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 types 2 and 3 represent two distinct clinical entities with different pathophysiological mechanisms. In type 1 cryoglobulinemia, high concentrations of monoclonal immunoglobulins can increase blood viscosity and promote red blood cell aggregation (rouleaux formation), while the cryoglobulins themselves precipitate directly into intravascular hyaline plugs and microthrombi that occlude small- and medium-sized blood vessels. In contrast, types 2 and 3 cryoglobulinemia involve immune complexes that trigger classical complement pathway activation, resulting in an inflammatory leukocytoclastic 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.
Classification Since the first description of cryoglobulinemia in association with the clinical triad of purpura, joint pain, and weakness by Meltzer et al. in 1966, 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.
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 Type II Monoclonal IgM plus polyclonal IgG or, rarely, IgA 50–60% Infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection; hematological diseases particularly B cell disorders; autoimmune diseases Type III Polyclonal IgM plus polyclonal IgG or IgA 25–30% Autoimmune diseases, particularly Sjögren syndrome and less commonly systemic lupus erythematosus and rheumatoid arthritis; infectious diseases particularly HCV infection
The monoclonal or polyclonal IgM proteins involved in Types II and III cryoglobulinemic disease have rheumatoid factor activity, meaning they bind to polyclonal immunoglobulins and activate the blood complement system. They therefore form tissue deposits that contain IgM, IgG or, rarely, IgA, and components of the complement system, including in particular complement component 4. The vascular deposition of these types of cryoglobulin-containing immune complexes and complements can cause a clinical syndrome of cutaneous small-vessel vasculitis characterized by systemic vasculitis and inflammation termed cryoglobulinemic vasculitis. 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.
More recent high-resolution protein electrophoresis methods have detected a small monoclonal immunoglobulin component in type III cryoglobulins, a micro-heterogeneous composition of oligoclonal (i.e., more than one monoclonal) immunoglobulin components, and immunoglobulins with structures that do not fit into any classifications in the cryoglobulins of approximately 10% of type II and III disease cases. 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.
Epidemiology The prevalence of mixed cryoglobulinemia is estimated at approximately 1 in 100,000 individuals, although geographical variations exist with higher rates reported in Southern Europe and the Mediterranean basin compared to Northern Europe or North America.
Mixed cryoglobulinemia displays a marked female predominance, with a female-to-male ratio of approximately 2:1 to 3:1. Clinical presentation most commonly manifests in the fourth to sixth decades of life. In contrast, Type I cryoglobulinemia exhibits no clear sex predilection, occurring with equal frequency in men and women, and presents primarily in older demographics reflecting the incidence patterns of underlying lymphoproliferative disorders.
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.
In type 1 disease, increased blood viscosity (hyperviscosity syndrome) reducing blood flow to tissues, may cause headache, confusion, blurry or loss of vision, hearing loss, coma, incoordination (ataxia) or strokes. Bleeding from mucosal surfaces, such as the nose, mouth or vaginal area is possible.
In type 2 or 3 disease, immunoglobulin and complement deposition in small arteries and capillaries causes vasculitis, thereby initiating the systemic vascular inflammatory reaction termed cryoglobulinemic vasculitis.
Purpura seen in cryoglobulinemia may also be referred to as cryoglobulinemic purpura. 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.
Kidney disease in cryoglobulinemia presents as nephrotic range proteinuria, hematuria, kidney failure and high blood pressure. Symptoms due to kidney disease are similar in type 1 and type 2 or 3 disease. Type 2 or 3 cryoglobulinemic kidney disease usually presents as membranoproliferative glomerulonephritis with immune globulin and complement deposition in the glomerular basement membrane.
Essential cryoglobulinemic disease 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.
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.
Types II and III cryoglobulinemic disease Types II and III cryoglobulinemic disease present with deposition of cryoglobulins within blood vessels and activation of inflammatory cascades, including those of complement, leading to cryoglobulinemic vasculitis. "Meltzer's triad" of palpable purpura, joint pain, and generalized weakness occurs in ≈33% of patients presenting with type II or type III disease. One or more skin lesions including palpable purpura, ulcers, digital gangrene, and areas of necrosis occur in 69-89% of these mixed disease cases; less common findings include painful peripheral neuropathy (often manifesting as mononeuritis multiplex in 19-44% of cases), kidney disease (primarily membranoproliferative glomerulonephritis (30%), joint pain (28%), and, less commonly, dry eye syndrome and Raynaud phenomenon (i.e., episodic painful reductions in blood flow to the fingers and toes). 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.
Mechanism Cryoglobulins Cryoglobulins consist of one or more of the following components: monoclonal or polyclonal IgM, IgG, IgA antibodies, monoclonal κ, or λ free light chain portions of these antibodies, and proteins of the blood complement system, particularly complement component 4 (C4). The particular components involved are a reflection of the disorders that are associated with, and considered to be the cause of, the cryoglobulinemic disease. The cryoglobulin compositions and disorder associations in cryoglobulinemic disease are as follows: