Longterm efficacy of interferon-alpha for extrahepatic disease associated with hepatitis C virus infection.

OBJECTIVE: To investigate longterm responsiveness to interferon-alpha (lFN-alpha) of patients with extrahepatic manifestations of hepatitis C virus (HCV) in a nonendemic area. METHODS: We prospectively evaluated 11 patients with extrahepatic manifestations of HCV infection, including 10 with Type II cryoglobulins, treated with IFN-alpha--9 had cutaneous vasculitis, 6 arthralgias, 7 neuropathy, and 4 glomerulonephritis. Liver biopsies were performed on all patients, although 6/11 had normal liver function tests. All received 3 M units IFN-alpha tiw, with total length of treatment ranging from 3 mo to 5 yrs. Periodic assessments were made of clinical activity, biochemical variables, cryoglobulin quantitation, and HCV copy number. RESULTS: Three patients were withdrawn because of toxicity. Three were nonresponders at 6, 16, and 17 mo of therapy, based on persistence of HCV RNA in blood, cryoprecipitates, and peripheral blood mononuclear cells. One patient was a partial responder at 3 yrs, with 2 major flares of cutaneous vasculitis occurring on separate attempts to withdraw IFN-alpha. Three patients (27.2%) were complete responders based on resolution of symptoms (purpura, neuropathy) and disappearance of cryoprecipitates and HCV RNA, but only one successfully tapered IFN-alpha after 3 yrs of treatment, with sustained resolution at followup 15 mo later. CONCLUSION: IFN-alpha is safely tolerated for prolonged periods in patients with extrahepatic HCV infection, and is particularly effective for treatment of cutaneous vasculitis. Careful monitoring is needed for evolution of liver pathology to cirrhosis, or for progression of renal or neurologic disease.

Hepatitis C virus, autoimmunity and lymphoproliferation.

We summarize clinical, laboratory and pathologic details regarding a patient who presented with extrahepatic disease manifestations of hepatitis C virus (HCV) infection, including cryoglobulinemic leg ulcers due to cutaneous vasculitis, peripheral sensorimotor neuropathy, and recurrent pulmonary infiltrates. The patient had evidence for B-cell lymphoproliferation, diagnosed as extranodal lymphoma on initial (though not subsequent) bone marrow examination, retroperitoneal lymphadenopathy, and the presence of a Type II IgM6 monoclonal rheumatoid factor which became cryoprecipitable on complexing to IgG. Chronic hepatitis was mild on liver biopsy, though fibrotic changes developed over a three-year period of follow-up. She had consistently normal liver function tests, except for a brief rebound effect on discontinuing interferon-alpha, and preterminally. Symptoms were only partially responsive to trials of corticosteroids, cytotoxic agents, plasmapheresis and interferon, and the patient ultimately died at The Mount Sinai Hospital of sepsis. We review current information regarding the spectrum of extrahepatic HCV infection, including pathogenic factors relevant to its overlapping autoimmune, rheumatic and lymphoproliferative disease manifestations. The exact prevalence of these HCV-related syndromes among the 1% of the world population estimated to be infected by this virus remains to be delineated. Chronicity of infection, and lack of efficacy of currently available therapy in effecting sustained clearance of the virus from the host, have made this an important public health problem that is likely to increase in significance. Possible relationships to non-Hodgkin's lymphoma may present novel opportunities to delineate the basis for oncogenesis in HCV infection.

Evaluation of cryoglobulins.

Cryoglobulins are immunoglobulins that precipitate as serum is cooled below core body temperatures. A cryoglobulin screen is the observation of a serum specimen collected and separated while warm for cryoprecipitation over a period of up to 7 days. Values of the screening may be reported as a cryocrit, which is the volume percent of the precipitate compared with the total volume of serum. Further proof that the precipitate is indeed a cryoglobulin can be obtained by demonstrating resolubilization with warming and immunochemical analysis by immunofixation. Detailed characterization of cryoglobulins may also require rigorous washing of the precipitate, quantitation of total protein and immunoglobulins, and evaluation of serum for monoclonal gammopathy, rheumatoid factor activity, evidence of complement activation, and presence of hepatitis C virus seroreactivity or hepatitis C virus RNA. The single most important variable confounding standardization of cryoglobulin testing is the frequently improper separation of warm serum from other blood elements prior to screening and characterization.