Cryoglobulinemia is a condition in which cryoglobulins are present in the serum. Cryoglobulins are immunoglobulins that precipitate at temperatures below 37°C (98.6°F) and then redissolve when above 37°C. Cryoglobulins are classified into 3 types: Type I cryoglobulins are monoclonal immunoglobulins (ie, IgG, IgM) or free light chains. They usually develop in cases of monoclonal gammopathies such as monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, or some B-lymphoproliferative disorders. Type II cryoglobulins are monoclonal immunoglobulins (ie, IgM, IgG) in combination with rheumatoid factor (RF) and polyclonal immunoglobulin. Type III cryoglobulins refer to the combination of polyclonal IgG and polyclonal IgM.

When more than one type of immunoglobulin component is present (types II and III cryoglobulinemia), the term mixed cryoglobulinemia is used. Mixed cryoglobulinemia is often caused by infection with hepatitis C virus (HCV) and less commonly with hepatitis B virus (HBV), an underlying autoimmune condition (such as systemic lupus erythematosus, rheumatoid arthritis, or Sjögren syndrome), or lymphoproliferative disease. In around half of cases, no underlying cause is found; this is termed essential mixed cryoglobulinemia.

The pathogenesis of essential mixed cryoglobulinemia involves deposition of the mixed cryoglobulin-antigen complexes in small vessels, causing vasculitis and possible resultant end-organ damage.

Patients may complain of muscle aches or weakness, fevers, unexplained weight loss, joint pain, or skin changes that worsen when exposed to the cold. Cutaneous findings include palpable purpura, retiform purpura, dermal nodules, livedo reticularis, digital necrosis, and Raynaud phenomenon. Extracutaneous involvement includes arthralgias and rare arthritis, glomerulonephritis, peripheral neuropathy, and interstitial lung infiltrates.