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ESSENTIALS OF DIAGNOSIS

  • Vasculitis associated with mixed cryoglobulinemia (MC) involves both small- and medium-sized vessels. The skin is the most commonly involved organ.

  • Other frequently affected organs include the joints, peripheral nerves, and kidneys. The central nervous system, gastrointestinal tract, and lungs are involved rarely or very rarely in MC.

  • Virtually all patients are rheumatoid factor (RF) positive.

  • Many cases of type II cryoglobulinemia are still associated with hepatitis C virus.

  • Lower survival rates are observed with age over 60 years, male sex, and renal involvement.

General Considerations

Cryoglobulins are immunoglobulins (Ig) that precipitate from the serum at low temperatures (see method of collection under Laboratory Findings). Cryoprecipitates are composed most commonly of IgG and IgM (either singly or, in the case of mixed cryoglobulinemia, together). Occasionally IgA may be associated with clinically relevant cryoglobulin syndromes, as well. Cryoglobulinemia is divided into three clinical subsets—types I, II, and III (Table 32–1)—based on two features: the clonality of the IgM component and the presence of rheumatoid factor (RF) activity. RF activity, by definition, is the reactivity of an IgM component with the Fc portion of IgG. This chapter focuses on cryoglobulinemia types II and III, both of which are referred to as “mixed cryoglobulinemia” (MC). Type I cryoglobulinemia is usually not “mixed” and is associated with only a monoclonal IgG or IgM, often in the setting of a malignancy. Overall, cryoglobulinemia is rare, with a prevalence of roughly 1 in 100,000 people, and with a female to male ratio of 3:1.

Table 32–1.Types of cryoglobulinemia.

Formerly referred to as “essential” MC, hepatitis C virus (HCV) infections are now known to be associated with approximately 90% of all cases of MC. Latency periods of up to 15 years between the occurrence of HCV infection and the development of clinical signs of MC have been reported. In some cases, the presentation of HCV may be the development of the clinical features of MC (usually palpable purpura). Cryoglobulins also occur in the setting of other types of infections such as HIV as well as in connective tissue disorders (eg, Sjögren syndrome) and hematopoietic malignancies.

The presence of cryoglobulins is not always associated with clinical disease, but these proteins may result in a wide variety of immune complex–mediated complications. The term “mixed cryoglobulinemia” was coined to differentiate types II and III (both of which contain mixtures of both IgG and IgM) from type I (which contains only a single monoclonal ...

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