Detection of immunoglobulin heavy chain gene rearrangement and Bcl-2-JH translocation [t [14 ; 18]] in patients with chronic hepatitis C virus infection

ABSTRACT

The mechanism of lymphomagenesis by HCV is still obscure. The present study was carried out on 64 untreated patients previously diagnosed as having chronic liver disease due to HCV infection, 30 patients with HCV negative chronic liver disease [CLD] and 30 healthy controls. Serum cryoglobulins were tested in all subjects. In addition, the presence of immunoglobulin heavy chain gene [IgH] rearrangement and Bcl-2-JH translocation in peripheral blood mononuclear cells [PBMC] were assessed by seminested and nested polymerase chain reaction [PCR], respectively. Percutaneous liver biopsies were performed in 61 of the 64 patients with HCV related CLD and 26 of the 30 patients with HCV negative CLD to determine the severity of chronic liver injury. None of the patients received immunomodulatory drugs or had hepatocellular carcinoma, lymphoma or other malignancies. Cryoglobulinaemic and non-cryoglobulinaemic chronic HCV infected patients had significantly higher rates of monoclonal IgH rearrangement than patients with HCV negative CLD [P=0.006 and 0.047, respectively] and healthy controls [P=0.001 and 0.005, respectively].There were no statistically significant differences between chronic HCV infected patients with and without monoclonal IgH rearrangement with respect to age, sex, mean ALT and AST levels. Furthermore, the frequency of monoclonal IgH rearrangement in PBMC did not differ significantly according to histologic severity of chronic liver injury. On the other hand, cryoglobulinaemic and non-cryoglobulinaemic chronic HCV infected patients had significantly higher rates of Bcl-2-JH translocation than non HCV infected CLD patients [P=0.0002 and 0.001, respectively] and healthy controls [P=0.0002 and 0.001, respectively]. There were no statistically significant differences between chronic HCV infected patients with and without Bcl-2-JH translocation with respect to age, sex, mean ALT and AST levels. Moreover, the frequency of Bcl-2-JH translocation in PBMC did not differ significantly according to histologic severity of liver injury. Interestingly, the frequency of coexisting monoclonal IgH rearrangement and Bcl-2-JH translocation was significantly higher in cryoglobulinaemic than non-cryoglobulinaemic chronic HCV infected patients [P=0.05], HCV negative CLD patients [P=0.009] and healthy controls [P=0.009]. We concluded that patients with chronic HCV infection are more liable to develop monoclonal IgH rearrangement or Bcl-2-JH translocation in PBMC. Moreover, coexisting monoclonal IgH rearrangement and Bcl-2-JH translocation is a frequent finding in cryoglobulinaemic patients with chronic HCV infection suggesting that these aberrations may be involved, at least in part, in the complex multistep mechanisms occurring in HCV infected patients ending in B cell lymphoproliferative diseases [LPD]. Further studies are needed to establish whether determination of these aberrations in PBMC of chronic HCV infected patients could be useful as non invasive molecular markers for the predisposition to acquire cryoglobulinaemia and/or other B cell LPD