Криоглобулинемия: симптомы, причины и механизмы развития.

Medical condition

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells. Cryoglobulins typically precipitate (clumps together) at temperatures below normal body temperature37 °C (99 °F)and will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become gangrenous. While this disease is commonly referred to as cryoglobulinemia in the medical literature, it is better termed cryoglobulinemic disease for two reasons: 1) cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease and 2) 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 and is commonly associated with various pre malignant, malignant, infectious, or autoimmune diseases that are the underlying cause for production of the cryoglobulins.

The clinical features of cryoglobulinemic disease can reflect those due not only to the circulation of cryoglobulins but also to any underlying hematological premalignant or malignant disorder, infectious disease, or autoimmune syndrome. The following sections of clinical features focuses on those attributed to the cryoglobulins. Cryoglobulins cause tissue damage by three mechanisms; they can:
a) increase blood viscosity thereby reducing blood flow to tissues to cause the hyperviscosity syndrome (i. e., headache, confusion, blurry or loss of vision, hearing loss, and epistaxis;
b) deposit in small arteries and capillaries thereby plugging these blood vessels and causing infarction and necrosis of tissues including in particular skin (e. g., ears), distal extremities, and kidneys;
c) in type II and type III disease, deposit on the endothelium of blood vessels and activate the blood complement system to form pro inflammatory elements such as C5a thereby initiating the systemic vascular inflammatory reaction termed cryoglobulinemic vasculitis.

The signs and symptoms in the increasingly rare cases of cryoglobulinemic disease that cannot be attributed to an underlying disease generally resemble those of patients suffering Type II and III (i. e., mixed) cryoglobulinemic disease.

Signs and symptoms due to the cryoglobulins of type I disease reflect the hyperviscosity and deposition of cryoglobulins within the blood vessels which reduce or stop blood perfusion to tissues. These events occur particularly in cases where blood cryoglobulin levels of monoclonal IgM are high in patients with IgM MGUS, smoldering Waldenström's macroglobulinemia, or Waldenström's macroglobulinemia and in uncommon cases where the levels of monoclonal IgA, IgG, free κ light chains, or free λ light chains are extremely high in patients with non IgM MGUS, non IgM smoldering multiple myeloma, or multiple myeloma. The interruption of blood flow to neurological tissues can cause symptoms of confusion, headache, hearing loss, and peripheral neuropathy. Interruption of blood flow to other tissues in type I disease can cause cutaneous manifestations of purpura, blue discoloration of the arms or legs (acrocyanosis), necrosis, ulcers, and livedo reticularis; spontaneous nose bleeds, joint pain, membranoproliferative glomerulonephritis; and cardiovascular disturbances such as shortness of breath, inadequate levels of oxygen in the blood (hypoxemia), and congestive heart failure. While the glomerulonephritis occurring in mixed disease appears to be due to inflammatory vasculitis, the glomerulonephritis occurring in type I disease appears due to the interruption of blood flow. These molecules precipitate at lower temperatures (e. g., 4 °C). Since cryofibrinogens are present in plasma but greatly depleted in serum, precipitation tests for them are positive in plasma but negative in serum. Cryoglobulinemic disease must also be distinguished from frostbite as well as numerous other conditions that have a clinical (particularly cutaneous) presentation similar to cryoglobulinemic disease but are not exacerbated by cold temperature, e. g., dysfibrinogenemia and dysfibrinogenemic disease (conditions involving the intravascular deposition of genetically abnormal circulating fibrinogens), purpura fulminans, cholesterol emboli, warfarin necrosis, ecthyma gangrenosum, and various hypercoagulable states. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be followed closely for any changes that may indicate development of cryoglobulinemic disease.

People affected by the severest, often life threatening, complications of cryoglobulinemic disease require urgent plasmapharesis and/or plasma exchange in order to rapidly reduce the circulating levels of their cryoglobulins. Complications commonly requiring this intervention include: hyperviscosity disease with severe symptoms of neurological (e. g., stroke, mental impairment, and myelitis) and/or cardiovascular (e. g., congestive heart failure, myocardial infarction) disturbances; vasculitis driven intestinal ischemia, intestinal perforation, cholecystitis, or pancreatitis, causing acute abdominal pain, general malaise, fever, and/or bloody bowel movements; vasculitis driven pulmonary disturbances (e. g., coughing up blood, acute respiratory failure, X ray evidence of diffuse pulmonary infiltrates caused by diffuse alveolar hemorrhage); and severe kidney dysfunction due to intravascular deposition of immunoglobulins or vasculitis. Along with this urgent treatment, severely symptomatic patients are commonly started on therapy to treat any underlying disease; this treatment is often supplemented with anti inflammatory drugs such as corticosteroids (e. g., dexamethasone) and/or immunosuppressive drugs. Cases where no underlying disease is known are also often treated with the latter corticosteroid and immunosuppressive medications.

Treatment of Type I disease is generally directed towards treating the underlying pre malignant or malignant disorder (see plasma cell dyscrasia, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia). This involves appropriate chemotherapy regimens which may include bortezomib (promotes cell death by apoptosis in cells accumulating immunoglobulins) in patients with monoclonal immunoglobulin induced kidney failure and rituximab (antibody directed against CD20 surface antigen bearing lymphocytes) in patients with Waldenstroms macroglobulinemia).

Treatment of mixed cryoglobulinemic disease is, similar to type I disease, directed toward treating any underlying disorder. This includes malignant (particularly Waldenström's macroglobulinemia in type II disease), infectious, or autoimmune diseases in type II and III disease. Recently, evidence of hepatitis C infection has been reported in the majority of mixed disease cases with rates being 70 90% in areas with high incidences of hepatitis C. The most effective therapy for hepatitis C associated cryoglobulinemic disease consists of a combination of anti viral drugs, pegylated INFα and ribavirin; depletion of B cells using rituximab in combination with antiviral therapy or used alone in patients refractory to antiviral therapy has also proven successful in treating the hepatitis C associated disease. Data on the treatment of infectious causes other than hepatitis C for the mixed disease are limited. A current recommendation treats the underlying disease with appropriate antiviral, anti bacterial, or anti fungal agents, if available; in cases refractory to an appropriate drug, the addition of immunosuppressive drugs to the therapeutic regimen may improve results. Mixed cryoglobulinemic disease associated with autoimmune disorders is treated with immunosuppressive drugs: combination of a corticosteroid with either cyclophosphamide, azathioprine, or mycophenolate or combination of a corticosteroid with rituximab have been used successfully to treated mixed disease associated with autoimmune disorders.