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| | {{SI}} |
| | {{Infobox medical condition |
| | | name = Cryoglobulinemia |
| | | image = [[File:Cryoglobulinemia2.jpg|left|thumb|Cryoglobulinemia]] |
| | | caption = Cryoglobulinemia can cause a variety of symptoms due to the precipitation of proteins in the blood. |
| | | field = [[Rheumatology]] |
| | | symptoms = [[Purpura]], [[arthralgia]], [[weakness]], [[Raynaud's phenomenon]], [[glomerulonephritis]] |
| | | complications = [[Renal failure]], [[peripheral neuropathy]], [[skin ulcers]] |
| | | onset = Variable |
| | | duration = Chronic |
| | | causes = [[Hepatitis C]], [[autoimmune diseases]], [[lymphoproliferative disorders]] |
| | | risks = [[Chronic hepatitis]], [[autoimmune disorders]], [[lymphoma]] |
| | | diagnosis = [[Blood test]] for cryoglobulins, [[serology]], [[biopsy]] |
| | | differential = [[Vasculitis]], [[multiple myeloma]], [[cold agglutinin disease]] |
| | | treatment = [[Corticosteroids]], [[immunosuppressants]], [[plasmapheresis]], [[antiviral therapy]] |
| | | prognosis = Variable, depends on underlying cause |
| | | frequency = Rare |
| | }} |
| | [[File:Cryoglobulinemia2.jpg|Cryoglobulinemia|left|thumb]] |
| {{Use mdy dates|date=August 2017}} | | {{Use mdy dates|date=August 2017}} |
| {{Use American English|date=August 2017}} | | {{Use American English|date=August 2017}} |
| | | '''Cryoglobulinemia''' is a medical condition characterized by the presence of abnormal proteins, known as cryoglobulins, in the [[blood]]. These proteins precipitate at cold temperatures and dissolve when warmed. Cryoglobulinemia can cause various health issues, including inflammation, organ damage, and blood vessel blockage, leading to severe complications such as tissue necrosis and gangrene. |
| '''Cryoglobulinemia''' is a medical condition in which the blood contains large amounts of [[pathological cold sensitive antibodies]] called [[cryoglobulin]]s – proteins (mostly [[antibody|immunoglobulins]] themselves) that become [[Solubility|insoluble]] at reduced temperatures.<ref>{{DorlandsDict|two/000025728|Cryoglobulinemia}}</ref> This should be contrasted with [[cold agglutinin disease|cold agglutinins]], which cause agglutination of [[red blood cell]]s. | | This condition is distinct from cold agglutinin disease, which involves different immune system processes that affect red blood cells. While some individuals with cryoglobulinemia may have no symptoms, others develop serious complications requiring medical intervention. |
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| Cryoglobulins typically [[Precipitation (chemistry)|precipitate]] (clumps together) at temperatures below normal body temperature{{snd}}{{convert|37|C|F|abbr=off}}{{snd}}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.<ref name="pmid24575538">{{cite journal |vauthors = Retamozo S, Brito-Zerón P, Bosch X, Stone JH, Ramos-Casals M |title = Cryoglobulinemic disease |journal = Oncology (Williston Park, N.Y.) |volume = 27 |issue = 11 |pages = 1098–1105, 1110–6 |year = 2013 |pmid = 24575538 |doi = |url = }}</ref>
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| 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 disease|infectious]], or [[autoimmune disease|autoimmune]] diseases that are the underlying cause for production of the cryoglobulins.<ref name="pmid24575538" /><ref name="pmid25399942">{{cite journal |vauthors = Ghetie D, Mehraban N, Sibley CH |title = Cold hard facts of cryoglobulinemia: updates on clinical features and treatment advances |journal = Rheumatic Diseases Clinics of North America |volume = 41 |issue = 1 |pages = 93–108, viii–ix |year = 2015 |pmid = 25399942 |doi = 10.1016/j.rdc.2014.09.008 |url = }}</ref>
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| | | == '''Types of Cryoglobulinemia''' == |
