Hepatitis C and Mixed Cryoglobulinemia

5/17/00 (Del Rio)

Group: Wednesday Residents

RE: A 54 year old female, veteran ADVR, with 1 wk watery diarrhea

Question: What relationship exists between Hepatitis C infection and mixed cryoglobulinemia?

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Unique Identifier: 20224629

Authors: Hausfater P. Rosenthal E. Cacoub P.

Institution: Service de Medecine Interne, CHU Pitie-Salpetriere, Paris.

Abstract: The putative role of hepatitis C virus (HCV) infection in the pathophysiology of lymphoproliferative diseases (LPD) is: supported by north-American and south-European studies reporting high HCV seroprevalence in patients with: B-cell-non-Hodgkin lymphoma (NHL). However, controversial data were reported from other areas. The review of: available reports to data on HCV-associated LPD points to some features: predominance of low-grade malignant: lymphoma, frequent involvement of extranodal sites, absence of particular HCV genotype distribution (except in Italy for: genotype 2), important geographical seroprevalence discrepancies. In our experience in 43 cases of HCV-associated: LPD in France, we noted a predominance of B-cell NHL (31/43 cases), and the frequency of LPD among: HCV-infected patients approximates 2.5%. Pathophysiology hypotheses are discussed, particularly in view of the: lympho tropism of HCV. HCV is frequently associated with type II mixed cryoglobulinemia, a benign monoclonal: lymphoproliferation which sometimes evolves to overt B-cell lymphoma. The recent finding of HCV binding on CD81, a: surface-expressed protein present on lymphocyte membrane, enhances the putative role of HCV in lymphomagenesis.: Further investigations are needed to characterize interaction between B lymphocytes and HCV, and to determine: putative cofactors involved in the multistep process leading to clonal lymphoproliferation in HCV patients. [References:: 35]

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Unique Identifier: 20224626

Authors: Sasso EH.

Institution: Department of Medicine, University of Washington, Seattle 98105, USA.

Abstract: Studies of mixed cryoglobulins (MC) from patients infected with hepatitis C virus (HCV) show that the principal: constituents in cryoprecipitate are IgM rheumatoid factors (RF), polyclonal IgG anti-HCV antibodies, and HCV RNA.: The HCV-induced RF response is biased to produce IgM RF encoded by a restricted set of Ig V genes, predominantly: the VH/VL gene pair 51p1/kv325. The propensity of such IgM RF to cryoprecipitate is likely a coincidental property of: their V region sequences, but the clinical effect of this bias is increased by the persistence of circulating HCV-IgG: immune complexes. These complexes might induce production of cryoprecipitable IgM RF and furnish multi-molecular: structures that favor binding by cryoprecipitable IgM RF. The V gene sequences of HCV-induced IgM RF have: features seen in other RF responses, suggesting a common immunological mechanism that is independent of HCV. B cell: proliferation is probably enhanced by HCV-specific properties, however, including the ability of HCV proteins to bind to: CD81 on the B cell surface, and to influence intracellular regulatory functions following viral entry into B cells. The V: gene bias in HCV-induced RF is most apparent among the B cells in monoclonal expansions responsible for type II: cryoglobulins, but it might originate early the polyclonal RF response, before MC are detectable. Monoclonal B cell: expansions and lymphomatoid bone marrow infiltrates in HCV+ patients predominantly involve CD5-negative IgM RF B: cells. Non-RF B cells can also be expanded, including producers of IgG1 and IgG3 that are likely anti-HCV antibodies.: The initial site of B cell clonal expansion may be in the liver, where lymphoid aggregates are abundant and RF are: produced. Sorting out how MC formation is influenced by properties that are inherent to the RF response, or specific to: HCV infection, will be a challenge to future HCV research. [References: 103]

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Unique Identifier: 20224625

Authors: Cacoub P. Hausfater P. Musset L. Piette JC.

Institution: Service de Medecine Interne, Hopital Pitie-Salpetriere, Paris. patrice.cacoub@psl.ap-hop-paris.fr

Abstract: Cryoglobulins are immunoglobulins that persist in the serum, precipitate with cold temperature and resolubilize when: rewarmed. Types II and III are mixed cryoglobulins (MC), composed of different immunoglobulins, with a monoclonal: component in type II and only polyclonal immunoglobulins in type III. Mixed cryoglobulins are associated with: connective-tissue disease, malignant hematological disorder (type B lymphoproliferation) or obvious infectious process.: Mixed cryoglobulinemia syndrome is characterized by the clinical triad of purpura, arthralgia and asthenia associated: with type II or type III MC. The disorder is the consequence of an immune-complex-type vasculitis as supported by: clinical features, analysis of the cryoglobulins, the usually depressed level of complement during the active phase of the: disease, and the deposition of immunoglobulins and complement in the lesions. Such cryoglobulinemia vasculitis may: involve numerous organs, particularly the peripheral nervous system and the kidneys. MC is frequently associated with: clinical and biological evidence of liver disease. There has been some controversy about which comes first, MC or: chronic liver disease, but it seems fairly clear that MC is often a manifestation of underlying chronic active or persistent: hepatitis. In MC patients, the hepatotropic antigen(s) capable of triggering production of antibodies which can later: form immune complexes has been sought for many years. In the last ten years, numerous studies have demonstrated that: infection with hepatitis C virus is involved in the pathogenesis of most mixed cryoglobulinemia. This review analyzes: the main published data on hepatitis C virus-mixed cryoglobulinemia, the role of liver alterations, the predictive: factors associated with MC production in HCV patients and its symptomatic nature or not, and the different types of: vasculitis associated with HCV chronic infection. [References: 100]

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[Link Directly to Fulltext Article in OVID]

Unique Identifier: 20135305

Authors: Cacoub P. Renou C. Rosenthal E. Cohen P. Loury I. Loustaud-Ratti V. Yamamoto AM. Camproux AC. Hausfater P.: Musset L. Veyssier P. Raguin G. Piette JC.

