The Expanding Spectrum of Clinical Features in HCV-Related Mixed Cryoglobulinemia

Mixed cryoglobulinemia (MC) is a relatively rare disorder that may complicate numerous infectiousor immuno/hematological diseases. Classical MC syndrome is associated with hepatitis C virus (HCV)infection in the large majority of patients and the virus is suspected in the etiopathogenesis of the disease.MC syndrome, or cryoglobulinemic vasculitis, is characterized by a clinical triad of purpura, weakness,and arthralgias and by variable organ and, in many cases, endocrine involvement. As a late complication,some patients develop malignancies, particularly B-cell lymphomas and/or hepatocellular carcinoma.To date, there are no available diagnostic criteria for MC, but classification criteria must account for itsserological and clinical hallmarks. Leukocytoclastic vasculitis, especially of the small blood vessels,is the typical pathological finding of affected tissues. An important pathogenetic step in MC is HCVlymphotropism, which is responsible for poly/oligoclonal B-lymphocyte expansion. The consequence isa wide production of different autoantibodies and immune complexes, mainly cryoglobulins, responsiblefor organ- and non-organ-specific immunological alterations. Thus, MC, characterized by the simultaneouspresence of autoimmune and lymphoproliferative diseases, is the crossroads of these disorders andrepresents the prototype of HCV-associated pathologies. The oncogenic potential of HCV is demonstratedby several studies showing its pathogenetic link with some malignancies, particularly the hepatocellularcarcinoma and B-cell lymphomas. HCV-related disorders have a heterogeneous geographical distribution,suggesting other important genetic and/or environmental co-factors. Although the majority of individualswith chronic HCV infection exhibit hepatic manifestations only or are totally asymptomatic, a notnegligible percentage develop autoimmune and/or lymphoproliferative/neoplastic disorders through amultifactorial and multistep pathogenetic process, reflected by the name “HCV syndrome.”