Get your own Free Home PageCRYOGLOBULINEMIA
One-third to one-half of people with chronic hepatitis C infection have cryoglobulinemia (antibodies in the bloodstream attached to the hepatitis C RNA that happen to solidify when cold). Hepatitis C is recognized as the most common cause of mixed cryoglobulinemia. Most of the people with cryoglobulinemia from hepatitis C have had their hepatitis for a long time or have cirrhosis. People with higher concentrations of hepatitis C RNA in their blood do not seem to have a higher risk of having cryoglobulinemia. Usually the cryoglobulins are in low concentration and cause no symptoms. About twenty-percent of people with hepatitis C and cryoglobulinemia have symptoms. Symptoms most often associated with cryoglobulinemia include mild fatigue, joint pains, or itching.
INFECTION OF PERIPHERAL BLOOD MONONUCLEAR CELLS BY HEPATITIS C VIRUS IN MIXED CRYOGLOBULINEMIA
C Ferri, M Monti, L La Civita, G Longombardo, F Greco, G Pasero, P Gentilini, S Bombardieri and AL Zignego; Istituto Patologia Medica I, University of Pisa, Italy. Blood, Volume 82, Issue 12, pp. 3701-3704, 12/15/1993
A striking association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia (MC) has been shown; thus, HCV seems to play an important etiopathogenetic role in this lymphoproliferative disorder. Because HCV is both a hepatotropic and lymphotropic virus, this study aimed to investigate the prevalence of HCV infection of peripheral blood mononuclear cells (PBMCs) in a series of 16 patients with type II (IgMk) MC. Antibodies against HCV were detected by commercially available kits (Second Generation Chiron enzyme-linked immunosorbent assay [ELISA] and recombinant-based immunoblot assay [RIBA]), and the presence of HCV RNA was evaluated in both sera and isolated PBMCs using the polymerase chain reaction technique. A previous exposure to HCV was shown by ELISA and confirmed by RIBA in all cases (100%). Moreover, HCV RNA was present in the sera of 8 of 16 patients (50%), whereas its frequency markedly increased (13 of 16 [81%]) when genomic sequences were detected in peripheral lymphocytes. HCV RNA was never detected in the PBMCs of 20 control subjects. These findings showed that HCV infection, alone or in combination with other factors, may be responsible for the clonal B-cell expansion underlying the systemic manifestations of MC, and may explain the appearance of a malignant non- Hodgkin's lymphoma in some subjects.
LONG-TERM RESULTS OF THERAPY WITH INTERFERON-ALPHA FOR TYPE II ESSENTIAL MIXED CRYOGLOBULINEMIA
M Casato, B Lagana, G Antonelli, F Dianzani and L Bonomo; Third Department of Internal Medicine, University of Rome La Sapienza, School of Medicine, Italy. Blood, Volume 78, Issue 12, pp. 3142-3147, 12/15/1991
Severe type II essential mixed cryoglobulinemia (EMC) bears a poor prognosis. Treatment with corticosteroids and/or cytotoxic drugs infrequently results in long-term remissions, and is associated with significant toxicity. We conducted a prospective study with interferon (IFN) in 21 patients with severe type II EMC unresponsive to immunosuppressive regimens. They were treated with recombinant IFN- alpha 2a (18 patients) or with natural IFN-beta (three patients), alone, at a dosage of 3 megaunits (MU)/d for 3 months, followed by 3 MU every other day as maintenance. We observed 11 complete remissions, five partial remissions, and five minor responses. Of 16 patients observed for more than 1 year, 11 remained in remission for 14 to 40 months; five of them remained in complete remission for 18 to 40 months after withdrawal of treatment. Four patients discontinued treatment because of side effects. In four patients who relapsed while on maintenance therapy with recombinant IFN-alpha 2a, remission could be reinduced by treatment with natural IFN-alpha. The response rate of 77% achieved in this study prompts the use of IFN-alpha as a first-choice drug for type II EMC.
VIRUSES AND CRYOGLOBULINEMIA.
Galli M; Clinica delle Malattie Infettive, Università di Milano, Italy.Clin Exp Rheumatol, 1995 Nov-Dec, 13 Suppl 13:, S63-70
Circulating cryoglobulins have been reported in association with several acute and chronic viral diseases. In all of the reported cases, the viruses involved have been hepatotropic, lymphocytotropic or both. Among the hypotheses concerning the causes of cryoglobulinemia, two possible pathways have been more frequently debated: an impairment of the macrophagic system of the liver, with the consequent impairment of the clearance of gut antigens and immunoglobulins, as the first ring of a chain of events including the activation of the B cell compartment with increased production (and decreased clearance) of cryoglobulins; and a low-grade malignant lymphomatous process involving rheumatoid factor producing clones. Recent evidence of a close association between hepatitis C virus (HCV) and "essential" mixed cryoglobulinemia has focused the attention of several researchers on the mechanisms by which the virus is capable of causing cryoglobulin synthesis. The open questions include: (1) Why do only a minority of chronically HCV-infected people (mainly "sporadically" infected elderly women) develop a cryoglobulinemic syndrome? (2) What kind of mechanisms can up- or down-regulate cryoglobulin production? (3) Are immunoregulatory mechanisms involved? (4) Is there a connection between HCV infection and the low-grade malignant lymphoma hypothesis identifying cryoglobulinemias as the consequence of the slow proliferation of CD5+ B cells? and (5) Are particular HCV genotypes specifically involved in causing cryoglobulinemias? Several of these questions still remain unanswered. HCV has been detected in the peripheral blood mononuclear cells of both cryoglobulinemic and non-cryoglobulinemic infected subjects; on the other hand, the detection of viral RNA in the bone marrow cells of virtually all cryoglobulinemic patients suggests that this might be related to the pathogenesis of the disease.