Institution: Department of Internal Medicine, Hopital La Pitie-Salpetriere, Paris, France. patrice.cacoub@psl.ap.hop-paris.fr

Abstract: From January 1996 to January 1997, 321 patients with an average age of 46 +/- 16 years and chronically infected with: hepatitis C virus (HCV) were prospectively enrolled in a study designed to determine the prevalence of extrahepatic: manifestations associated with HCV infection in a large cohort of HCV patients, to identify associations between clinical: and biologic manifestations, and to compare the results obtained in human immunodeficiency virus (HIV)-positive versus: HIV-negative subsets. In a cross-sectional study, clinical extrahepatic manifestations, viral coinfections with HIV and/or: hepatitis B virus, connective tissue diseases, and a wide panel of autoantibodies were assessed. Thirty-eight percent: (122/321) of patients presented at least 1 clinical extrahepatic manifestation including arthralgia (60/321, 19%), skin: manifestations (55/321, 17%), xerostomia (40/321, 12%), xerophthalmia (32/321, 10%), and sensory neuropathy: (28/321, 9%). Main biologic abnormalities were mixed cryoglobulins (110/196, 56%), thrombocytopenia (50/291,: 17%), and the presence of the following autoantibodies: antinuclear (123/302, 41%), rheumatoid factor (107/280,: 38%), anticardiolipin (79/298, 27%), antithyroglobulin (36/287, 13%) and antismooth muscle cell (27/288, 9%). At: least 1 autoantibody was present in 210/302 (70%) of sera. By multivariate logistic regression analysis, 4 parameters: were significantly associated with cryoglobulin positivity: systemic vasculitis (p = 0.01, odds ratio OR[ = 17.3), HIV: positivity (p = 0.0006, OR = 10.2), rheumatoid factor positivity (p = 0.01, OR = 2.8), and sicca syndrome (p = 0.03,: OR = 0.27). A definite connective tissue disease was noted in 44 patients (14%), mainly symptomatic mixed: cryoglobulinemia and systemic vasculitis, HIV coinfection (23%) was associated with 3 parameters: anticardiolipin (p: = 0.003, OR = 4.18), thrombocytopenia (p = 0.01, OR = 3.56), and arthralgia or myalgia (p = 0.017, OR = 0.23).: HIV-positive patients presented more severe histologic lesions (p = 0.0004). Extrahepatic clinical manifestations in HCV: patients involve primarily the skin and joints. The most frequent immunologic abnormalities include mixed cryoglobulins,: rheumatoid factor, antinuclear, anticardiolipin, and antithyroglobulin antibodies. Cryoglobulin positivity is associated with: systemic vasculitis and rheumatoid factor and HIV positivity. HIV coinfection is associated with arthralgia or myalgia,: anticardiolipin antibodies, and thrombocytopenia.

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Unique Identifier: 20112481

Authors: Ferri C. Zignego AL.

Institution: Dipartimento Medicina Interna, Rheumatology Unit, University of Pisa, Italy. c.ferri@int.med.unipi.it

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. [References: 73]

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Unique Identifier: 20074442

Authors: Kiyomoto H. Hitomi H. Hosotani Y. Hashimoto M. Uchida K. Kurokouchi K. Nagai M. Takahashi N. Fukunaga M.: Mizushige K. Matsuo H. Yuasa S.

Institution: Second Department of Internal Medicine, Kagawa Medical University, Japan. kiyo@kms.ac.jp

Abstract: Cryofiltration, which has developed from double filtration plasmapheresis (DFPP) with a cooling unit, is an on-line: technique to remove cryoglobulin. We report on a patient who suffered from progressive edema and renal insufficiency: caused by cryoglobulinemic membranoproliferative glomerulonephritis (MPGN), probably due to chronic hepatitis C: virus (HCV) infection. To remove cryoglobulins and terminate the HCV infection, we utilized combination therapy with: cryofiltration and interferon-alpha injection with corticosteroids. Interferon-alpha was capable of decreasing proteinuria: but not diminishing cryoglobulin. Additional cryofiltration could remove cryoglobulin to an undetectable level. This: combination therapy was partially successful to reduce proteinuria and prevent the progressive deterioration of renal: function. The major adverse effects of this therapy were bleeding and myelosuppression. We conclude that this: combination therapy may be effective and should be considered as treatment for cryoglobulinemic MPGN.

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Unique Identifier: 20071768

Authors: Mazzaro C. Faelli A. Baracetti S. Mezzoran L. Pussini E. Zorat F. Pozzato G.

