Cryoglobulinemia

Cryoglobulinemia is a rare medical condition characterized by the presence of cryoglobulins in the blood. Cryoglobulins are abnormal proteins composed of immunoglobulins and sometimes complement components. Cryoglobulins specifically form gel-like solids by clumping together and becoming insoluble at temperatures below 37 °C.

In the human body, these cryoglobulins precipitate together in small- and medium-sized blood vessels causing occlusions and triggering inflammatory reactions. This leads to a range of symptoms, including joint pain, skin rashes, and kidney problems.

Cryoglobulinemia is classified into three groups. Type I cryoglobulinemia has only monoclonal proteins, developing in lymphoproliferative disorders. Type II cryoglobulinemia is the most common, occurring when both monoclonal and polyclonal proteins are present in the bloodstream and is usually linked to chronic Hepatitis C infection. Type III cryoglobulinemia has only polyclonal proteins and is often linked to autoimmune diseases. These cryoglobulins are not to be confused with cold agglutinins, which cause agglutination of red blood cells. Cryoglobulins typically precipitate below normal human body temperature (37 °C (99 °F)) and dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause extremities to become gangrenous.

Type 1 cryoglobulinemia and Type 2 and 3 are thought to be two distinct disease entities with different pathophysiological mechanisms. Type 1 cryoglobulinemia causes organ damage and skin manifestations through the formation of small blood clots (microthrombi) in small and medium sized vessels. Immune globulins form large macromolecular structures (known as Rouleaux formations) which trap blood cells, causing clots. Type 2 and 3 cryoglobulinemia involve immunoglobulins activating complement leading to a complement mediated vasculitis.

The main causes of cryoglobulinemia are Waldenstrom's macroglobulinemia, multiple myeloma, Non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), monoclonal gammopathy of clinical significance, lupus, Sjogren's syndrome, rheumatoid arthritis and chronic viral infections including hepatitis C (most commonly in type 2 disease), hepatitis B and HIV.

While this disease is commonly referred to as cryoglobulinemia in the medical literature, Retamozo et al. argue it is better termed cryoglobulinemic disease for two reasons: cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease, and healthy individuals can develop transient asymptomatic cryoglobulinemia following certain infections.

In contrast to these benign instances of circulating cryoglobulins, cryoglobulinemic disease involves the signs and symptoms of precipitating cryoglobulins, commonly associated with various pre-malignant, malignant, infectious, or autoimmune diseases that are the underlying cause for the production of the cryoglobulins.