Relationship Between Cryoglobulinemia-associated Nephritis and HCV Infection

Dario Roccatello; Osvaldo Giachino; Elisa Menegatti; Simone Baldovino

Disclosures

Expert Rev Clin Immunol. 2008;4(4):515-524. 

In This Article

Abstract and Introduction

The pathogenetic mechanisms in hepatitis C virus (HCV)-related cryoglobulinemia are sustained by the chronic lymphocyte stimulation of HCV infection, and include the synthesis of IgM rheumatoid factor and tissue deposition of immunocomplexes, characterized by abnormal kinetics and an underlying lymphoproliferative disorder. Based on postulated pathogenetic mechanisms, therapeutic strategies include antiviral, immunosuppressive and immunomodulatory treatments. Combined interferon and ribavirin has shown a better response rate than interferon alone. Pegylated interferons are currently recommended in association with ribavirin. Advances in tolerance might be achieved by tailoring doses and treatment duration according to genotype and individual factors. Conventional immunosuppressive therapy has been widely used in patients with progressive renal involvement or relapsing disease. Rituximab is a promising alternative treatment option for severe cryoglobulinemic vasculitis and nephritis. Although the optimal treatment strategy in HCV-related cryoglobulinemia has not been determined yet, an algorithm based on the clinical severity of disease could be proposed, in which rituximab might be a first-line option in severe cases.

The clinical symptoms of mixed cryoglobulinemia (MC) range from mild palpable purpura, arthralgias and fatigue to severe vasculitis with skin necrosis, as well as peripheral neuropathy and, less frequently, involvement of the CNS, GI tract, lungs and myocardium. The kidney is rarely spared in the long term and glomerulonephritis (GN) is a key factor affecting prognosis.

The primary role that hepatitis C virus (HCV) infection plays in the development of cryoglobulinemia is supported by the presence of a HCV concentration in the cryoprecipitate that ranges from 20- to 1000-fold higher than in the serum supernatant.[1]

It has been estimated that HCV entered a human host several hundred years ago. Genotype 1 shows a worldwide distribution, whereas genotypes 2 and 3 originated more recently and are geographically more restricted, genotype 2 being more common in western Africa and genotype 3 in the northern Indian subcontinent. Approximately 150 million people worldwide are infected with HCV,[2] with a seroprevalence rate of less than 1% in Western Europe but 2-3% in some Mediterranean areas. Seroprevalence can be nonhomogeneous in the same country. For instance, in Italy, genotype 1 is remarkably more prevalent in the north-west and south than in the north-east.[3] In the USA, genotype 1 infection is significantly more prevalent in the northeastern, southeastern and middle western areas than in patients from the west and south, and African-Americans are more likely to be infected with genotype 1 than Caucasians.

Genotype 4 is predominant in the Middle East and Africa, genotype 5 in South Africa and genotype 6 in South-East Asia, although recent evidence suggests that genotype 4 is spreading in Western countries, especially among intravenous drug users.[4]

Approximately 40% of chronically infected patients have circulating cryoglobulins.[5] However, the clinical features of MC develop in a strict minority of HCV-infected persons,[5] while nephropathy develops in 0.1-0.2% of this population.[3] Genetic background is probably important in determining which subjects are doomed to develop the syndromic manifestations.

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