Institution: Third Division of Medicine, Pordenone General Hospital, Pordenone, Italy.

Abstract: The association between mixed cryoglobulinaemia and chronic hepatitis C virus infection has recently been described.: Cryoglobulinaemic glomerulonephritis, a complication of mixed cryoglobulinaemia, is usually treated with: immunosuppressive therapy, but, given the presence of viral infection, this therapy is no longer recommended. This: report concerns a case of a 30-year-old patient with cryoglobulinaemic glomerulonephritis, refractory to steroid: treatment, in whom recovery from hepatitis C virus infection was obtained as well as from cryoglobulinaemic: glomerulonephritis after interferon therapy. The clinical symptoms and laboratory tests were normal after prolonged: interferon therapy and, 3 years after the end of treatment, the patient is free from disease.

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Unique Identifier: 99119419

Authors: Rasul I. Shepherd FA. Kamel-Reid S. Krajden M. Pantalony D. Heathcote EJ.

Institution: Department of Medicine, The Toronto Hospital, University of Toronto, Toronto, Ontario, Canada.

Abstract: Hepatitis C virus (HCV) is both hepatotropic and lymphotropic and has been shown to be associated with the benign: lymphoproliferative disorder, mixed cryoglobulinemia (MC). Preliminary studies suggest that there may be an: association between chronic hepatitis C, MC, and non-Hodgkin's lymphoma (NHL). The aim of this study was to: determine whether patients with chronic HCV and MC have occult bone marrow NHL. Sixteen patients with chronic: HCV and clinically active MC underwent bone marrow biopsy and aspiration. Flow cytometry was performed looking: for abnormal B-cell lineage. Molecular genetic studies were performed to identify B-cell monoclonality. Nine of 16: patients (56%) had abnormal marrow morphology, 7 (44%) were interpreted as suspicious for lymphoma, and 2 (13%): as consistent with lymphoma. Flow cytometry on 13 patients identified 5 (39%) with increased B-cell populations.: Molecular analysis on 13 patients identified 3 (23%) with monoclonal proliferation of the B-cell lineage. All 13 patients: tested for Epstein-Barr virus were negative by polymerase chain reaction (PCR). Four of 16 patients (25%) had marrow: morphology and evidence of a monoclonal B-cell population by flow cytometry and/or molecular studies, consistent with: B-cell NHL. These findings confirm the presence of lymphoproliferative disorders in patients with chronic HCV and: MC. Some of these disorders meet the morphological and molecular criteria for the diagnosis of malignant lymphoma.

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Unique Identifier: 20086270

Authors: Manns MP. Rambusch EG.

Institution: Dept. of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.: manns.michael@mh-hannover.de

Abstract: Hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations: mixed cryoglobulinaemia,: membranoproliferative glomerulonephritis and, in southern Europe, to some extent with porphyria cutanea tarda. The: association of haplotype HLA B-8 and DR-3 mixed cryoglobulinaemia and HCV infection has recently been: demonstrated. Interferon alpha therapy decreases hepatitis C viraemia and improves the clinical signs and biochemical: abnormalities of cryoglobulinaemia. There seems to be a south-north gradient in the prevalence of HCV-associated: cryoglobulinaemia. The rare combination of hepatitis C and panarteritis nodosa has still not been confirmed. The sicca: syndrome also seems to be associated with hepatitis C virus, but this is not the typical Sjogren syndrome. Existing: studies have not answered the question of whether HCV plays a pathogenic role in the development of thyroid: dysfunction and autoimmune thyroiditis. There seems to be a genetic predisposition for the manifestations of thyroid: disease in the case of hepatitis C infection and interferon therapy. This predominantly affects women with haplotype: HLA DR-3. Before beginning interferon therapy, these patients often show thyroid autoantibodies against the thyroid: peroxidase and/or thyroglobulin. It is still unclear whether the rare combination of hepatitis C with aplastic anaemia and: lymphoma has pathogenic aspects. These haematological manifestations are thought to be induced by the infection of: haematopoietic cells with the hepatitis C virus. In rare cases, a stimulated HCV-induced interferon gamma synthesis by: haematopoietic stem cells has been shown. Although an epidemiological association of hepatitis C with lichen planus,: neuropathies and other diseases has been observed, the aetiological role and the pathogenic involvement of the hepatitis: C infection remains unclear. Furthermore, the question of whether these extrahepatic diseases are autoimmune has not: been clarified. On the other hand, a number of autoantibodies may be observed during the course of hepatitis C. Of: particular interest are liver/kidney microsomal antibodies (LKM). Their occurrence in viral hepatitis may indicate an: increased risk for treatment with interferons. In the clinical setting, the presence of these diseases should suggest: hepatitis C infection and hepatitis C antibodies should be tested and, if positive, hepatitis C-RNA is indicated. If: there is any evidence of an aetiological association of replicative hepatitis C infection and the above-mentioned: extrahepatic diseases, antiviral treatment should be considered. [References: 23]

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Unique Identifier: 20039296

Authors: Pellicano R. Marietti G. Leone N. Arena V. Palmas F. Rizzetto M. Ponzetto A.

Institution: Department of Gastroenterology, Molinette Hospital, Turin, Italy.

