Cryoglobulins are single or mixed immunoglobulins that undergo reversible precipitation at low temperatures. Several types of cryoglobulins have been identified, and the potential clinical manifestations vary by cryoglobulin type. 
Cryoglobulinemia is characterized by the presence of cryoglobulins in the serum. This may result in a clinical syndrome of systemic inflammation (most commonly affecting the kidneys and skin) caused by cryoglobulin-containing immune complexes.
Cryoglobulinemia may be classified based on cryoglobulin composition with the Brouet classification, which is as follows:
Type I cryoglobulinemia, or simple cryoglobulinemia, is the result of a monoclonal immunoglobulin, usually immunoglobulin M (IgM) or, less frequently, immunoglobulin G (IgG), immunoglobulin A (IgA), or light chains.
Types II and III cryoglobulinemia (mixed cryoglobulinemia) contain rheumatoid factors (RFs), which are usually IgM and, rarely, IgG or IgA. These RFs form complexes with the fragment, crystallizable (Fc) portion of polyclonal IgG. The actual RF may be monoclonal (in type II cryoglobulinemia) or polyclonal (in type III cryoglobulinemia) immunoglobulin. Types II and III cryoglobulinemia represent 80% of all cryoglobulins.
Cryoglobulinemia may also be classified based on the association of the syndrome with an underlying disease. Cryoglobulinemia without an associated disease has been known as essential, or idiopathic, cryoglobulinemia. However, the discovery of a close association between hepatitis C virus (HCV) and mixed cryoglobulinemia has cast doubt on the existence of essential, or idiopathic, cryoglobulinemia.  Cryoglobulinemia associated with a particular disease (lymphoproliferative disorder, autoimmune disease, infectious disease) is known as secondary cryoglobulinemia.
In a French study of 36 patients with type I cryoglobulinemia, skin or vasomotor symptoms were present in 75%; nephropathy in 30%; and neuropathy in 47%. The underlying B cell disease was a nonmalignant monoclonal gammopathy in 36% and hematologic malignancy in 64%.Treatments included fludarabine and rituximab-based regimens. Five-year survival was 82%. 
In another study, of 64 patients with type I cryoglobulinemia vasculitis (CryoVas), Terrier et al identified 28 patients with monoclonal gammopathy of unknown significance and 36 with hematologic malignancy. Type I monoclonal CryoVas was characterized by severe cutaneous involvement (necrosis and ulcers) in almost 50% the patients, as well as high serum cryoglobulin levels. Survival rates were 97% at 1 year; 94% at 3 years; 94% at 5 years; and 87% at 10 years. Treatments included alkylating agents, rituximab, thalidomide or lenalinomide, and bortezomib. Clinical response rates ranged from 80-86%. 
In a study of patients with type II cryoglobulinemia, peripheral blood mononuclear cells from 18 patients were separated into CD3+ (T cells), CD19+ (B cells), and CD14+ (monocytes) and analyzed for the presence of negative-strand HCV RNA and for HCV nonstructural protein 3 (NS3). Negative-strand HCV RNA was detected in 6 patients, most frequently in B cells (3 patients), followed by T cells (2 patients) and monocytes (2 patients). NS3 protein was also detected in 6 patients: 5 were positive in T cells, 3 in B cells, and 3 in monocytes. 
The mechanisms of cryoprecipitation are poorly understood, but several factors have been investigated. The solubility of cryoglobulins has been found to be partially related to the structure of component immunoglobulin heavy and light chains. [6, 7, 8] Alteration in protein conformation with temperature changes also leads to decreased solubility and subsequent vasculitic damage. [9, 10] The ratio of antibody to antigen in circulating cryoglobulin aggregates or immune complexes affects the rate of clearance from the circulation and the resultant rate and location of tissue deposition. 
Some of the sequelae of cryoglobulinemia are thought to be related to immune-complex disease (eg, glomerulonephritis, chronic vasculitis), but not all persons with cryoglobulinemia present with these manifestations. Individuals with cryoglobulinemia may have intravascular cryoglobulin deposits, a reduced level of complement, and complement fragments (C3a, C5a) that act as chemotactic mediators of inflammation; however, the pathophysiologic process of this disease has not been fully explained.
