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Hepatitis C Virus Infection and Cutaneous Vasculitis in Mixed Cryoglobulinemia

      To the Editor. We read with interest the review by Daoud and colleagues, which was published in the June 1995 issue of the Mayo Clinic Proceedings (pages 559 to 564), that discussed the intriguing association between hepatitis C virus (HCV) infection and skin diseases, one of which was cryoglobulinemic cutaneous vasculitis. The presence of HCV infection has been demonstrated in a large majority of patients with mixed cryoglobulinemia (MC).
      • Ferri C
      • La Civita L
      • Longombardo G
      • Greco F
      • Bombardieri S
      Hepatitis C virus and mixed cryoglobulinaemia.
      MC is an immune complex (IC)-mediated disorder characterized by purpura, weakness, arthralgias, circulating mixed (IgG and IgM) cryoglobulins, and multiple organ involvementnamely, chronic hepatitis, glomerulonephritis, peripheral neuropathy, and diffuse vasculitis.
      • Ferri C
      • La Civita L
      • Longombardo G
      • Greco F
      • Bombardieri S
      Hepatitis C virus and mixed cryoglobulinaemia.
      The pathogenesis of vasculitis, the typical hallmark of the cutaneous and visceral manifestations of MC, is due to tissue deposition of circulating IC and complement.
      • Ferri C
      • La Civita L
      • Longombardo G
      • Greco F
      • Bombardieri S
      Hepatitis C virus and mixed cryoglobulinaemia.
      Usually, cutaneous vasculitis (classically as palpable purpura on the legs) is the manifesting symptom of the disease,
      • Ferri C
      • La Civita L
      • Longombardo G
      • Greco F
      • Bombardieri S
      Hepatitis C virus and mixed cryoglobulinaemia.
      • Cohen SJ
      • Pittelkow MR
      • Su WPD
      Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients.
      and the most frequent histopathologic pattern of this manifestation is leukocytoclastic vasculitis (LCV).
      • Cohen SJ
      • Pittelkow MR
      • Su WPD
      Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients.
      In consideration of the high prevalence of HCV infection (more than 90%) and the frequent skin involvement in patients with MC, we performed a preliminary histopathologic and virologic study on skin biopsy specimens from five consecutive patients with MC (Table 1) who had active purpuric skin eruption. MC was diagnosed on the presence of the typical clinical syndrome and on the exc lusion of other well-known systemic disorders.
      • Ferri C
      • La Civita L
      • Longombardo G
      • Greco F
      • Bombardieri S
      Hepatitis C virus and mixed cryoglobulinaemia.
      These heterosexual patients denied having a history of exposure to blood products or drug abuse. Visceral complications and alterations in serologic findings were evaluated as previously described,
      • Ferri C
      • Monti M
      • La Civita L
      • Longombardo G
      • Greco F
      • Pasero G
      • et al.
      Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia.
      All patients received long-term low-dose corticosteroids; no patient was given interferon treatment previously. The histopathologic diagnosis was performed by evaluation of skin biopsy specimens, including the characterization of the inflammatory infiltrate and the presence and type of vascular involvement. Clinicopathologic and virologic features of the patients are summarized in Table 1. In four of the five patients, skin biopsies showed the presence of neutrophil infiltrates and fibrinoid necrosis involving the dermal vessels and a LCV pattern. HCV seropositivity with ongoing HCV infection was found in all patients with use of a second-generation recombinant immunoblot assay (Chiron, Emeryville, California) and “one-tube nested” polymerase chain reaction, as previously described.
      • Ferri C
      • Monti M
      • La Civita L
      • Longombardo G
      • Greco F
      • Pasero G
      • et al.
      Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia.
      Furthermore, HCV RNA was detected in 100% of peripheral lymphocytes and in three of the five skin biopsy specimens (Table 1). In no patients were human immunodeficiency virus (HIV) and hepatitis B virus markers detected.
      Table 1Main Epidemiologic, Clinicopathologic, and Virologic Features of Five Patients With Mixed Cryoglobulinemia
      * CH = chronic hepatitis; HCV = hepatitis C virus; LCV = leukocytoclastic vasculitis; LI = lymphocytic infiltrate; MC = mixed cryoglobulinemia; N = peripheral neuropathy; PBMC = peripheral blood mono-nuclear cells; SS = sicca syndrome; U = skin ulcers.
      HCV RNA
      Age (yr) and sexDuration of MC (yr)Systemic featuresCryocrit (%)Skin biopsySerum anti-HCV/HCV RNAPBMCSkin biopsy
      80 F2CH, SS1.7LCV+/+++
      40 F6CH.SS1.2LCV+/++
      53 F20N0.5LI+/+++
      77 F14CH, N, U9.7LCV+/+++
      68 F9CH, SS, N0.5LCV+/++
      * CH = chronic hepatitis; HCV = hepatitis C virus; LCV = leukocytoclastic vasculitis; LI = lymphocytic infiltrate; MC = mixed cryoglobulinemia; N = peripheral neuropathy; PBMC = peripheral blood mono-nuclear cells; SS = sicca syndrome; U = skin ulcers.
      Our preliminary study shows the presence of HCV infection in skin biopsy specimens from patients with MC; in particular, HCV was detected in 50% of those with LCV. This complication is usually associated with IC-related diseases.
      • Cohen SJ
      • Pittelkow MR
      • Su WPD
      Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients.
      To date, only the anecdotal case reports by Daoud and colleagues have described the association between HCV infection and LCV. Our data seem to confirm this association, a suggestion that the vascular damage underlying the cryoglobulinemic purpura could be mediated by circulating HCV-containing IC or, alternatively, by autoantibodies reacting with antigens of endothelial cells infected by HCV. Indirectly, the pathogenetic relevance of HCV in LCV seems to be proved by the beneficial effects of interferon alfa treatment of the cryoglobulinemic purpura.
      • Ferri C
      • Marzo E
      • Longombardo G
      • Lombardini F
      • La Civita L
      • Vanacore R
      • et al.
      Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial.
      If confirmed in a larger scries of patients with MC, these findings could definitively clarify the pathogenetic role of HCV in cryoglobulinemic vasculitis.

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        • Bombardieri S
        Hepatitis C virus and mixed cryoglobulinaemia.
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        • Cohen SJ
        • Pittelkow MR
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        Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients.
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        • Monti M
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        • Greco F
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        • et al.
        Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia.
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        • Ferri C
        • Marzo E
        • Longombardo G
        • Lombardini F
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        • et al.
        Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial.
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