Cryoglobulinemia
Alejandro A. Gru
DEFINITION
Cryoglobulins are abnormal serum immunoglobulins that reversibly precipitate at low temperature. Two forms of cryoglobulinemias are distinguished based on the composition of the cryoglobulins and associated vascular pathology. In simple cryoglobulinemia, type I cryoglobulins are composed of monoclonal immunoglobulins, which result in dermal vasculopathy (thrombosis) as they precipitate in vessels. In mixed cryoglobulinemia, cryoglobulins are immune complexes made up of either monoclonal (type II) or polyclonal (type III) rheumatoid factor (RF) bound to the Fc portion of polyclonal IgG. Mixed cryoglobulinemia induces leukocytoclastic vasculitis (LCV), typically involving both superficial and deep dermal vessels.1,2
LABORATORY FINDINGS
Type I cryoglobulinemia (CG) represents approximately 25% of all cases of cryoglobulins. The associated monoclonal immunoglobulin is most frequently IgG or IgM and less frequently IgA or light chains.1,3 Types II and III CG (mixed cryoglobulinemia) contain RFs, which are usually IgM and, rarely, IgG or IgA. These RFs form complexes with the fragment, crystallizable (Fc) portion of polyclonal IgG. The actual RF may be monoclonal (in type II cryoglobulinemia) or polyclonal (in type III cryoglobulinemia) immunoglobulin. Types II and III CG represent 80% of all cryoglobulins.4,5 Mixed CG takes the form of immune complexes that bind complement and ultimately lead to an inflammatory response.
ETIOLOGY
Type I CG caused by monoclonal IgG is associated with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, chronic lymphocytic leukemia, and lymphoplasmocytic lymphoma (LPL).3,6,7,8,9,10,11,12,13 Type I CG containing monoclonal IgM is typically linked to MGUS and LPL (Waldenstrom macroglobulinemia). Cases without associated hematologic dyscrasias are referred to as essential simple cryoglobulinemia.14
Mixed CG (types II and III) is most frequently associated with hepatitis C virus (HCV) infection. More than 50% of HCV patients have mixed cryoglobulins. Other frequent associations include connective tissue disease (lupus, Sjögren syndrome) and hematologic malignancies.15 Rare occurrences with EBV,16 HIV,17 parvovirus B19,18 syphilis,19 and leprosy20 have been described. An underlying disease cannot be identified in about one-third of mixed CG cases (essential mixed cryoglobulinemia).
CLINICAL FINDINGS
Approximately half of patients with type I CG have cutaneous manifestations on presentation.6 The cutaneous symptoms include Raynaud phenomenon, livedo reticularis, and recurrent episodes of cold-induced necrotic purpura of the extremities and urticaria, either cold related or not (Fig. 62-1). Leg ulcers are also a frequent clinical manifestation. Systemic manifestations also include high-grade proteinuria (nephrotic range), nephritic syndrome, acute renal failure, and severe hypertension. Neurologic findings are also seen in 25% of cases, usually in the form of predominantly sensitive polyneuropathy with associated axonal loss. Type I CG is associated with an approximately 10% mortality, related to the hemopathy.
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