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

Anna Linda Zignego, MD, PhD; Clodoveo Ferri, MD; Francesca Giannelli, PhD; Carlo Giannini, PhD; Patrizio Caini, PhD; Monica Monti, PhD; Maria Eugenia Marrocchi, PhD; Elena Di Pietro, MD; Giorgio La Villa, MD; Giacomo Laffi, MD; and Paolo Gentilini, MD
[+] Article and Author 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@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.


Ann Intern Med. 2002;137(7):571-580. doi:10.7326/0003-4819-137-7-200210010-00008
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The Table shows the clinical, epidemiologic, and pathologic characteristics of patients with HCV-related mixed cryoglobulinemia. The mean duration of mixed cryoglobulinemia syndrome was 9.2 ± 5.2 years. Most of these patients (91%) had chronic liver diseases. Liver biopsy showed chronic hepatitis in 27 patients (72.9%) and cirrhosis in 7 patients (18.9%); of the latter patients, 1 also had superimposed hepatocellular carcinoma. Liver biopsy was not performed in the remaining 3 patients because they had persistently normal alanine aminotransferase levels. Other frequent systemic manifestations were peripheral neuropathy (89%) and the sicca syndrome (41%). Four patients had clinically overt B-cell lymphoma, 1 had mucosa-associated lymphoid tissue (MALT)–derived marginal zone B-cell lymphoma (gastric MALT lymphoma), 1 had diffuse large B-cell lymphoma, and 2 had follicular lymphomas. The patient with MALT lymphoma also had evidence of Helicobacter pylori infection. Serum mixed cryoglobulins with rheumatoid factor were detected in all patients (type II in 20 patients and type III in 17 patients), and 92% of patients with mixed cryoglobulinemia had low levels of complement C4.

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Figures

Grahic Jump Location
Figure 1.
Schematic representation of the t(14; 18) translocation and its effects on B cells. Top.bcl-2HBottom.

Translocation of the gene from chromosome 18 to a position adjacent to the immunoglobulin heavy chain gene on chromosome 14 results in deregulated overexpression of Bcl-2 antiapoptotic protein. J = IgH joining segment; C = IgH constant region. Bcl-2 and Bax are homologous proteins that have opposing effects on cell survival: Bcl-2 blocks apoptosis, and Bax promotes it. The ratio of Bcl-2 to Bax is important in determining susceptibility to apoptosis. The t(14; 18) translocation causes increases in the ratio of Bcl-2 to Bax and inhibition of B-cell apoptosis.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Sequence ofbcl-2and IgH joining segments (J H ) detected in total DNA extracted from peripheral blood mononuclear cells of 10 representative patients with mixed cryoglobulinemia.bcl-2Hbcl-2Hbcl-2H

“Bcl-2,” “N segment,” and “JH” represent sequences of the /J junction corresponding to the gene (chromosome 18), N-segment and J region of the IgH gene (chromosome 14), respectively. Alignment was done on (GenBank accession number M14745) and IgH gene J regions (accession number M25625) (line bcl-2/J ). “Pre” and “post” designate sequences corresponding to peripheral blood samples obtained before and after interferon-α treatment, respectively. Dots indicate identical nucleotides. Gaps in sequences (–) were introduced for clarity.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Expression of Bax and Bcl-2 proteins in peripheral blood mononuclear cell samples from patients with type II mixed cryoglobulinemia. Top.Middle.Bottom.

Immunoblot analysis showing expression of Bcl-2 and Bax proteins in peripheral blood mononuclear cells from two patients with hepatitis C virus infection and type II mixed cryoglobulinemia (patients 15 and 33) and from two healthy persons who served as negative controls. Ratio of Bcl-2 to Bax in two patients with hepatitis C virus infection and type II mixed cryoglobulinemia (patients 15 and 33) and from two healthy persons who served as negative controls. Expression of Bcl-2 protein in B cells and in non–B peripheral blood mononuclear cells (T cells and monocytes and macrophages) separated from peripheral blood mononuclear cell samples of three patients with the t(14;18) translocation. Lanes 1 and 2 show data in patients with mixed cryoglobulinemia (number 15 and 33). Lane 3 shows data from a patient with chronic liver disease but not mixed cryoglobulinemia.

Grahic Jump Location

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Summary for Patients

Effects of Hepatitis C Virus Infection on Genetic Material and on Manifestations of a Related Blood Disease

The summary below is from the full report titled “Prevalence of bcl-2 Rearrangement in Patients with Hepatitis C Virus–Related Mixed Cryoglobulinemia with or without B-Cell Lymphomas.” It is in the 1 October 2002 issue of Annals of Internal Medicine (volume 137, pages 571-580). The authors are AL Zignego, C Ferri, F Giannelli, C Giannini, P Caini, M Monti, ME Marrocchi, E Di Pietro, G La Villa, G Laffi, and P Gentilini.

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