Cryoglobulinemia

Cryoglobulins are immunoglobulins that precipitate in cold temperatures. This occurs in the bloodstream and in test tubes. These immunoglobulins are antigen-antibody complexes, most commonly IgG-IgM complexes. They result from hypersensitivity reactions against normal immunoglobulins. These antigen-antibody complexes are commonly found circulating in the bloodstream of patients with rheumatoid arthritis, Hepatitis B, or Hepatitis C.

In order to determine if a patient’s blood sample contains cryoglobulins, you have to tell the lab specifically that you’re looking for cryoglobulins. The lab takes 2 samples of the blood – one to be kept at room temperature and the other into the refrigerator overnight. The one at room temperature will not have any precipitate forming, whereas the chilled sample will contain precipitated, sedimented immunoglobulins (cryoglobulins!).

Type I Cryoglobulinemia

·        It constitutes 25% of all cryoglobulinemia.

·        Type I is characterized by single monoclonal immunoglobulins.

·        Diseases that may cause Type I cryoglobulinemia include:

o        Multiple Myeloma (IgG)

o        Waldenstrom’s Macroglobulinemia (IgM)

Type II Cryoglobulinemia

·        It constitutes 25% of all cryoglobulinemia.

·        Type II is characterized by mixed cryoglobulins. It may contain a polyclonal IgG and a monoclonal antiglobulin called rheumatoid factor (RF), which is usually IgM. The rheumatoid factor (IgM) complexes with the Fc portion of polyclonal IgG.

·        There is usually an underlying lymphoproliferative, autoimmune chronic infectious disease associated with Type II.

·        Type II usually gives rise to kidney disease.

Type III Cryoglobulinemia

·        It constitutes 50% of all cryoglobulinemia and is the most common type in patients.

·        It is a mixed essential cryoglobulinemia, containing a polyclonal IgG and a polyclonal antiglobulin (rheumatoid factor), which is usually IgM. The rheumatoid factor (IgM) complexes with the Fc portion of polyclonal IgG.

·        It can be caused by a viral infection, most commonly Hep C.

Both Types II and III Cryoglobulinemia have underlying infectious or connective tissue disease. There is no overt associated disease in 30% of cases.

Clinical Presentation (usually Types II & III)

·        Petechiae/Purpura – small spots due to hemorrhages of small blood vessels (arterioles)

·        Neurologic symptoms

o        There is a ganglionic dispersion of cryoglobulins, with associated necrosis.

·        Ischemic necrosis

o        Antigen-antibody complexes precipitate in the lumen of blood vessels and obstruct bloodflow.

·        Acute vasculitis

o        Complement fragments (C3a & C5a) are found in patients, which act as chemotactic inflammatory mediators, resulting in vasculitis.

·        Meltzer’s Triad is evident in primary essential cryoglobulinemia.

o        Purpura

o        Arthralgia

o        Weakness

·        Pulmonary symptoms, such as wheezing

o        Immune complexes can also deposit in pulmonary intra-alveolar capillaries.

Biopsy Findings

·        Acute nephritic syndrome

·        Hypersensitive glomeruli

·        Cryoglobulin precipitates in vascular lumen

Laboratory Findings

·        Immunofluorescence

o        Cryoglobulinemia results in hypocomplementemia, a reduced level of complement.

o        Complement fragments C1q and C3 are found (classical activation pathway).

o         chains are 4x more common than  chains to be involved as part of the antibodies in cryoglobulinemia.

·        Intra- and sub-endothelial microtubular inclusion bodies (shown above) are found histologically. These bodies are characteristic of viral-induced diseases. Therefore, microtubular inclusion bodies are present in cryoglobulinemia (since it’s primarily viral-induced – i.e.Type III), AIDS, and SLE. ***super-important!!!***

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