Abstract: BACKGROUND AND AIMS: Mixed cryoglobulinaemia (MC) is a frequent finding among patients infected with: hepatitis C virus (HCV). The response to treatment with alpha-interferon (alpha-IFN) in these patients is linked to: predictive factors. The aim of this study was to ascertain whether the presence of MC was a predictive factor of: response in patients treated with alpha-IFN for chronic hepatitis due to HCV. METHODS: Thirty-two patients with: MC and HCV infection (24 with chronic hepatitis and eight with cirrhosis) were compared with 30 patients with HCV: infection without MC (23 chronic hepatitis, seven cirrhosis) of a similar mean age. All were treated with lymphoblastoid: alpha-IFN, at 3 MU, t.i.w., for 6-12 months and then followed up. RESULTS: No statistical difference was observed: between the two groups in terms of sustained response (P = 0.83), relapse (P = 0.88) and non-response (P = 0.92).: The mean follow up was 24.3 months (range 17-28) for patients with sustained response and for the patients with MC: and 22.6 months (range 15-26) for patients without MC. CONCLUSIONS: The presence of cryoglobulinaemia does: not influence the response to alpha-IFN in patients with chronic HCV infection.

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Unique Identifier: 20039665

Authors: Horcajada JP. Garcia-Bengoechea M. Cilla G. Etxaniz P. Cuadrado E. Arenas JI.

Institution: Service of Internal Medicine, Hospital Ntra Sra de Aranzazu, Donostia-San Sebastian, Spain. jgallego@medicina.ub.es

Abstract: In order to analyse the prevalence and significance of cryoglobulinaemia in patients with chronic hepatitis C virus: (HCV) infection and the possible relationship of cryoglobulinaemia with the genotypes of HCV, we studied 89 patients: with chronic HCV infection, 42 healthy controls and 22 patients with alcoholic cirrhosis. The patients with HCV were: divided into three different groups according to the presence of cirrhosis and alanine aminotransferase levels. Moreover,: in 20 patients with HCV and cryoglobulinaemia, HCV RNA sequences were quantified in serum and in cryoprecipitate.: Cryoglobulins were detected more frequently in patients with chronic HCV infection than in healthy controls (42.6% vs.: 4.7%; P<0.0001). Cryoglobulins were present in 68.4% of patients with HCV-related cirrhosis, which was nearly twice: the figure in noncirrhotic HCV-infected patients and alcoholic cirrhotic patients. There were no differences in age, sex,: aminotransferase levels or HCV genotype distribution in HCV-infected patients with or without cryoglobulinaemia. Only: 13% of patients with chronic HCV infection and cryoglobulins showed symptoms of cryoglobulinaemia. There was a: linear association between HCV RNA concentration in sera and in cryoprecipitates (P<0.0005). Patients with chronic: HCV infection had a high prevalence of cryoglobulinaemia, especially in advanced forms of the disease, but clinical: findings are few. There was no relationship with the genotype of HCV. The presence of HCV RNA in cryoprecipitates: supported the hypothesis on the aetiological role of HCV in mixed cryoglobulinaemia.

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Unique Identifier: 99332808

Authors: Pozzato G. Burrone O. Baba K. Matsumoto M. Hijiiata M. Ota Y. Mazzoran L. Baracetti S. Zorat F. Mishiro S.: Efremov DG.

Institution: Instituto di Medicina Clinica, School of Medicine, University of Trieste, Italy. pozzato@imc12.univ.trieste.it

Abstract: BACKGROUND/AIM: In previous studies we demonstrated that all patients affected by HCV-positive type II mixed: cryoglobulinaemia have a monoclonal B-cell population in peripheral blood mononuclear cells, and that a large fraction: of HCV-infected patients develop a monoclonal B-cell expansion, even in the absence of dosable serum cryoglobulins.: However, the prevalence of Type II mixed cryoglobulinaemia in HCV-infected individuals seems to be high in Italy,: whereas it is very low in Japan. This study was performed to investigate whether there are ethnic differences in the: prevalence of asymptomatic HCV-associated monoclonal B-cell expansions. METHODS: Forty-four Japanese: patients affected by HCV-positive chronic liver disease (two healthy carriers, 31 chronic hepatitis and 11 cirrhosis): were compared with a group of 60 Italian patients (one healthy carrier, 49 chronic hepatitis, and 10 cirrhosis) without: dosable levels of cryoglobulins. The monoclonality of peripheral blood mononuclear cells was investigated by RT/PCR: analysis of Immunoglobulin gene rearrangements. Liver function tests, rheumatoid factor, cryocrit level, anti-HCV: antibodies, HCV-RNA, and HCV genotype were performed according to standard methodology. RESULTS: A B-cell: monoclonal population was found in 26% of Italian patients, whereas all Japanese patients were negative. No correlation: was found between B-cell monoclonality and severity of liver disease, length or source of the infection, HCV genotype,: sex, clinical and biochemical parameters. CONCLUSIONS: This study indicates that a monoclonal B-cell proliferation: in peripheral blood mononuclear cells is common in HCV infection, but only in Italy, whereas it is absent in Japan. This: explains the very low prevalence of Type II mixed cryoglobulinaemia in HCV-positive Japanese subjects, and suggests: that HCV is able to determine a B-cell expansion only in the presence of, presently undetermined, host factors.