| == Classification == | | Cryoglobulinemia is classified into three main types based on the composition of the cryoglobulins and their association with other diseases: |
| | |
| Since the first description of cryoglobulinemia in association with the clinical triad of skin [[purpura]], [[arthralgia|joint pain]], and [[asthenia|weakness]] by Meltzer et al. in 1967, the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia, that is 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.<ref name="pmid4216269">{{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 }}</ref> The classification distinguishes three subtypes of cryoglobulinemic diseases based on two factors, the class of immunoglobulins in the cryoglobulin and the association of the cryoglobulinemic disease with other disorder. The following table lists these three types of cryoglobulinemic disease, characterized on the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, percentage of total cryoglobulinemic disease cases, and class of disorders associated for each type.<ref name="Ferri2002">{{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 }}</ref><ref>{{DorlandsDict|two/000025727|Cryoglobulin}}</ref>
| |
| | |
| {| class="wikitable" | | {| class="wikitable" |
| |- | | |- |
| ! Type | | ! Type |
| ! Composition | | ! Composition |
| ! Percent of cases
| | ! Association with Other Diseases |
| ! Association with other diseases | |
| |- | | |- |
| | Type I | | | Type I |
| | [[Monoclonal]] IgG, IgM, IgA, or [[Immunoglobulin light chain|their κ or λ light chains]] | | | Monoclonal IgG, IgM, or IgA |
| | 10–15% | | | Hematologic malignancies, such as [[multiple myeloma]], [[Waldenström's macroglobulinemia]], and chronic lymphocytic leukemia. |
| | Hematological diseases, particularly [[plasma cell dyscrasias#MGUS stage|MGUS]], [[smoldering multiple myeloma]], [[multiple myeloma]], [[Waldenström's macroglobulinemia]], and [[B-cell chronic lymphocytic leukemia|chronic lymphocytic leukemia]]<ref name="pmid17289231">{{cite journal |vauthors = Tedeschi A, Baratè C, Minola E, Morra E |title = Cryoglobulinemia |journal = Blood Reviews |volume = 21 |issue = 4 |pages = 183–200 |year = 2007 |pmid = 17289231 |doi = 10.1016/j.blre.2006.12.002 |url = }}</ref><ref name="item11" />
| |
| |- | | |- |
| | Type II | | | Type II |
| | Monoclonal IgM plus polyclonal IgG or, rarely, IgA | | | Monoclonal IgM and polyclonal IgG |
| | 50–60%
| | | Chronic infections (e.g., [[Hepatitis C]], [[HIV]]), autoimmune diseases (e.g., [[Sjögren syndrome]], [[rheumatoid arthritis]]). |
| | Infectious diseases, particularly [[hepatitis C]] infection, [[HIV]] infection, and [[Hepatitis C and HIV coinfection]]; hematological diseases particularly B cell disorders; autoimmune diseases<ref name="pmid17289231" /><ref name="item11" /> | |
| |- | | |- |
| | Type III | | | Type III |
| | Polyclonal IgM plus polyclonal IgG or IgA | | | Polyclonal IgM and IgG |
| | 25–30%
| | | Autoimmune diseases (e.g., [[systemic lupus erythematosus]], [[rheumatoid arthritis]]), chronic infections. |
| | [[Autoimmune disease]]s, particularly [[Sjögren syndrome]] and less commonly [[systemic lupus erythematosus]] and [[rheumatoid arthritis]]; infectious diseases particularly [[Hepatitis C virus|HCV]] infection<ref name="pmid17289231" /><ref name="item11" /> | |
| |} | | |} |
| | | Both Type II and Type III are often referred to as mixed cryoglobulinemia, as they involve immune complex formation and inflammation of blood vessels, leading to cryoglobulinemic vasculitis. |
