Hepatitis C virus (HCV) seems to be the aetiologic agent of mixed cryoglobulinaemia, and as this 'benign' lymphoproliferative disorder can frequently develop into more aggressive haematological disorders, this study was undertaken to determine the prevalence of HCV infection in non-Hodgkin's lymphomas. 199 unselected subjects treated by three haematological centres in Northeast Italy were investigated for the presence of HCV infection. As controls, the prevalence of HCV infection was determined in a group of patients affected by other haematological malignancies (153 subjects) and in the general population of the same geographical area in the cohort study called the Dyonisos project (6917 subjects). The presence of anti-HCV antibodies was determined by a commercial kit and, in positive cases, by PCR amplification of the 5' untranslated region of the virus. The HCV genotype was also obtained by PCR amplification of the Core region with type-specific primers. The presence of serum cryoglobulins was determined in each case of NHL. HCV infection was significantly (P < 0.00000001) higher in patients with non-Hodgkin's lymphomas (28.0%) when compared with that of the general population (2.9%), and with the group of patients affected by other malignancies (3.1%). The prevalence is particularly high in low-grade (38.4%), as compared with intermediate (11.4%), or high-grade (15.2%) lymphomas. The presence of the virus is significantly (P < 0.000001) associated with the presence of detectable levels of cryoglobulins. On the basis of these findings. HCV seems to play an important role in the development of low-grade non-Hodgkin's lymphomas.
BACKGROUND Several authors have reported on the effectiveness of α‐interferon (IFN‐α) in the treatment of patients with mixed cryoglobulinemia. This prompted the authors to investigate the long term effects of this drug on clinical, hematologic, and virologic parameters in a group of 20 patients (13 women and 7 men) affected by mixed cryoglobulinemia. METHODS In all patients, bone marrow biopsy, phenotyping of marrow cells, and polymerase chain reaction (PCR) immunoglobulin gene rearrangement in peripheral blood lymphocytes were performed before therapy and at the end of the follow‐up. A liver biopsy was obtained in patients with biochemical signs of chronic liver disease. The presence of hepatitis C virus (HCV) RNA in serum was assessed by detection of anti‐HCV antibodies, and by PCR amplification of the 5′ untranslated region of HCV. The HCV genotype was also determined by PCR amplification of the core region of the virus with type‐specific primers. The treatment schedule followed by all patients was 3 million units of recombinant IFN‐α 2b 3 times weekly for 1 year. RESULTS In 6 patients, the marrow histology before therapy showed a massive (more than 50%) monomorphous infiltration by plasmacytoid lymphocytes, indicating the presence of low grade non‐Hodgkin's lymphoma. Anti‐HCV antibodies were present in 19 (95%) subjects, and HCV‐RNA was detectable in all patients. In addition, all patients affected by Type II mixed cryoglobulinemia showed a monoclonal B‐cell expansion in peripheral blood mononuclear cells (PBMC). With therapy, 5 patients (25%) achieved a complete response and 11 patients (55%) a partial response, whereas minor responses were observed in the remaining 4 patients (20%). One of the complete responders and all patients showing partial responses relapsed a few months after therapy withdrawal. At the end of the follow‐up, four patients had obtained a complete remission. Bone marrow examination showed that B‐lymphocytic monoclonal infiltrate disappeared in three patients. Moreover, these three patients had become negative for B‐cell expansion in PBMC. Lack of response, or relapse, was associated with the presence of Type II HCV. CONCLUSIONS HCV may be the cause of mixed cryoglobulinemia. The disease is associated with a high prevalence of bone marrow B‐cell lymphomas. IFN‐α appears to be an effective agent for the treatment of mixed cryoglobulinemia. It also seems able to determine regression of the lymphoproliferative disorder. The HCV genotype appears to be the most important predictive factor for the response to antiviral therapy. Cancer 1996;77:2604‐13.
. Mazzaro C, Panarello G, Tesio F, Santini G, Crovatto M, Mazzi G, Zorat F, Tulissi P, Pussini E, Baracetti S, Campanacci L, Pozzato G (Pordenone General Hospital, Pordenone; University of Trieste, School of Medicine, Trieste, Italy). Hepatitis C virus risk: a hepatitis C virus‐related syndrome. J Intern Med 2000 247: 535–545. Background. The association between mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) infection has been recently described in many reports. Objective. The aim of this study was to evaluate the long‐term prognosis of hepatitis C virus‐positive patients affected by mixed cryoglobulinemia with or without kidney involvement. Patients. At total of 119 hepatitis C virus‐positive patients affected by mixed cryoglobulinemia were divided in two groups. Group A: mixed cryoglobulinemia without kidney involvement (103 cases); group B: mixed cryoglobulinemia with glomerulonephritis (GN) (16 cases). A further 37 patients affected by mesangio‐proliferative glomerulonephritis (MPGN) were evaluated as controls (group C). Methods. Anti‐hepatitis C virus antibodies were determined by commercial kits and hepatitis C virus‐RNA was detected by polymerase chain reaction (PCR) amplification of the 5′ untranslated region (5′UTR) of the virus. The hepatitis C virus genotype was determined according to Okamoto. Liver biopsy was performed in 62 patients, bone marrow biopsy in 65 patients, and kidney biopsy in all patients with proteinuria. Results. In group A, 46 patients (45%) were affected by chronic liver disease (CLD), 21 (20%) by low‐grade non‐Hodgkin’s lymphoma (NHL) and 16 (15%) by both diseases. All patients of group B were affected by type I membrano‐proliferative glomerulonephritis, 3 (19%) by chronic liver disease, 6 (37%) by low‐grade non‐Hodgkin’s lymphoma, and 7 (44%) by both diseases. Several genotypes of hepatitis C virus were found, but Type 1b was prevalent. In group C, no patient showed chronic liver disease or non‐Hodgkin’s lymphoma. Younger age, higher mean blood pressure, lower C4 serum level, and poorer survival significantly distinguished group B from group A. Survival rates at 5 years were: 87.4% for group A, 89.5% for group C, and 50.0% for group B. None of the patients of group B developed kidney failure requiring dialysis, whilst infections were the leading cause of death. Conclusions. In hepatitis C virus‐positive patients, the presence of mixed cryoglobulinemia associated with kidney involvement seems to indicate a new syndrome characterized by immune system impairment, lack of progression to kidney failure, and poor survival (hepatitis C virus‐Risk syndrome).
Mixed cryoglobulinaemia is associated with HCV infection in the nearly all cases. Several HCV genotypes are involved in the pathogenesis of this disease. Mixed cryoglobulinaemia is associated with a high prevalence of chronic liver disease, low-grade non-Hodgkin's lymphomas and membrano-proliferative glomerulonephritis.
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