Cryoglobulinemia

Cryoglobulins are antibodies that precipitate at temperatures below 37 degrees Celsius. Its important to recognize that cryoglobulinemia is by definition the presence of precipitating proteins at low temperatures, however, clinicians tend to use this label to mean the clinical syndrome it is associated with. Cryoglbulins are classified into several categories, with each having its own clinical features and associations. :

Type 1 cryoglobulinemia - is monoclonal antibodies of one type, ie IgG or IgM. Associated with hematologic malignancies (Waldenstroms macroglobulinemia or myeloma). The primary clinical concern here is hyperviscosity syndrome where patients presents with infarcted digits, TIA/stroke like symptoms or thrombosis.

Type 2 cryoglobulinemia aka essential mixed cryoglobulinemia - results from monoclonal and polyclonal antibodies, including rheumatoid factor. The large majority of these patients have hepatitis C (30-100%), although connective tissue disease (Sjogren's syndrome) and lymphomas can also lead to this condition. Other less common infectious causes include HIV, streptococcal infections and brucellosis.

Type 3 cryoglobulinemia - is another form of mixed cryoglobulinemia, where all antibodies are polyclonal.

The classic triad was described by Meltzer in 1966, as purpura, arthritis and myalgia. These symptoms suggest cryoglobulinemic vasculitis. Palpable purpura is the most common manifestation, present in up to approximately 80% of patients. Purpura refers to bleeding under the skin that is larger than 3mm, when less than 3mm its termed petechiae. Other dermatologic findings include ulceration, levido reticularis and digital necrosis. Renal involvement is present in 30% of patients, where proteinuria, hematuria and active sediment production can occur. Nephrotic and nephritic syndrome occur in 21% and 14% of cases respectively. Neuropathy is also common, with up to 60% of patients describing symptoms burning and parasthesias. Mononeuritis multiplex (neuropathy involving a nerve with a name) is also seen, where patients can develop wrist or foot drop.

Testing for cryoglobulinemia is problematic, where samples need to be obtained in warmed syringes and kept at 37 degrees. Once serum is isolated it can be stored in a refrigerator at 4 degrees. It takes days for mixed immunoglobulin to precipitate, but type 1 proteins can be identified within hours. The quantity of cryoprecipitate can also be determined, using a test called the cryocrit. This is important because disease severity is proportional to amount of protein. Additional tests include complements, where low C4 is common, and elevated rheumatoid factor. Looking for an underlying disease association is also important if not already recognized.

Treatment is targeted towards the underlying cause and removing the monoclonal immunoglobulin. Considering HCV is so common in mixed cryoglobulinemia, ribavirin and interferon therapy should be considered with consultation by hepatology. Plasma exchange is helpful in life threatening disease with hyperviscosity. There is some growing evidence for the use of rituximab (monoclonal antibody targeting B-cells). A RCT from 2010 showed expedited rates of remission, improved renal involvement and higher rates of protein clearance compared to antiviral therapy in those with HCV. See a NEJM review on treatment in HCV associated cryoglobulinemia for more details (courtesy of the admitting physician).

HCV cryo treatment