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Unique Identifier: 99411896

Authors: Chowla A. Malhi-Chowla N. Chidambaram A. Surick B.

Institution: Division of Surgery, Mayo Clinic Jacksonville, Florida 32224, USA.

Abstract: Primary B-cell lymphoma of the liver is an extremely rare tumor. The higher incidence of hepatocellular carcinoma in: hepatitis C is well known, but the relationship with lymphoma is unclear. An increased incidence has been reported in: patients with chronic hepatitis C. Hepatitis C virus is known to be a lymphotropic virus. Mixed cryoglobulinemia,: which is a benign lymphoproliferative disorder, has a definite association with hepatitis C. It is postulated that the virus: may also induce a malignant transformation. We describe an unusual presentation of a case of asymptomatic left hepatic: mass in a patient with hepatitis C with a preoperative diagnosis of hepatocellular carcinoma. He underwent a left lateral: segmentectomy, and the pathologic examination revealed non-Hodgkin's lymphoma. The clinical features, radiologic: investigations, and pathologic findings are presented. A review of the literature discussing clinical features, postulated: pathogenetic mechanisms, and management options is also presented. [References: 6]

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[Link Directly to Fulltext Article in OVID]

Unique Identifier: 99298227

Authors: Cresta P. Musset L. Cacoub P. Frangeul L. Vitour D. Poynard T. Opolon P. Nguyen DT. Golliot F. Piette JC. Huraux: JM. Lunel F.

Institution: Laboratoire de Bacterio-Virologie, CHU Angers, Angers, France.

Abstract: BACKGROUND: Mixed cryoglobulinaemia is closely associated with hepatitis C virus (HCV) infection. AIM: To: assess in a prospective open study the efficiency of interferon alpha treatment of cryoglobulinaemia, as reflected by the: disappearance of cryoglobulins and clinical manifestations of the disease, and to analyse the factors predictive of a: response to interferon. METHOD: Eighty seven consecutive patients with chronic hepatitis C treated for the first time: with interferon at a dose of 3 x 10(6) international units three times a week for six months were studied. Forty three: patients had cryoglobulins, which were responsible for clinical manifestations in 12. RESULTS: At the end of interferon: treatment, cryoglobulins had disappeared in 39% of the patients. A clinical improvement (except for neuropathies) was: observed in all patients. Six months after interferon treatment was stopped, the same rate of response (normal alanine: aminotransferase values and undectable HCV RNA) was observed in patients with or without cryoglobulins. Only 14%: of patients still had undetectable cryoglobulins, and all of them also had undetectable serum HCV RNA. The: disappearance of cryoglobulins was found less frequently in patients with clinical symptoms than in asymptomatic ones,: but the difference was not significant. Sustained responders were more often men, infected by genotype 2 or 3, with a: lower pretreatment viral load. CONCLUSION: The presence of cryoglobulins does not seem to affect the response to: interferon in HCV infected patients. The improvement in cryoglobulinaemia is strongly associated with a virological: response, reinforcing the hypothesis of a direct role for HCV in the pathogenesis of this disease.

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Unique Identifier: 99244175

Authors: Gomez-Tello V. Onoro-Canaveral JJ. de la Casa Monje RM. Gomez-Casero RB. Moreno Hurtrez JL. Garcia-Montes: M. Armas LC.

Institution: Intensive Care Unit, Clinica Moncloa, Madrid, Spain. med010958@nacom.es

Abstract: A case of diffuse and recidivant alveolar hemorrhage is presented in a patient with hepatitis C virus-related type II: mixed cryoglobulinemia with membranoproliferative glomerulonephritis. The patient was a 48-year-old white woman: who suffered several outbreaks of pulmonary hemorrhage refractory to treatment with steroids, cyclophosphamide,: azathioprine, plasmapheresis and interferon-alpha. The patient also presented persistent increased titers of immune: complexes and rheumatoid factor with no histological hepatic alterations. Some considerations about evolution and: treatment are given according to the updated physiopathology of this disease.

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[Link Directly to Fulltext Article in OVID]

Unique Identifier: 99266759

Authors: Vallisa D. Berte R. Rocca A. Civardi G. Giangregorio F. Ferrari B. Sbolli G. Cavanna L.

Institution: First Internal Department, Civil Hospital, Piacenza, Italy.

