cryoglobulinemia

Since the first description of cryoglobulinemia in association with the clinical triad of purpura, joint pain, and weakness by Meltzer et al. in 1966,{{Cite journal |last1=Meltzer |first1=M. |last2=Franklin |first2=E.C. |last3=Elias |first3=K. |last4=McCluskey |first4=R.T. |last5=Cooper |first5=N. |date=June 1966 |title=Cryoglobulinemia—A clinical and laboratory study |url=http://dx.doi.org/10.1016/0002-9343(66)90200-2 |journal=The American Journal of Medicine |volume=40 |issue=6 |pages=837–856 |doi=10.1016/0002-9343(66)90200-2 |pmid=4956871 |issn=0002-9343|url-access=subscription }}{{Cite journal |date=January 1967 |title=Cryoglobulinemia—A study of twenty-nine patients. I. IgG and IgM cryoglobulins and factors affecting cryoprecipitability |url=http://dx.doi.org/10.1016/s0011-2240(67)80017-8 |journal=Cryobiology |volume=3 |issue=4 |pages=346 |doi=10.1016/s0011-2240(67)80017-8 |issn=0011-2240|url-access=subscription }} the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia (cryoglobulinemic disease that is unassociated with an underlying disorder) has fallen.{{Cite journal |date=2024-10-28 |title=Cryoglobulinemia: Practice Essentials, Pathophysiology, Etiology |url=https://emedicine.medscape.com/article/329255-overview?form=fpf#a1}} 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.{{Citation |last=Bhandari |first=Jenish |title=Cryoglobulinemia |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK557606/ |access-date=2025-03-14 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32491538 |last2=Awais |first2=Mashal |last3=Aeddula |first3=Narothama R.}} This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification.{{cite journal |vauthors = Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M |title = Biologic and clinical significance of cryoglobulins. A report of 86 cases |journal = Am. J. Med. |volume = 57 |issue = 5 |pages = 775–88 |year = 1974 |pmid = 4216269 |doi = 10.1016/0002-9343(74)90852-3 }} 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.{{cite journal |vauthors = Ferri C, Zignego AL, Pileri SA |title = Cryoglobulins |journal = J. Clin. Pathol. |volume = 55 |issue = 1 |pages = 4–13 |year = 2002 |pmid = 11825916 |doi = 10.1136/jcp.55.1.4 |pmc = 1769573 }}{{DorlandsDict|two/000025727|Cryoglobulin}}

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.{{Citation needed|date=December 2024}} 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.{{cite journal |vauthors = Ostojic P, Jeremic IR |title = Managing refractory cryoglobulinemic vasculitis: challenges and solutions |journal = Journal of Inflammation Research |volume = 10 |pages = 49–54 |year = 2017 |pmid = 28507447 |pmc = 5428757 |doi = 10.2147/JIR.S114067 |doi-access = free }} Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease.{{cite journal |vauthors = Tedeschi A, Baratè C, Minola E, Morra E |title = Cryoglobulinemia |journal = Blood Rev. |volume = 21 |issue = 4 |pages = 183–200 |year = 2007 |pmid = 17289231 |doi = 10.1016/j.blre.2006.12.002 }} 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 ≈10% of type II and III disease cases.{{Cite journal |last=Morra |first=Enrica |date=2005-01-01 |title=Cryoglobulinemia |url=https://ashpublications.org/hematology/article/2005/1/368/19313/Cryoglobulinemia |journal=Hematology |volume=2005 |issue=1 |pages=368–372 |doi=10.1182/asheducation-2005.1.368 |pmid=16304405 |issn=1520-4391|url-access=subscription }} 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.{{cite journal |vauthors = Tissot JD, Schifferli JA, Hochstrasser DF |title = Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide |journal = J. Immunol. Methods |volume = 173 |issue = 1 |pages = 63–75 |year = 1994 |pmid = 8034987 |doi = 10.1016/0022-1759(94)90284-4 |display-authors = etal }}

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.{{Cite web |title=Cryoglobulinemia - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/cryoglobulinemia/symptoms-causes/syc-20371244 |access-date=2025-04-12 |website=Mayo Clinic |language=en}} Clinical symptoms are diverse, as cryoglobulinemia may affect any organ system.

Increased blood viscosity (hyperviscosity syndrome), thereby reducing blood flow to tissues may cause headache, confusion, blurry or loss of vision, hearing loss, and epistaxis (nose bleeds) in type 1 disease.

