2 and IgH joining segments in positive samples. RESULTS: Rearrangement of bcl-2 was observed in 28 of 37 (75.7%) patients with mixed cryoglobulinemia (65% of those with type III disease and 85% of those with type II disease, including 3 of 4 patients with lymphoma) and in 38 of 101 (37.6%) patients with chronic HCV infection but not mixed cryoglobulinemia (P < 0.001). Overexpression of Bcl-2 protein and a high ratio of Bcl-2 to Bax were observed in samples from patients with bcl-2 rearrangement. In 2 patients followed over time, peripheral blood cells bearing the t(14;18) translocation disappeared after antiviral therapy. CONCLUSIONS: Rearrangement of bcl-2 was found with increased frequency in patients with chronic HCV infection and mixed cryoglobulinemia. The frequency was greatest in patients with type II mixed cryoglobulinemia. The high ratio of Bcl-2 to Bax in patients with bcl-2 rearrangement and disappearance of the rearrangement with antiviral therapy suggest that the translocation is associated with the antiapoptotic function of Bcl-2 and that HCV infection is linked to inhibition of B-cell apoptosis.

Giannini C, Caini P, Giannelli F, Fontana F, Kremsdorf D, Bréchot C, Zignego AL. · Department of Internal Medicine, University of Florence, Florence, Italy. · J Gen Virol. · Pubmed #12075085 links to  free full text

Abstract: Hepatitis C virus (HCV) chronic infection has been associated with many lymphoproliferative disorders. Several studies performed on hepatoma and fibroblast cell lines suggest a role of the HCV core protein in activation of cellular transduction pathways that lead to cell proliferation and inhibition of apoptosis. However, no data are available concerning the effects of HCV core expression on B-lymphocyte proliferation and apoptosis. B-lymphocyte cell lines permanently expressing full-length HCV 1b core sequences isolated from chronically infected patients were established using B-cell lines at different degrees of differentiation. Clones and pools of clones permanently expressing the HCV core were selected and characterized for protein expression by Western blot and FACS. Expression of HCV core proteins did not significantly enhance cell proliferation rates under normal culture conditions or under mitogenic stimulation. Analysis of NF-kappa B, CRE, TRE and SRE pathways by luciferase reporter genes did not show a significant influence of HCV core expression on these signal transduction cascades in B-lymphocytes. The effects of HCV core on anti-IgM and anti-FAS-induced apoptosis in B-cell lines was also analysed. In this experimental model, HCV core expression did not significantly modify the apoptotic profile of the B-lymphocyte cell lines tested. These data underline a cell type-specific effect of HCV core expression. In fact, it was not possible to show a significant contribution of the HCV core protein in activation of the major B-cell signal transduction pathways involved in the regulation of proliferation and programmed cell death, which is in contrast with the results reported in hepatoma cell lines.

Zignego AL, Giannelli F, Marrocchi ME, Mazzocca A, Ferri C, Giannini C, Monti M, Caini P, Villa GL, Laffi G, Gentilini P. · Department of Internal Medicine, University of Florence, School of Medicine, 50134 Florence, Italy. · Hepatology. · Pubmed #10655273 No free full text.

Abstract: Pathogenic mechanisms of B-cell lymphoproliferative disorders in chronic hepatitis C virus (HCV) infection are unclear. We studied t(14;18) translocation by polymerase chain reaction in peripheral blood mononuclear cells from 50 patients with HCV-related liver disease (group A), 7 with mixed cryoglobulinemia syndrome (group B), 55 with HCV-negative liver disease (group C), and 30 with HCV-negative chronic rheumatic disorders or chronic infection by nonhepatotropic agents (group D). T(14;18) was significantly more frequent in group A (13/50 patients = 26 %) and group B (5/7 = 71.4%) patients than in group C (1/55 = 3.6%) and group D (1/30 = 3.3%) ones. Immunoblot analysis showed bcl-2 over-expression in all t(14;18)-positive samples. In group A, 10/13 (77%) patients with t(14;18) and 13/37 (35%) without t(14;18) had serum cryoglobulins in the absence of mixed cryoglobulinemia symptoms (P <.05). These data indicate that t(14;18) and bcl-2 over-expression in lymphoid cells are frequent in chronic HCV infection and suggest that this event may contribute to the pathogenesis of HCV-related lymphoproliferative disorders.

Giannini C, Gragnani L, Piluso A, Caini P, Petrarca A, Monti M, Laffi G, Zignego AL. · No affiliation provided · Blood. · Pubmed #18988879 No free full text.

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Giannini C, Petrarca A, Monti M, Arena U, Caini P, Solazzo V, Gragnani L, Milani S, Laffi G, Zignego AL. · No affiliation provided · Blood. · Pubmed #18299456 links to  free full text

This publication has no abstract.