Abstract: PURPOSE: Because an etiologic role for hepatitis C virus in non-Hodgkin's B-cell lymphoma has been suggested by: several reports, we assessed the prevalence of hepatitis C virus infection in patients with non-Hodgkin's B lymphoma: and in controls, and evaluated the influence of viral infection on histologic and clinical features of the lymphoma patients.: PATIENTS AND METHODS: We prospectively investigated 175 consecutive patients with non-Hodgkin's: lymphoma and 350 controls for serologic and molecular markers of hepatitis C virus infection. Controls were selected: from inpatients (n = 175) and outpatients (n = 175) cared for at our hospital. Patients with lymphoma who had hepatitis: C virus infection were tested for mixed cryoglobulinemia. Aminotransferase levels were measured in all lymphoma: patients at baseline and during and after chemotherapy. RESULTS: Hepatitis C virus prevalence in patients with: non-Hodgkin's lymphoma was significantly greater than in control subjects (37% vs 9%, P = 0.0001). Among patients: with lymphoma, viral infection was associated with older mean (+/-standard deviation) age (67 +/- 14 vs 61 +/- 8 years,: P = 0.001), and women (41 of 87, 47%) were more likely than men (24 of 88, 27%) to have evidence of hepatitis C: infection (P = 0.006). Thirteen of the 20 cases of immunocytoma were associated with hepatitis C virus infection, which: was also more common in patients with orbital and conjunctival localization of lymphoma. Patients with: mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach were less likely to have evidence of hepatitis C: infection. Mixed cryoglobulinemia was much more common in patients with hepatitis C virus infection (14 of 65 vs 1: of 110, P = 0.0001); it was not associated with the histologic type of lymphoma. Patients with and without hepatitis C: virus infection underwent similar chemotherapy regimens and had no differences in response to chemotherapy or in: overall and disease-free survival. Hepatic toxicity from chemotherapy was seen only in patients with hepatitis C virus: infection, although all but one of these patients were able to complete their planned treatment. CONCLUSION: These: findings suggest that the hepatitis C virus may have a role as an etiologic agent in non-Hodgkin's B-cell lymphoma.: Some clinical and pathologic features of the disease are associated with hepatitis C virus infection, but the virus does: not seem to affect prognosis.

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Unique Identifier: 99183782

Authors: Valentini G. Mantelli A. Persico M. Tuccillo C. Del Vecchio Blanco G. Morisco F. Improta RD. Migliaresi S. Gualdieri: L. Caporaso N.

Institution: Institute of Clinical Medicine and Rheumatology, School of Medicine, Second University of Naples, Italy.

Abstract: OBJECTIVE: To investigate whether the serological markers of autoimmunity and the clinical features of autoimmune: disease which occur in hepatitis C virus (HCV)-infected subjects are correlated to each other and/or to the clinical: pattern of the disease. METHODS: Seventeen symptom-free, anti-HCV antibody positive subjects, 17 patients with: chronic hepatitis C, 21 patients with mixed cryoglobulinemia (MC), and as controls 17 anti-HCV negative patients: with dyspepsia were enrolled in a prospective study. A patient history, clinical examination, self-administered: questionnaire and laboratory investigations (hepatic enzyme levels, serum HCV-RNA and anti-HCV antibody testing,: and serum autoantibody profile) were performed to detect liver and/or autoimmune disease. RESULTS: Serological: markers of autoimmunity and clinical findings of autoimmune disease were found to be more frequent in the: HCV-infected patients considered as a whole than in controls. However, rheumatoid factor and clinical findings of: autoimmune disease were more frequent in MC patients, while anti-smooth muscle antibodies not linked to symptoms or: signs of autoimmune disease were detected in all groups of HCV-infected individuals, including healthy carriers and: subjects who had recovered from a previous HCV infection. CONCLUSION: Anti-smooth muscle antibodies, a: serological marker of autoimmunity, are detectable in HCV-infected subjects whatever their clinical status. Clinical: findings of autoimmune disease prevalently occur in patients with mixed cryoglobulinemia.

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Unique Identifier: 99191202

Authors: Mazzaro C. Pozzato G. Zorat F. Panarello G. Silvestri F. Barillari G. Mazzoran L. Baracetti S. Crovatto M. Santini GF.: Donadon V. Faccini L. Campanacci L.

Institution: Third Department of Medicine, University of Trieste, School of Medicine, Italy.

Abstract: BACKGROUND/AIM: A striking correlation between mixed cryoglobulinaemia and chronic hepatitis C virus: infection has recently been described. Since membrano-proliferative glomerulonephritis is a rare complication of mixed: cryoglobulinaemia, this study was undertaken to determine the prevalence of Hepatitis C virus infection in: membrano-proliferative glomerulonephritis. PATIENTS: Eighteen patients, selected among a group of 121 affected by: mixed cryoglobulinaemia, with renal involvement were included in the present study. A group of 148 patients affected by: renal disease of different aetiology and the general population (6,917 people) were used as control groups.: METHODS: The presence of anti-hepatitis C virus antibodies was determined by a commercial kit. The hepatitis C: virus genotype was determined according to Okamoto. All patients underwent kidney and bone marrow biopsy, while: the hepatic biopsy was performed in those showing signs of chronic liver disease. RESULTS: In patients with renal: involvement, the kidney biopsy showed the presence of membrano-proliferative glomerulonephritis Type I in all cases.: Chronic liver disease was present in eleven patients (61%). All patients were positive for serum hepatitis C virus-RNA.: Bone marrow biopsy was normal in five cases, while in the others paratrabecular foci of infiltration by small lymphocytes: were present. In six of these, the massive bone marrow infiltration by lymphoplas-macytoid lymphocytes suggested the: diagnosis of low grade non-Hodgkin's lymphoma. In the group of patients affected by other chronic renal disease, the: prevalence of hepatitis C virus infection (3.1%) was not different from that of the general population (3.2%).: CONCLUSIONS: Hepatitis C virus seems to be the aetiologic agent of mixed cryoglobulinaemia and, consequently,: of membrano-proliferative glomerulonephritis.

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Unique Identifier: 99152038

Authors: Gungor E. Cirit A. Alli N. Karakayali G. Gur G. Artuz F.

Institution: Dermatology and Venereology Department, Ankara Numune Hospital, Ankara, Turkey.

