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

1 October 2002 | Volume 137 Issue 7 | Pages 571-580

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.

Editors' Notes Context Rearrangement of bcl-2 has an antiapoptotic effect and has been implicated as a potential cause of benign lymphoproliferation (causing mixed cryoglobulinemia) and B-cell lymphoma. Mixed cryoglobulinemia is strongly associated with hepatitis C virus (HCV) infection. Contribution In patients with HCV-associated chronic liver disease, bcl-2 rearrangement occurred significantly more often in patients with chronic HCV infection and mixed cryoglobulinemia than in HCV-infected patients without mixed cryoglobulinemia; it also occurred in three of four patients with B-cell lymphoma. Transient suppression of HCV in two patients was associated with remission of clinical manifestations of mixed cryoglobulinemia. Implications Viral induction of gene sequence translocations may help explain some benign and malignant lymphoproliferative disorders. –The Editors

 

Author and Article Information

From University of Florence, School of Medicine, Florence; and University of Pisa, School of Medicine, Pisa, Italy.

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.