HCV and lymphoproliferation

Abstract

Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury--potentially evolving to cirrhosis and hepatocellular carcinoma--but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously with Helicobacter pylori related lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data.

Figure 1

Pathogenesis of HCV-related lymphoproliferative disorders (LPDs). Main working hypotheses and their principal interconnections.

Figure 2

HCV-related LPD pathogenesis is a multifactorial and multistep process. Current data suggest that the starting points of this process are represented by the cooperation between a sustained and persistent stimulation—by direct or indirect action of viral particles or proteins—and antiapoptotic mechanisms acting on B-cell compartment. A predisposing genetic background would be responsible for the final evolution to a particular LPD (namely, MC). The progressive addition of genetic aberrations would lead to a frank neoplastic transformation, gradually making the process less dependent on the etiologic agent.