Abstract: BACKGROUND: Several dermatologic manifestations of hepatitis C virus (HCV) infection have been described. The: association of HCV infection, essential mixed cryoglobulinemia and leukocytoclastic vasculitis (LV) have been: published mainly in case reports. OBJECTIVE: The aim of the present study was to determine the prevalence of HCV: infection and cryoglobulinemia in patients with LV. METHODS: Twenty-five cases of LV were tested for anti-HCV: antibodies by means of a third-generation enzyme-linked immunosorbent assay, and cryoglobulins were detected by the: precipitation method. Thirty healthy volunteers served as control group. RESULTS: Anti-HCV antibodies were: detected in 2/25 patients with LV (8%) and none of the control group. Cryoglobulinemia was detected in 1 patient: with LV and none in the control group. CONCLUSION: Although no significant difference between patients and the: control group was detected, the prevalence of anti-HCV antibodies in LV patients is as high as 8%. Considering this, it: seems reasonable to investigate the presence of HCV in unexplained cases of LV.

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Unique Identifier: 99397959

Authors: Calleja JL. Albillos A. Moreno-Otero R. Rossi I. Cacho G. Domper F. Yebra M. Escartin P.

Institution: Department of Gastroenterology, Clinica Puerta de Hierro, University Autonoma, Madrid, Spain.

Abstract: BACKGROUND: Hepatitis C virus (HCV) infection has been associated with mixed cryoglobulinaemia. AIM: To: investigate the efficacy of anti-viral therapy on the eradication of HCV and its clinical manifestations in patients with: HCV-associated symptomatic mixed cryoglobulinaemia. PATIENTS AND METHODS: 18 out of 32 patients with: symptomatic mixed cryoglobulinaemia (MC group) received a 12-month course of interferon (3 MU three times a: week, subcutaneously). Nonresponders or relapsers to this therapy were treated with interferon plus ribavirin (1200: mg/day, orally) for 12-months. 226 patients with HCV infection and without cryoglobulins were studied in comparison: (Hepatitis C group). Serial quantification of serum HCV-RNA and cryoglobulins were performed. RESULTS: In the: MC group, 10 out of 18 patients (55%) receiving interferon showed an end of treatment response, but at the end of: follow-up, only five (28%) patients had a sustained response. In the hepatitis C group, 91 patients (47%) showed an: end of treatment response but only 42 (20%) a sustained response. In the MC group alanine transaminase, cryocrit and: rheumatoid factor decreased significantly in responders, with an improvement or disappearance of the MC-associated: clinical manifestations. Alanine transaminase, cryocrit and rheumatoid factor increased in the relapsers and the clinical: manifestations reappeared. Nonresponders and relapsers to interferon in the MC group were retreated with interferon: plus ribavirin. Five out of eight nonresponders showed a end of treatment response but it was sustained in three of them.: In the relapsers, treatment with combined therapy achieved a sustained response in four out of the five patients (80%).: CONCLUSIONS: Interferon as monotherapy or combined with ribavirin is a safe and effective treatment in patients: with HCV-associated MC. The presence of cryoglobulins does not affect the response to anti-viral treatment in patients: with HCV infection. The eradication of HCV is associated with an improvement or disappearance of MC-associated: clinical manifestations.

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Unique Identifier: 99432069

Authors: Mangia A. Andriulli A. Zenarola P. Lomuto M. Cascavilla I. Quadri R. Negro F.

Institution: Division of Gastroenterology, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

Abstract: The extent of extrahepatic hepatitis C virus (HCV) replication seems to be low-level and confined to cells of: hematopoietic lineage. However, given the spectrum of extrahepatic manifestations associated with HCV, several tissues: other than the liver have been suggested as targets of HCV replication and damage. The presence and level of HCV: RNA were examined in 19 skin tissue samples from patients chronically infected with HCV and referred for lichen ruber: planus (n = 11) or cutaneous vasculitis associated with mixed cryoglobulinemia (n = 8). Serum HCV RNA was: quantitated and genotyped by assays that are available commercially. Tissue HCV RNA of genomic- and minus-strand: polarity was titrated by a strand-specific semiquantitative RT-PCR. Low titers of genomic-strand HCV RNA were: found in three skin specimens from patients with cutaneous vasculitis due to mixed cryoglobulinemia, but in none with: lichen ruber planus. The replication intermediate HCV RNA was not detected in any of the skin tissues examined,: independent of the serum HCV RNA level or genotype. It is concluded that the occurrence of cutaneous vasculitis and: lichen ruber planus in chronic hepatitis C patients is unlikely to be due to HCV replication in the skin. Copyright 1999: Wiley-Liss, Inc.

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Unique Identifier: 99441963

Authors: Liu F. Knight GB. Agnello V.

Institution: Lahey Clinic Medical Center, Burlington, Massachusetts 01805, USA.