Immunoglobulin and complement deposition in small arteries and capillaries causing vasculitis in type 2 or 3 disease, thereby initiating the systemic vascular inflammatory reaction termed cryoglobulinemic vasculitis.{{cite journal |vauthors=Retamozo S, Brito-Zerón P, Bosch X, Stone JH, Ramos-Casals M |year=2013 |title=Cryoglobulinemic disease |journal=Oncology (Williston Park, N.Y.) |volume=27 |issue=11 |pages=1098–1105, 1110–6 |pmid=24575538}}

Purpura seen in cryoglobulinemia may also be referred to as cryoglobulinemic purpura.{{cite journal | last1=Toyonaga | first1=Ellen | last2=Iwata | first2=Hiroaki | last3=Hotta | first3=Moeko | last4=Yoshimoto | first4=Norihiro | last5=Izumi | first5=Kentaro | last6=Shimizu | first6=Hiroshi | title=Keep It Cool: Cryoglobulinemic Purpura | journal=The American Journal of Medicine | publisher=Elsevier BV | volume=129 | issue=11 | year=2016 | issn=0002-9343 | doi=10.1016/j.amjmed.2016.08.002 | pages=1163–1165| pmid=27566501 }}

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.

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.{{cite web |url = https://www.uptodate.com/contents/overview-of-cryoglobulins-and-cryoglobulinemia |title = Overview of cryoglobulins and cryoglobulinemia |website = www.uptodate.com |access-date = August 31, 2017 }}

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. Skin findings in type 1 disease are closely linked to external or ambient cold temperatures.

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).{{cite journal |vauthors = Muchtar E, Magen H, Gertz MA |title = How I treat cryoglobulinemia |journal = Blood |volume = 129 |issue = 3 |pages = 289–298 |year = 2017 |pmid = 27799164 |doi = 10.1182/blood-2016-09-719773 |doi-access = free }} 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. Skin findings in type 2 and 3 disease are usually precipitated by physical exertion or standing.

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.{{citation needed|date=November 2022}} The cryoglobulin compositions and disorder associations in cryoglobulinemic disease are as follows:

• Monoclonal IgM-based cryoglobulin occurs in cases of Waldenström's macroglobulinemia and the pre-malignant precursors to this cancer, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenstrom's macroglobulinemia.
• Monoclonal IgG or, rarely, IgA, κ light chain, or λ light chain cryoglobulins occur in cases of multiple myeloma and the pre-malignant precursors to this cancer, non-IgM monoclonal gammopathy of undetermined significance and non-IgM smoldering multiple myeloma. Non-IgM monoclonal immunoglobulin-based cases of cryoglobulinemic disease are less commonly associated with other B-cell lymphocytic diseases viz., Non-Hodgkin lymphoma, Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and Castleman disease; they occur rarely in non-B cell hematological disorders such as myelodysplastic syndromes and chronic myelogenous leukemia. Among these purely monoclonal immunoglobulin causes of cryoglobulinemic disease, Waldenström macroglobulinemia and multiple myeloma together account for ≈40% of cases; their pre-malignant precursors account for ≈44% of cases; and the other cited hematological diseases account for ≈16% of cases.{{cite journal |vauthors=Ghetie D, Mehraban N, Sibley CH |year=2015 |title=Cold hard facts of cryoglobulinemia: updates on clinical features and treatment advances |journal=Rheumatic Disease Clinics of North America |volume=41 |issue=1 |pages=93–108, viii-ix |doi=10.1016/j.rdc.2014.09.008 |pmid=25399942}}
• 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. In these mixed-protein depositions, the monoclonal or polyclonal IgM typically possesses rheumatoid factor activity, and therefore binds to the Fc region of polyclonal IgG antibodies, activates the blood complement system, and complexes with complement components to form precipitates composed of IgM, IgG or IgG, and complement components, particularly complement component 4 (C4).
• In mixed disease (type 2 or 3 cryoglobulinemia) over 50% of cases are due to systemic lupus erythematosus and Sjogren's syndrome and less commonly other autoimmune diseases. Hepatitis C is less prevalent as a cause of mixed disease owing to effective viral treatments for hepatitis C. Successful cure of hepatitis C usually resolves type 2 or 3 mixed cryoglobulinemic disease. However, 12.6% of people may have relapsed cryoglobulinemic disease after treatment of hepatitis C. In this case, persistent circulating cryoglobulins after successful hepatitis C treatment indicates persistent disease.

