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Background: Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatment is ill-defined., Aims: To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the efficacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine, was explored., Methods: In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45-70) were enrolled., Results: The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy (29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobulinemias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1-14), rheumatoid factor was 200U/L (range 20-5850), C4 was 12mg/dl (range 2-31), ALT 71U/L (range 36-114). All patients were HBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight), Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no disease progression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regression of purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidney failure and two of liver cirrhosis., Conclusion: NUC therapy appeared to be safe and effective in CV-related HBV., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The most frequent form of renal involvement in patients with hepatitis C infection is cryoglobulinemic membrano-proliferative glomerulonephritis. Nonetheless, some reports indicate that the eradication of the hepatitis C virus may also lead to the remission of this renal disease., Methods: The virological, immunological and nephrological response to pegylated interferon α plus ribavirin (48 weeks in patients infected with genotype 1, and 24 weeks for patients infected with genotypes 2 and 3) was evaluated retrospectively in 10 patients with cryoglobulinemic glomerulonephritis., Results: 6 patients obtained end of treatment virological response (60%); during follow-up, 2 relapsed, and 4 patients maintained a sustained virological response (40%). At the end of follow-up, three patients obtained a significant nephrological response and decrease in cryoglobulin levels (p<0.05). No significant changes in clinical and biological parameters were observed in non-responders/relapsers., Conclusions: Eradication of hepatitis C may be associated with the regression of cryoglobulinemic glomerulonephritis., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: No effective therapy is available for hepatocellular carcinoma. To identify novel therapeutic strategies, we explored the effects of the depletion of E2F1, cyclin E1-E2 whose inter-relationships in hepatocellular carcinoma cell proliferation have never been defined., Methods: siRNA-mediated depletion of the targets was studied in the hepatocellular carcinoma cells HepG2, HuH7 and JHH6 characterized by high, medium and low hepatocyte differentiation grade, respectively; a model of normal human hepatocytes was also considered., Results: The depletion of each target mRNA reduced the levels of the other two mRNAs, thus demonstrating a close regulatory control, also confirmed by over-expression experiments. At the protein level, an exception to this trend was observed for cyclinE1 whose amount increased upon cyclin E2 (HepG2, HuH7, JHH6) and E2F1 (HepG2) depletion. In HepG2, reduced cyclinE1 proteolysis accounted for this observation. Additionally, cyclin E1-E2-E2F1 targeting decreased the levels of cyclin A2 mRNA and of the hyper-phosphorylated form of pRb thus leading to an S-phase cell decrease; migration was impaired as well. Finally, the model of human hepatocytes used was clearly less affected by target mRNAs depletion than hepatocellular carcinoma cells., Conclusion: Our data provide novel mutual relationships amongst cyclin E1-E2-E2F1 and indicate their role in sustaining hepatocellular carcinoma cell proliferation/migration, validating the concept of an anti-cyclin E1-E2-E2F1 therapeutic approach for hepatocellular carcinoma., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. All rights reserved.)

The treatment of mixed cryoglobulinemia (MC) includes several drugs--steroids, cyclosporins, colchicine, plasmapheresis--but given the documented association between MC and hepatitis C virus (HCV), the treatment of choice seems to be antiviral therapy. Several authors have reported the efficacy of interferon (IFN) alpha in the inhibition of HCV replication and reduction of cryoglobulin levels. The therapy with IFN as monotherapy in MC shows a complete response rate in only 10 -12% of cases. Complete response to therapy using a combination of IFN plus ribavirin varies in different studies from 18% to 64% of cases. There are only two studies on the treatment of MC with peginterferon plus ribavirin. Both studies, given the high number of complete responders, reinforce the idea that peginterferon plus ribavirin is, at present, the best available treatment for cryoglobulinemic syndrome. The results obtained with peginterferon combined therapy are superior to standard interferon plus ribavirin in treatment-naive patients. In fact, a sustained virological response was observed in 44% of patients; the same results were obtained for clinical (purpura and arthralgia disappearance) and biochemical (aminotransaminases normalization) responses. New drug combinations, like peginterferons plus anti-CD20 antibodies, should be considered for treatment of MC in the future.

