Chapter 52 - Cryoglobulins and Cryoglobulins Secondary to Hepatitis C Virus Infection

The term cryoglobulinemia refers to the presence in the serum of one (monoclonal cryoimmunoglobulinemia) or more immunoglobulins (mixed cryoglobulinemia, MC), which precipitate at temperatures below 37 °C and redissolve on rewarming; this is an in vitro phenomenon that can be associated to a large number of benign or malignant disorders. In addition, type II mixed cryoglobulins are often composed by oligoclonal IgM or a mixture of polyclonal and monoclonal IgM. This type II–III MC could represent an intermediate, evolutive state from type III to type II MC; it may be in keeping with the most recent molecular studies showing the presence of oligoclonal B-lymphocyte proliferation in liver and bone marrow biopsies from patients with MC. Commonly, serum cryoglobulins represent an isolated laboratory finding without any clinical consequence; type I cryoglobulinemia is frequently associated with well-known hematologic disorders, as well as mixed cryoglobulins (type II and III) are detectable in a great number of infectious or systemic disorders. On the contrary, the so-called ‘essential’ MC represents a distinct disorder, classified among systemic vasculitides; this vasculitis is secondary to vascular deposition of circulating IC, mainly cryoglobulins and complement. It is included in the subgroup of systemic vasculitides involving small and medium arteries, capillaries, and veins; they are characterized by leukocytoclastic vasculitis of the skin. The terms MC syndrome and ‘cryoglobulinemic vasculitis’ are often used as synonyms. MC syndrome is considered to be a rare disorder; numerous cohort studies of series of patients from different countries suggest its geographically heterogeneous distribution; the disease is more common in southern Europe than in northern Europe or Northern America. Considering the clinical polymorphism of MC (skin vasculitis, hepatitis, nephritis, peripheral neuropathy, etc.), the patients with MC are often referred to different specialties according to the prevalent clinical feature(s); consequently, a correct diagnosis might be delayed or overlooked entirely and the actual prevalence of the disease might be underestimated.