Cryoglobulins

Abstract

Serum cryoglobulins are found in a wide spectrum of disorders but are often transient and without clinical implications. Monoclonal cryoglobulins are usually associated with haematological disorders, whereas mixed cryoglobulins are found in many infectious and systemic disorders. So called essential mixed cryoglobulinaemia shows a striking association with hepatitis C virus (HCV) infection (> 90%). It is a systemic vasculitis (leucocytoclastic vasculitis) with cutaneous and multiple visceral organ involvement. Chronic HCV infection can lead to a constellation of autoimmune and neoplastic disorders. In this review, the aetiology, diagnosis, disease heterogeneity, and treatment of cryoglobulinaemia are discussed.

Figure 1

Possible aetiopathogenesis of mixed cryoglobulinaemia (MC) and other hepatitis C virus (HCV) related disorders. HCV infection may exert a chronic stimulus on the immune system. The interaction between HCV envelope protein E2 and CD81 on both hepatocytes and lymphocytes may be an important step in the cascade of events. T(14;18) translocation is commonly found in HCV infected individuals, particularly in patients with MC. The activation of the Bcl2 proto-oncogene may lead to prolonged B cell survival. B cell expansion is responsible for the production of various autoantibodies, including rheumatoid factor and cryoprecipitable immune complexes. Consequently, various autoimmune disorders and cryoglobulinaemic vasculitis may develop. In a minority of cases, indolent B cell proliferation may be complicated by frank malignant lymphoma. HCV is the major causative factor of hepatocellular carcinoma; moreover, a possible link between HCV and thyroid cancer has been hypothesised. There is a clinicoserological and pathological overlap among different HCV related diseases; mixed cryoglobulinaemia syndrome represents a crossroad between these autoimmune and neoplastic disorders.

Figure 2

Type II mixed cryoglobulinaemia (MC) associated monotypic lymphoproliferative disorder of undetermined significance (MLDUS) shows two main pathological patterns: B cell chronic lymphocytic leukaemia/small lymphocytic lymphoma (B-CLL)-like and immunocytoma (Ic)-like MLDUS. (A) lymphoid infiltrate in a portal tract of the liver; note the substantial lack of activity (haematoxylin and eosin; original magnification, ×100); (B) lymphoid infiltrate in a portal tract of the liver with moderate activity (Giemsa; original magnification ×100); at higher magnification, the infiltrate shows either B-CLL-like (C) or Ic-like (D) morphology (Giemsa; original magnification, ×400); (E) nodular lymphoid infiltrate in the bone marrow showing indistinct borders (Giemsa; original magnification, ×100). (F–H) B-CLL-like MLDUS: the lymphoid population of a liver infiltrate strongly expresses the CD22 antigen (F) and is in turn CD5 positive (G) and CD3 negative (H); CD3 is expressed by some T cells. Immunochemistry in frozen (F) and paraffin wax embedded sections (G,H) (alkaline phosphatase anti-alkaline phosphatase (APAAP) technique; Gill's haematoxylin counterstaining; original magnification, ×150). (I,J) Ic-like-MLDUS: the lymphoid infiltrate in the bone marrow shows a clear cut positivity for CD20 and turns out to be negative for CD5, which is confined to reactive T cells (immunochemistry in paraffin wax embedded sections; APAAP technique; Gill's haematoxylin counterstaining; original magnification, ×150).

Figure 3

Hepatitis C virus (HCV) related lymphoproliferation shows consistent similarities with the model of lymphomagenesis already accepted for subjects with Helicobacter pylori positive gastritis.

Figure 4

Different clinicoserological patterns of mixed cryoglobulinaemia (MC) at presentation; complete MC syndrome is a combination of serological findings (mixed cryoglobulins with rheumatoid factor activity and frequent low C4) and clinicopathological features (purpura, leucocytoclastic vasculitis with multiple organ involvement; tables 1, 4). MC can appear as an incomplete syndrome, mainly in the early stages of the disease.

Figure 5

Mixed cryoglobulinaemia is a combination of three main clinicopathological alterations: chronic hepatitis C virus (HCV) infection, B cell lymphoproliferation, and immune complex vasculitis. We can treat the disease at different levels and by means of combined—aetiological, pathogenetic, and symptomatic—treatments. LAC, low antigent content.