Other sequelae are directly related to cryoprecipitation in vivo, including plugging and thrombosis of small arteries and capillaries in the extremities (gangrene) and glomeruli (acute kidney injury). Circulating large–molecular-weight cryoprotein complexes, even when unprecipitated in vivo, can lead to clinical hyperviscosity syndrome.
Type I cryoglobulins are usually monoclonal IgM and, less frequently, IgG, IgA, or light chains. Type I cryoglobulins rarely have RF activity and do not activate complement in vitro. This disorder is typically related to an underlying lymphoproliferative disease and, as such, may be clinically indistinguishable from Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia.
Type I cryoglobulinemia may result in hyperviscosity due to high levels of circulating monoclonal cryoglobulin, leading to physical obstruction of vessels. Concentrations may reach up to 8 g/L. In addition, nonobstructive damage may be mediated by immune complex deposition and subsequent inflammatory vasculitis.
Types II and III, also known as the mixed cryoglobulinemias, are associated with chronic inflammatory states such as systemic lupus erythematosus (SLE), Sjögren syndrome, and viral infections (particularly HCV). In these disorders, the IgG fraction is always polyclonal with either monoclonal (type II) or polyclonal (type III) IgM (rarely IgA or IgG) with RF activity (ability to bind IgG). B-cell clonal expansion, particularly RF-secreting cells, is a distinctive feature in many of these disease states. [2, 12, 13, 14]
The resultant aggregates and immune complexes are thought to outstrip reticuloendothelial-clearing activity. Tissue damage results from immune complex deposition and complement activation. Of note, in HCV-related disease, HCV-related proteins are thought to play a direct role in pathogenesis and are present in damaged skin, blood vessels, and kidneys. [13, 15, 16, 17]
Cryoglobulins are reported in otherwise healthy individuals, so the true prevalence of the disease is unknown. Overall, cryoglobulinemia is thought to be rare. However, cryoglobulinemia may be underestimated based on the medical literature (perhaps because of the various clinical presentations); Gorevic et al evaluated only 126 cases of cryoglobulinemia from over 18 years in their medical center in New York.  The prevalence of essential mixed cryoglobulinemia is reported as approximately 1:100,000.
The reported relative frequencies of the different types of cryoglobulinemia vary. Brouet et al reported the following frequencies  :
Type I, 25%
Type II, 25%
Type III, 50%
The prevalence of mixed cryoglobulinemia is related to the endemic presence of HCV infection. Therefore, the prevalence varies from country to country. The incidence of HCV infection in mixed cryoglobulinemia in the Mediterranean Basin is 90%.
Mortality and morbidity in individuals with cryoglobulinemia often depend on concomitant disease (eg, lymphoproliferative disorder, viral hepatitis); for example, the prognosis in patients with chronic hepatitis C depends on their response to treatment; manifested by their decrease in viral load. The overall prognosis is worse in persons with concomitant renal disease, lymphoproliferative disease, or plasma cell disorders. Mean survival is approximately 50% at 10 years after diagnosis.
Morbidity due specifically to cryoglobulinemia may be significant, with infection and cardiovascular disease being major considerations. Hepatic failure may result from chronic viral hepatitis.
Survival rates reported among patients with renal involvement vary from greater than 60% at 5 years of follow-up to 30% at 7 years of follow-up. The risk of renal failure appears to be greater in those with HCV-associated disease.  The prognosis of renal disease in the more common type II cryoglobulinemia varies. Most patients experience a slowly progressive course punctuated by acute exacerbations, with up to one third of patients undergoing some degree of clinical remission. Bryce et al, in a prospective study, found only age (and no laboratory parameters) to be a significant predictor of mortality in type II cryoglobulinemic renal disease. 
Lymphoproliferative disease is more common in individuals with cryoglobulinemia. Patients with mixed cryoglobulinemia may develop benign lymphoid infiltrates in the spleen and bone marrow. Less frequently, some patients develop B-cell non-Hodgkin lymphoma. The reported incidence of malignant lymphoma in mixed cryoglobulinemia varies widely, from less than 10% of patients to as high as 40%, with onset 5-10 years after disease diagnosis. [22, 23, 24]
Sex- and age-related demographics
The female-to-male ratio is 3:1. The mean age reported is 42-52 years.
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