November 2007

Fig.3

Fig.4

DIAGNOSIS: Type II cryoglobulinemia

Additional lab work revealed:
· Serum cryoglobulins: 1454 (normal 0-20)
· Cryoglobulin rheumatoid factor: positive

HISTOLOGY: Vasculopathic dermatitis with mixed cellularity vasculitis and vasculo-occlusive disease (Figs.3 &4).

DISCUSSION:
Cryoglobulins are immunoglobulins that precipitate from the serum in the cold and dissolve upon rewarming. In most cases, cryoglobulinemia remains asymptomatic. But, it can lead to immune complex deposition and vasculitis. There are three main types of cryoglobulinemia. Type I features a monoclonal IgM (sometimes IgG or IgA) and is usually associated with an underlying lymphoproliferative disease or plasma cell dyscrasia such as multiple myeloma, Waldenstrom's macroglobulinemia, or monoclonal gammopathy of unknown significance (MGUS). Type II features both a polyclonal IgG and a monoclonal IgM rheumatoid factor directed against the IgG. Most cases are associated with chronic hepatitis C infection. Type III features both polyclonal IgG and polyclonal rheumatoid factor IgM. It is often seen in chronic inflammatory and autoimmune disorders (such as lupus and leukocytoclastic vasculitis), lymphoproliferative malignancies, and HCV infection. Types II and III are considered "mixed" cyroglobulinemias because of their polyclonal component.
Clinical manifestations of type II cryoglobulinemia include: palpable purpura, arthralgias, lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, hypocomplementemia, and deficits in attention and higher cognitive function. Renal disease in mixed cryoglobulinemia is present in approximately 20 percent of patients at the time of diagnosis and eventually occurs in 35 to 60 percent of patients with type II disease. The prognosis of the renal disease is variable. Approximately one-third of patients undergo partial or complete remission. The remaining patients have a slowly progressive course that may be complicated by periodic acute exacerbations.
The association of mixed cryoglobulinemia with hepatitis C infection may be linked to the ability of the virus to bind to B lymphocytes. Binding lowers the activation threshold of these cells, thereby facilitating lymphoproliferation and the production of autoantibodies. Decreased clearance of cryoglobulins due to hepatic dysfunction may also promote cryoglobulin accumulation in the circulation and subsequent tissue deposition
To test for cryoglobulins, at least 20 mL of blood should be drawn into a tube not treated with an anticoagulant. Blood should be drawn in the fasting state since lipids may interfere with the test. The tubes should be placed in warm water or warm sand (37ºC) and transported to the laboratory. The serum is separated by centrifugation at 37ºC and placed in a 4ºC refrigerator to see if precipitation occurs over a 48 to 72 hour period.
Aggressive therapy is primarily reserved for patients with acute severe disease with progressive renal failure, distal necroses requiring amputation, or advanced neuropathy. The mainstay of treatment is a combination of plasmapheresis, methylprednisolone 1000mg daily times three, followed by prednisone, and cyclophosphamide to prevent new antibody formation. Renal function can usually be stabilized with this regimen, although death from active vasculitis remains a major problem. Two major theoretical concerns include possible enhancement of hepatitis C replication and possible exacerbation of low-grade non-Hodgkin's lymphoma. Rituximab has also shown promise as a potential new therapy. Treating hepatitis C patients with interferon-a may lead to a reduction in circulating cryoglobulin levels and potential clinical remission. It is recommended that patients with hepatitis C-associated symptomatic cryoglobulinemia receive interferon a, preferably pegylated interferon, plus ribavirin.
The patient in this case experienced continued fevers as well as altered mental status. He also experienced worsening renal insufficiency with his admission creatinine of 1.3 rising to 2.5. He was ultimately treated with prednisone and plasmapheresis with improvement.

References:
1. Braun GS, Horster S, Wagner KS, et al. Cryoglobulinaemic vasculitis: classification and clinical and therapeutic aspects. Postgrad Med J 2007;83:87-94.
2. Bryce AH, Kyle RA, Dispenzieri A, and Gertz MA. Natural history and therapy of 66 patients with mixed cryoglobulinemia. Am J Hematol 2006 Jul;81(7):511-8

This case is presented by Ds. Erica Rogers and Julia Graves. Histopathological photos are courtesy of Dr. Kimberly Crone.