Prevalence of bcl-2 Rearrangement in Patients with Hepatitis C Virus–Related Mixed Cryoglobulinemia with or without B-Cell Lymphomas

  1. Anna Linda Zignego, MD, PhD;
  2. Clodoveo Ferri, MD;
  3. Francesca Giannelli, PhD;
  4. Carlo Giannini, PhD;
  5. Patrizio Caini, PhD;
  6. Monica Monti, PhD;
  7. Maria Eugenia Marrocchi, PhD;
  8. Elena Di Pietro, MD;
  9. Giorgio La Villa, MD;
  10. Giacomo Laffi, MD; and
  11. Paolo Gentilini, MD
  1. From University of Florence, School of Medicine, Florence; and University of Pisa, School of Medicine, Pisa, Italy.

    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.

    Article and Author Information

    • Acknowledgments: The authors thank Gianpiero Buzzelli, MD; Antonio Mazzocca, MD, PhD; Roberto Giulio Romanelli, MD, PhD; Stefania Moscarella, MD; and Laura Gragnani, BS, for helpful discussion and expert technical assistance and Ms. Mary Diamond for help in the preparation of the manuscript.

    • Grant Support: By the Italian Liver Foundation, the Italian Ministero d'struzione, d'niversità e della Ricerca, the Associazione Italiana per la Ricerca sul Cancro, and the Fondazione Istituto di Ricerca Virologica O.B. Corsi.

    • Requests for Single Reprints: Anna Linda Zignego, MD, PhD, Department of Internal Medicine, University of Florence, Viale Morgagni, 85, 50134 Florence, Italy; e-mail, a.zignego{at}dmi.unifi.it.

    • Current Author Addresses: Drs. Zignego, Giannelli, Giannini, Caini, Monti, Marrocchi, Di Pietro, La Villa, Laffi, and Gentilini: Department of Internal Medicine, University of Florence, School of Medicine, Viale Morgagni, 85, 50134 Florence, Italy.

    • Dr. Ferri: Department of Internal Medicine, University of Pisa, School of Medicine, Via Roma, 67, 56100 Pisa, Italy.

    • Author Contributions: Conception and design: A.L. Zignego, F. Giannelli, C. Giannini, P. Caini, M. Monti.

    • Analysis and interpretation of the data: A.L. Zignego, C. Ferri, F. Giannelli, C. Giannini, P. Caini, M. Monti, M.E. Marrocchi, E. Di Pietro, G. La Villa, G. Laffi, P. Gentilini.

    • Drafting of the article: A.L. Zignego, F. Giannelli, C. Giannini, P. Caini, M. Monti, G. La Villa, G. Laffi.

    • Critical revision of the article for important intellectual content: A.L. Zignego, C. Ferri, F. Giannelli, C. Giannini, P. Caini, M. Monti, M.E. Marrocchi, E. Di Pietro, G. La Villa, G. Laffi, P. Gentilini.

    • Final approval of the article: A.L. Zignego, C. Ferri, F. Giannelli, C. Giannini, P. Caini, M. Monti, M.E. Marrocchi, E. Di Pietro, G. La Villa, G. Laffi, P. Gentilini.

    • Provision of study materials or patients: A.L. Zignego, C. Ferri, F. Giannelli, C. Giannini, P. Caini, M. Monti, E. Di Pietro, G. La Villa, G. Laffi, P. Gentilini.

    • Statistical expertise: C. Ferri, G. La Villa, P. Gentilini.

    • Obtaining of funding: A.L. Zignego, C. Ferri, F. Giannelli, C. Giannini, P. Caini, M. Monti, M.E. Marrocchi, P. Gentilini.

    • Administrative, technical, or logistic support: E. Di Pietro, P. Gentilini.

    • Collection and assembly of data: M.E. Marrocchi, E. Di Pietro.

    Summary for Patients

    • Summaries for Patients:Effects of Hepatitis C Virus Infection on Genetic Material and on Manifestations of a Related Blood Disease Ann Intern Med October 1, 2002 137:I-32
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    1. Ann Intern Med October 1, 2002 vol. 137 no. 7 571-580
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