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 syndrome (MCS), also known as symptomatic mixed cryoglobulinemia, refers to the presence of arthralgia, purpura, and fatigue in a patient with mixed cryoglobulinemia. Patients may further complain of muscle aches or weakness, fevers, or unexplained weight loss. Cutaneous findings include palpable purpura, retiform purpura, dermal nodules and livedo reticularis, digital necrosis, and Raynaud phenomenon. Extracutaneous involvement includes rare arthritis, glomerulonephritis, peripheral neuropathy, and interstitial lung infiltrates.

MCS is often caused by infection with hepatitis C virus (HCV) and is less commonly associated with hepatitis B virus (HBV) and HIV infection, but it can also be due to an autoimmune condition (such as systemic lupus erythematosus, rheumatoid arthritis, or Sjögren syndrome) or lymphoproliferative disease, or it may present without a specific cause identified (in around half of cases), known as essential mixed cryoglobulinemia.

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