Hepatitis C virus is associated with chronic liver disease as well as with lymphoproliferative disorders such as mixed cryoglobulinemia and, likely, non-Hodgkin's lymphomas. The association between hepatitis C virus infection and B-cell lymphoma is controversial since it shows a strong regional variation. In fact, the prevalence of hepatitis C virus infection in non-Hodgkin's lymphoma shows a prevalence ranging between 7.4 and 37.0%. However, the intimate pathogenetic mechanism involved in hepatitis C virus-associated lymphomas remains considerably unknown. Hepatitis C virus may exert its oncogenic potential via an indirect mechanism or utilise other pathways directly. It is reasonable to assume that several different pathogenetic mechanisms operate in the wide spectrum of hepatitis C virus-related lymphoproliferative disorders, which include the intermediate to high-grade lymphoma, and the more common indolent, low-grade lymphoma, preceded by long standing symptomatic mixed cryoglobulinemia Type II. In this review, the etiopathogenetic role of hepatitis C virus in non-Hodgkin's lymphoma is discussed on the basis of molecular, clinical and epidemiological considerations. The management of hepatitis C virus-associated non-Hodgkin's lymphoma is similar to that of conventional lymphoma, although viral reactivation or the underlying chronic liver disease can complicate chemotherapy. Whether to treat low-grade hepatitis C virus-related lymphomas with anti-viral therapy is still debatable, but encouraging data emerge from some recent studies.

Background and Aims: Hepatitis C virus infection is often associated with lymphoproliferative disorders such as essential mixed cryoglobulinemia and B-cell non-Hodgkin lymphoma, which show preferential expression of VHI family products. By analyzing immunoglobulin heavy chain usage, we addressed the question of whether or not clonal B-cell expansion occurrs in patients free of essential mixed cryoglobulinemia or non-Hodgkin lymphoma., Patients and Methods: Four hepatitis C virus-positive patients, all undergoing liver transplantation, were studied. Peripheral blood, intra-hepatic, and lymph node lymphocytes were used as a source of B cells. A patient with hepatocellular carcinoma and fresh blood from four healthy donors were used as negative controls. VHI family sequences were cloned and analyzed by reverse transcription-polymerase chain reaction., Results: Immunoglobulin heavy chain sequences from clonally expanded B lymphocytes were identified in three out of four hepatitis C virus-infected patients. The clonally expanded B lymphocyte populations showed a broad spectra of immunoglobulin heavy chain gene usage., Conclusions: HCV infection can induce B-cell expansion with larger clonal variation. The restricted V gene usage in hepatitis C virus-associated non-Hodgkin lymphoma suggests that there may be selection mechanisms to develop non-Hodgkin lymphoma from non-malignant, clonally expanded B-cell populations in hepatitis C virus-infected patients.

Aim: To assess the efficacy of different schedules of human leucocyte interferon alpha in chronic hepatitis C., Patients and Methods: A total of 213 naive patients with chronic hepatitis C were treated with 4 different schedules of human leucocyte interferon alpha. Sustained response was defined as persistently normal alanine amino transferase values with negative serum hepatitis C virus-RNA up to 12 months after therapy withdrawal., Results: Rates of sustained response were 16% with 3 MU tiw for 6 months, 33% with 6 MU tiw for 5 months after a priming dose of 9 MU tiw for a month, 32% with 3 MU tiw for 12 months and 20% with 3 MU daily for 6 months. The major factors affecting the response rate were age and the hepatitis C virus genotype, as a sustained response was significantly higher in patients under 45 years and infected by hepatitis C virus types other than hepatitis C virus-1. Treatment was well tolerated and side-effects and drop-out events were similar to those described with other types of alpha-interferons., Conclusions: Human leucocyte interferon alpha appears to be equivalent to recombinant interferon-alpha in the treatment of chronic hepatitis C.

Background/aims: The association between mixed cryoglobulinaemia, cryoglobulinaemic glomerulonephritis, and chronic hepatitis C virus infection has recently been described. The renal disease had usually been treated with immunosuppressive therapy, but, given the presence of viral infection, this therapy is no longer recommended. In this study, we compare steroid vs interferon therapy in a group of patients affected by hepatitis C virus-positive cryoglobulinaemic glomerulonephritis in the stationary phase., Patients/methods: The diagnosis of cryoglobulinaemic glomerulonephritis was made bearing in mind standard criteria. Patients were randomly assigned to 2 groups receiving oral prednisone 0.2 mg/kg/die for 6 months (6 patients, group A) or lymphoblastoid interferon 3 MU, three times a week for 6 months [7 patients, group B). Hepatitis C virus-RNA was determined by reverse transcription-polymerase chain reaction and hepatitis C virus genotype according to Okamoto. Hepatitis C virus-RNA quantitation was performed by competitive polymerase chain reaction. RESULTS; The 2 groups were comparable in terms of age and severity of kidney failure. All genotypes of hepatitis C virus were found with a prevalence of Type 1b. In group A, 4 patients showed a partial response; in group B, 1 patient achieved complete remission, 4 a partial response, 2 patients in both groups showed no response. At the end of the treatment, all patients in both groups relapsed. Only 1 patient in group B became hepatitis C virus-RNA negative, and recovered from cryoglobulinaemic glomerulonephritis., Conclusions: Interferon seems to be an effective drug in the treatment of cryoglobulinaemic glomerulonephritis, but dosage and length of treatment still need to be addressed by large multicentre studies.