Cryoglobulinemia and cryoglobulinemic disease must be distinguished from cryofibrinogenemia or cryofibrinogenemic disease, conditions that involve the cold-induced intravascular deposition of circulating native fibrinogens.{{cite journal |vauthors = Michaud M, Pourrat J |title = Cryofibrinogenemia |journal = Journal of Clinical Rheumatology |volume = 19 |issue = 3 |pages = 142–8 |year = 2013 |pmid = 23519183 |doi = 10.1097/RHU.0b013e318289e06e }}{{cite journal |vauthors = Caimi G, Carlisi M, Urso C, Lo Presti R, Hopps E |title = Clinical disorders responsible for plasma hyperviscosity and skin complications |journal = European Journal of Internal Medicine |volume = 42 |pages = 24–28 |year = 2017 |pmid = 28390781 |doi = 10.1016/j.ejim.2017.04.001 }} These molecules precipitate at lower temperatures (e.g., 4 °C). Since cryo fibrinogens are present in plasma but greatly depleted in serum, precipitation tests for them are positive in plasma but negative in serum. Cryofibrinogenemia is occasionally found in cases of cryoglobulinemic disease.{{cite journal |vauthors = Grada A, Falanga V |title = Cryofibrinogenemia-Induced Cutaneous Ulcers: A Review and Diagnostic Criteria |journal = American Journal of Clinical Dermatology |volume = 18 |issue = 1 |pages = 97–104 |year = 2017 |pmid = 27734332 |doi = 10.1007/s40257-016-0228-y |s2cid = 39645385 }} 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.

Rheumatoid factor is a sensitive test for cryoglobulinemia. The precipitated cryoglobulins are examined by immunoelectrophoresis and immunofixation to detect and quantify the presence of monoclonal IgG, IgM, IgA, κ light chain, or λ light chain immunoglobins. Other routine tests include measuring blood levels of rheumatoid factor activity, complement C4, other complement components, and hepatitis C antigen. Biopsies of skin lesions and, where indicated, kidney or other tissues can help in determining the nature of the vascular disease (immunoglobulin deposition, cryoglobulinemic vasculitis, or, in cases showing the presence of cryofibrinogenemia, fibrinogen deposition. In all events, further studies to determine the presence of hematological, infections, and autoimmune disorders are conducted on the basis of these findings as well as each case's clinical findings.

All patients with symptomatic cryoglobulinemia are advised to protect their extremities from exposure to cold temperatures, especially refrigerators, freezers, and air-conditioning. Such exposure to these can be very dangerous.

Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection. Those with a history of recent infection who also have a spontaneous and full resolution of their cryoglobulinemia need no further treatment. Individuals without a history of infection and not showing resolution of their cryoglobulinemia need to be further evaluated. Their cryoglobulins should be analyzed for immunoglobulin type(s) and complement component(s) and assessed for the presence of premalignant and malignant diseases associated with Type I disease, as well as infectious and autoimmune diseases associated with Type II and Type III disease. A study conducted in Italy on more than 140 asymptomatic individuals found five cases of hepatitis C-related and one case of Hepatitis B-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases.{{cite journal |vauthors = Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, Sarzi-Puttini P, Quartuccio L, De Vita S, Galli M |title = Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study |journal = Autoimmunity Reviews |volume = 13 |issue = 6 |pages = 609–14 |year = 2014 |pmid = 24418294 |doi = 10.1016/j.autrev.2013.11.005 }} 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.

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{{verify spelling|date=September 2022|reason=incidence is normally used only in the singular form, perhaps incidence, incidents, or instances was intended}} 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 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: a 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.

• Cryofibrinogenemia
• Cryoglobulinemic vasculitis
• Dysfibrinogenemia
• Hematopoietic ulcer
• Hyperviscosity syndrome
• Paraproteinemia
• Plasma cell dyscrasias

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{{Medical resources

| DiseasesDB = 3207

| ICD10 = {{ICD10|D|89|1|d|80}}

| ICD9 = {{ICD9|273.2}}

| ICDO =

| OMIM =

| MedlinePlus = 000540

| eMedicineSubj = med

| eMedicineTopic = 480

| MeshID = D003449

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{{Commons category|Cryoglobulinemia}}

{{Immunoproliferative immunoglobulin disorders}}

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Category:Hepatitis C virus-associated diseases

Category:Medical diagnosis

Category:Medical signs