Abstract: OBJECTIVE: Hepatitis C virus (HCV) infection is associated with type II cryoglobulinemia. HCV is specifically: concentrated in type II cryoglobulins and has been implicated in the cutaneous vasculitis associated with the disease. In: contrast to HCV, a role for hepatitis G virus (HGV) in type II cryoglobulinemia has not been defined, although: prevalences as high as 43% of HGV infections in type II cryoglobulinemia have also been reported. METHODS: We: studied 34 patients with type II and 29 patients with type III cryoglobulinemia associated with HCV infection, 6: patients with essential mixed cryoglobulinemia (EMC; all with type II), 50 hospital control patients, and 125 normal: individuals. Serum HCV and HGV RNA were detected by reverse transcription-polymerase chain reaction (RT-PCR).: In coinfected sera, HCV and HGV were quantitated by competitive RT-PCR assays. One coinfected patient was: studied longitudinally for 6 years. RESULTS: Two (5.9%) of 34 patients with HCV-infected type II: cryoglobulinemia, none of 29 patients with type III cryoglobulinemia, and none of 6 patients with EMC were: positive for HGV RNA, for an overall prevalence of 3.0% in mixed cryoglobulinemia. None of the control: populations were positive for HGV. No statistical difference was seen between the prevalence in patients with type II: cryoglobulinemia and the other populations studied. In coinfected sera, HCV, but not HGV, was concentrated in: cryoglobulins, and HCV, but not HGV, correlated with cryoglobulinemia in a longitudinal study. CONCLUSION:: There is a low prevalence of coinfection with HGV in patients with mixed cryoglobulinemia and HCV infection in the: United States. HCV is selectively precipitated by type II cryoglobulins in coinfected sera. HGV infection does not: appear to have a role in mixed cryoglobulinemia.

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Unique Identifier: 99119010

Authors: Dammacco F. Gatti P. Sansonno D.

Institution: Department of Biomedical Sciences, University of Bari Medical School, Italy.

Abstract: Hepatitis C virus (HCV) is a single-stranded RNA agent which expresses its genetic informations in the form of a: single, large polyprotein encoded by an open reading frame (ORF) that extends through most of its genomic RNA.: Proteolytic cleavage of the ORF product is essential for the virogenesis and the production of viral progeny. HCV is: responsible for chronic liver disease, cirrhosis and possibly hepatocellular carcinoma. Viral persistence is considered the: greatest problem in the management of HCV infection. It may result from several mechanisms, two of which are: established. In the first, the high rate of genetic variations during viral replication results in the production of mutants: capable of escaping the immune attack. In the second, the virus infects cells of the immune system itself, which represent: a privileged site that cannot be reached by virus-specific T cell response. Involvement of lymphoid cells in the early: stages of HCV infection may provide insight into the pathobiologic patterns of extrahepatic dissemination (lymph nodes,: major salivary glands, kidneys, blood vessels). Dissemination of HCV-infected lymphoid cells throughout the organism is: likely to maintain a mobile and extensive reservoir of the virus. In this respect, extrahepatic sites may act as a source of: continuous reinfection of hepatocytes. Studies of intrahepatic B lymphocytes indicate that they are infected with HCV,: clonally expanded and activated to secrete IgM molecules with rheumatoid factor activity. This strongly suggests that: HCV directly stimulates B cell expansion, which may result in an indolent stage of lymphoproliferation (i.e., mixed: cryoglobulinemia) or in frank B cell non-Hodgkin's lymphoma (NHL). The frequency of NHL, however, is much: lower than that of HCV infection, suggesting that HCV alone is not able to induce tumors and that cellular events, in: addition to the presence of virus and virus-encoded products, are necessary in order to obtain a malignant B cell: phenotype. The demonstration of HCV productive infection in bone marrow-recruited and circulating pluripotent: hematopoietic CD34+ stem cells indicates that HCV replication occurs in the early differentiation stages of: hematopoietic progenitors. These are stable cell populations and are likely to represent the initial site of infection and a: continuous source of virus production. [References: 89]

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Unique Identifier: 99063524

Authors: Markowitz GS. Cheng JT. Colvin RB. Trebbin WM. D'Agati VD.

Institution: Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.

Abstract: The most common form of glomerular disease seen in association with hepatitis C virus (HCV) infection is: membranoproliferative glomerulonephritis, with or without associated cryoglobulinemia. This study examines four cases: of fibrillary glomerulonephritis and two cases of immunotactoid glomerulopathy in association with HCV infection.: Findings at presentation included proteinuria, renal insufficiency, and hematuria. Renal biopsy revealed a: membranoproliferative pattern of glomerular disease in five cases, and a membranous glomerulopathy with mesangial: proliferative features in one. On immunofluorescence, all cases stained with IgG and C3. Electron microscopy revealed: fibrils of the expected diameter, 16 to 28 nm in fibrillary glomerulonephritis and 33 to 45 nm in immunotactoid: glomerulopathy. In only one case were cryoglobulins detected (at low titer and on only one of three assays). Antiviral: therapy was not given in any of the six cases. Outcomes were mixed, with progression to renal failure occurring in two: patients and persistent proteinuria with stable or improved renal function in three. Follow-up is not available on the sixth: case. Both fibrillary glomerulonephritis and immunotactoid glomerulopathy have features that overlap with: cryoglobulinemic glomerulonephritis. The relatedness of these three entities in a subset of patients with HCV infection: suggests a common pathogenic mechanism of glomerular deposition of organized deposits.

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Unique Identifier: 99169420

Authors: Agnello V.

Institution: Department of Laboratory Medicine, Lahey Clinic Medical Center, Burlington, Massachusetts, USA.