1. ¹Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
2. ²Department of Medicine, Division of Gastroenterology and Hepatology, Weill Medical College of Cornell University, New York, New York, USA

Correspondence: Edgar D. Charles, Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, Box 64, 1230 York Avenue, New York, New York 10065, USA. E-mail: charlee@rockefeller.edu

Received 1 April 2009; Revised 6 May 2009; Accepted 2 June 2009; Published online 15 July 2009.

Abstract

In this review we discuss the clinical manifestations, pathogenesis, and treatment of hepatitis C virus (HCV)–related cryoglobulinemia. HCV is a major cause of liver-related morbidity and is increasingly recognized as an instigator of B-cell lymphoproliferative disorders such as mixed cryoglobulinemia and non-Hodgkin lymphoma. Cryoglobulinemia is characterized by the clonal expansion of rheumatoid factor–expressing B cells in the liver, lymph nodes, and peripheral blood, resulting in the presence of cryoglobulins in the circulation. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor, polyclonal IgG, and HCV RNA that precipitate and deposit on vascular endothelium, causing vasculitis in organs such as the skin, kidneys, and peripheral nerves. A subset of patients develops a low-grade lymphoma composed of B cells that are immunophenotypically similar to the expanded B cells seen in cryoglobulinemia. HCV-related B-cell lymphoproliferative disorders likely comprise a spectrum of disease, ranging from asymptomatic clonal B-cell expansions to pathogenic cryoglobulinemia and lymphoma. It is unclear how B cells become dysregulated during the course of chronic HCV infection, and continued patient-centered research is necessary to elucidate the pathogenesis of HCV-related B-cell dysregulation.