HCV AND LYMPHOPROLIFERATIVE DISORDERS
G. Pozzato¤,$, C. Mazzaroum. and O. Burrone*; ¤Institute of Medicina Clinica, University of Trieste, Ospedale di Cattinara Strada di Fiume 447, 34100 Trieste, Italy; um.First Division of Medicine, Pordenone General Hospital, Pordenone; *International Centre of Genetic Engineering and Biotechnology, Area Science Park, Padriciano, Trieste, Italy. $: correspondence fax: 39-40-912881 e-mail: pozzato@univ.trieste.it ; The Cancer Journal - Volume 10, Number 2 (March-April 1997)
ABSTRACT Mixed cryoglobulinemia is considered a lymphoproliferative disorder characterized by several clinical symptoms (arthralgias, purpura and weakness) and often by organ involvement. Recently, evidence of hepatitis C virus infection in the majority of these patients has been shown, even in absence of clinical and/or laboratory signs of chronic liver disease, suggesting that this virus could be the main etiologic agent of mixed cryoglobulinemia. Finally, HCV has revealed a lymphotropism both in vitro and in vivo. On the basis of these findings, the systematic identification of HCV in different hematological diseases revealed an increased prevalence of HCV infection in non-Hodgkin's lymphomas, especially in immunocytomas. The present work offers an overview of a large number of experimental and clinical observations supporting the possible involvement of HCV in human lymphoproliferative disease.
CLASSIFICATION OF CRYOGLOBULINS
Three types of cryoglobulins can be distinguished on the basis of their structure (7):
Type I (Single cryoglobulins)These are formed by monoclonal immunoglobulins. IgM are most commonly involved, although sporadic cases with IgG have been reported. The presence of Type I cryoglobulins is confined to cases of Wandenstrom's disease.
Type II (Mixed cryoglobulinemia with a monoclonal component)The characteristic feature of this form is the presence of IgM/IgG complexes in the serum. The IgG fraction is polyclonal, while the IgM fraction is monoclonal, endowed with rheumatoid factor activity, due to preferential expression of particular VH and VK gene segments. This cryoglobulinemia is often associated with vasculitis, skin and neurological manifestations, and glomerulonephritis.
Type III (Mixed polyclonal cryoglobulins)The cryoglobulins are only polyclonal (without rheumatoid factor activity) and can be observed with a frequency similar to that of type II.
The presence of a B lymphoproliferative disorder is always associated with Type I cryoglobulins, while Type II cryoglobulinemia has been considered as a B monoclonal disease in only a fraction of patients. Type III is more problematic: those secondary to acute or chronic infection were regarded as responses (more or less transient) to antigenic stimulus, while the remainder as possible lymphoproliferative diseases.
MIXED CRYOGLOBULINEMIA AND HEPATITIS C VIRUS
Recently, several reports have shown that MC is closely associated with HCV infection (8) (9). When the presence of the viral infection was investigated by detection of circulating anti-HCV antibodies, about 60-75% of the patients were positive, but, when HCV-RNA was investigated in serum and/or in the cryoprecipitate by PCR, over 80% of patients resulted infected by HCV, even in the absence of anti-HCV antibodies. Furthermore, recent studies showed the presence of the viral genome in peripheral blood mononuclear cells (PBMC) of subjects affected by MC without detectable levels of anti-HCV antibodies and without HCV-RNA in serum (10. Ferri C, La Civita L, Monti M et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 82, 3701-3704, 1993). On the basis of these findings, HCV seems to be associated with MC in almost all cases, even in the absence of clinically evident chronic liver disease. The viral infection is present in Type II as well in Type III MC, suggesting no etiologic difference between these two subgroups of MC. (17). The involvement of HCV in Type I MC has not been established: a preliminary report (11) indicated the presence of HCV-RNA in several patients affected by Waldenstrom's disease, while anti-HCV antibodies were detectable in only a minority of cases. Other groups did not confirm this observation, but the question is open. In fact, it may be very difficult to demonstrate the presence of HCV infection in Waldenstrom's disease: firstly, the progressive decline in the concentration of normal (non monoclonal) antibodies (12) complicates the test to reveal anti-HCV antibodies, which may appear negative. Secondly, the high levels of monoclonal IgM cryoglobulins may bind the virus, and clear the serum; in this situation even PCR amplification would not be able to detect HCV-RNA.
The presence of HCV in the near- totality of patients affected by MC, often without liver disease, has opened up a new field of investigation: the potential role of HCV in lymphoproliferative disorders.
Get your own Free Home Page