Neuropathies associated with cryoglobulinemia

Kourosh Rezania MD (

Dr. Rezania of ​the University of Chicago received honorariums from Akcea for speaking engagements, consulting fees from Kaba Fusion for consulting work and speaking engagements, and consulting fees from Alnylam and Lendbeck as a member of advisory panels.

Peter Pytel MD (Dr. Pytel of The University of Chicago Medicine has no relevant financial relationships to disclose.)
Francesc Graus MD PhD, editor. (

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.

Originally released May 6, 1996; last updated January 28, 2020; expires January 28, 2023

This article includes discussion of neuropathies associated with all types of cryoglobulinemia (types I, II, and III), with emphasis on cryoglobulinemic vasculitic neuropathy associated with hepatitis C virus infection. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Cryoglobulins are plasma proteins that precipitate on cooling and dissolve after rewarming. Cryoglobulinemia may arise in association with an identifiable cause like an infection (mainly hepatitis C virus infection), a lymphoproliferative disorder, or an autoimmune disease (such as Sjögren syndrome). Alternatively, cryoglobulinemia may arise without a detectable underlying disease, in which case the term “essential cryoglobulinemia” is used. Cryoglobulinemia may lead to a variety of systemic complications, including purpura, arthritis, glomerulonephritis, and peripheral neuropathy, which could be potentially disabling. In this review, the authors review the pathogenesis, management, and treatment of neuropathies associated with cryoglobulinemia.

Key points


• Cryoglobulins are serum proteins (predominantly immunoglobulins) that precipitate at temperatures below 37° C and dissolve on rewarming.


• The majority of cryoglobulins are mixed antigen-antibody complexes that occur in autoimmune or infectious disorders, especially hepatitis C virus infection.


• Cryoglobulinemic neuropathy is one of the most common forms of vasculitic neuropathy.


• Sensory neuropathy is the commonest form of neuropathy in mixed cryoglobulinemia; however, a clinical presentation such as sensory motor neuropathy and mononeuritis multiplex is not uncommon.


• Treatment of neuropathy associated with cryoglobulinemia depends mainly on whether the patient has hepatitis C virus infection, in which case treatment with antivirals and rituximab may result in clinical remission. Cytotoxic, immunosuppressive, or immunomodulatory treatments may prove effective in some of the severe cases of cryoglobulinemic neuropathy associated with hepatitis C infection, as well as in cryoglobulinemia secondary to lymphoproliferative diseases and to an autoimmune disease.

Historical note and terminology

The term "cryoglobulin" was first employed in 1947, although the first description in the literature was that of Heidelberger in 1929 (Lerner and Watson 1947; Heidelberger and Kendall 1929). Wintrobe and Buell initially described the clinical manifestations accompanying the presence of a cryoglobulin in the serum, which included Raynaud phenomenon, purpura, and thrombosis of retinal veins (Wintrobe and Buell 1933).

The first description of cryoglobulinemic neuropathy was by Garcin and colleagues in 1957 (Garcin et al 1957). They described a 43-year-old patient who, over a period of months, developed mononeuritis multiplex, which was associated with purpura of the lower limbs and increased neuropathic symptoms in cold temperature. In 1962, Lospalluto and colleagues showed that cryoglobulins contain more than 1 immunoglobulin and that there may be rheumatoid factor activity within the cryoprecipitate (Lospalluto et al 1962). Since the report of Brouet and colleagues, cryoglobulinemia has been classified into three types (Brouet et al 1974):


Type I. The cryoprecipitate only consists of a monoclonal component (commonly IgM or IgG, less often IgA or free immunoglobulin light chains) in the setting of a B cell lymphoproliferative disease.


Type II. The cryoprecipitate consists of a mixture of monoclonal IgM with rheumatoid factor activity and polyclonal IgG in the setting of hepatitis C infection (most common cause for type II cryoglobulinemia), a lymphoproliferative disorder, or an autoimmune disease.


Type III. The cryoprecipitate only contains a polyclonal IgG and polyclonal IgM with RF activity, in the setting of a collagen vascular, infectious (including hepatitis C), or chronic inflammatory disease.

Types II and III are called mixed cryoglobulinemia.

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