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 percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia (cryoglobulinemic disease that is unassociated with an underlying disorder) has fallen. Currently, most cases of this disease are found to be associated with premalignant, malignant, infectious, or autoimmune disorders that are the known or presumed causes for the production of cryoglobulins. This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification. The classification distinguishes the subtypes of cryoglobulinemic diseases based on two factors: the class of immunoglobulins in the cryoglobulin and the association of the cryoglobulinemic disease with other disorders. The following table lists these three types of cryoglobulinemic disease, characterized by the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, the percentage of total cryoglobulinemic disease cases, and class of disorders associated with each type.
{| class="wikitable"
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! Type
! Composition
! Percentage
of cases
! Association with other diseases
|-
| Type I
| Monoclonal IgG, IgM, IgA, or their κ or λ light chains
| 10–15%
| Hematological diseases, particularly MGUS, smoldering multiple myeloma, multiple myeloma, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease. The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity. It has been proposed that these cases be termed an intermediate type II-III variant of cryoglobulinemic disease. Furthermore, it has also been proposed that some of the type III cases associated with the expression of low levels of one or more isotypes of circulating monoclonal immunoglobulin(s) are in transition to type II disease.
Signs and symptoms
The clinical features of cryoglobulinemic disease can appear due to the circulation of cryoglobulins. They can also appear due to an underlying hematological disorder, infectious disease, or autoimmune syndrome that contributed to the cryoglobulinemia. Clinical symptoms are diverse, as cryoglobulinemia may affect any organ system. Type 1 cryoglobulinemic disease usually presents with skin findings linked to external cold temperatures whereas skin findings in type 2 and 3 disease are linked to physical exertion or prolonged standing. Extremity hypoperfusion in type 1 disease may cause Raynaud phenomenon or damage to extremities, such as fingers, hands and toes.
Type I 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 form blood clots, which reduce or stop blood perfusion to tissues. 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.
- Mixtures of monoclonal or polyclonal IgM, IgG, and/or IgA along with blood complement proteins such as C4 are the cryoglobulins associated with cases of infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection, and, less commonly or rarely, with cases of other infectious diseases such as hepatitis B infection, hepatitis A infection, cytomegalovirus infection, Epstein–Barr virus infection, Lyme disease, syphilis, lepromatous leprosy, Q fever, poststreptococcal nephritis, subacute bacterial endocarditis, coccidioidomycosis, malaria, schistosomiasis, echinococcosis, toxoplasmosis, and Kala-azar. These mixed-protein cryoglobulins are also associated with autoimmune diseases, particularly Sjögren syndrome, less commonly systemic lupus erythematosus and rheumatoid arthritis, and rarely polyarteritis nodosa, systemic sclerosis, temporal arteritis, polymyositis, Henoch–Schönlein purpura, pemphigus vulgaris, sarcoidosis, inflammatory bowel diseases, and others. 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 monitored closely for any signs of developing cryoglobulinemic disease.