| The monoclonal or polyclonal IgM proteins involved in Types II and III cryoglobulinemic disease have [[rheumatoid factor]] activity. That is, they bind to polyclonal immunoglobulins, activate the blood [[complement system]], and thereby 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 complement can cause a clinical syndrome of [[cutaneous small-vessel vasculitis]] characterized by systemic vasculitis and inflammation termed [[cryoglobulinemic vasculitis]].<ref name="pmid28507447">{{cite journal |vauthors = Ostojic P, Jeremic IR |title = Managing refractory cryoglobulinemic vasculitis: challenges and solutions |journal = Journal of Inflammation Research |volume = 10 |issue = |pages = 49–54 |year = 2017 |pmid = 28507447 |pmc = 5428757 |doi = 10.2147/JIR.S114067 |url = }}</ref> Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease.<ref name="item11">{{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 }}</ref> The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity.<ref name="pmid28507447" />
| | == '''Causes and Risk Factors''' == |
| | | Cryoglobulinemia is often associated with underlying conditions that trigger the production of abnormal proteins. Some common causes include: |
| More recent high resolution [[Gel electrophoresis of proteins|protein electrophoresis]] methods have detected a small monoclonal immunoglobulin component in type III cryoglobulins and/or a micro-heterogeneous composition of oligo-clonal (i.e., more than one monoclonal) immunoglobulin components or immunoglobulins with structures that do not fit into any classifications in the cryoglobulins of ≈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 and that some of the type III cases associated with the expression of low levels of a one or more [[isotype (immunology)|isotypes]] of circulating monoclonal immunoglobulin(s) are in transition to type II disease.<ref name="pmid17289231" /><ref name="item12">{{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 }}</ref>
| | * Hematologic Disorders – Blood cancers such as [[multiple myeloma]], [[Waldenström's macroglobulinemia]], and B-cell lymphoma. |
| | | * Infections – Particularly chronic viral infections such as Hepatitis C, [[HIV]], and Hepatitis B. |
| == Signs and symptoms == | | * Autoimmune Diseases – Conditions like Sjögren syndrome, [[systemic lupus erythematosus]], and [[rheumatoid arthritis]]. |
| | | * Chronic Inflammatory Disorders – Persistent immune activation can contribute to cryoglobulin formation. |
| 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:
| | == '''Signs and Symptoms''' == |
| *'''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]]; | | Symptoms of cryoglobulinemia vary widely depending on the type and severity of the condition. Common clinical manifestations include: |
| *'''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;
| | 1. Vascular Symptoms |
| *'''c)''' in type II and type III disease, deposit on the epithelium of blood vessels and activate the blood complement system to form pro-inflammatory elements such as [[Complement component 5a|C5a]] thereby initiating the systemic vascular inflammatory reaction termed [[cryoglobulinemic vasculitis]].<ref name="pmid24575538" /><ref name="pmid28507447" /> | | * Raynaud's phenomenon – Reduced blood flow to fingers and toes in response to cold. |
| | | * Purpura – Red or purple skin discoloration due to small blood vessel inflammation. |
| === Essential cryoglobulinemic disease ===
| | * Livedo reticularis – A lace-like purplish skin discoloration caused by blood vessel abnormalities. |
| | | * Ulcers and gangrene – Tissue damage from blocked blood flow. |
| 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.<ref name="pmid28507447" /><ref>{{cite web |url = https://www.uptodate.com/contents/overview-of-cryoglobulins-and-cryoglobulinemia |title = Overview of cryoglobulins and cryoglobulinemia |author = |date = |website = www.uptodate.com |accessdate = August 31, 2017 }}</ref>
| | 2. Joint and Muscle Symptoms |
| | | * Arthralgia – Joint pain, often in the hands and knees. |
| === Type I cryoglobulinemic disease ===
| | * Myalgia – Muscle pain due to poor blood circulation and inflammation. |
| | | 3. Neurological Symptoms |
| Signs and symptoms due to the cryoglobulins of type I disease reflect the [[Hyperviscosity syndrome|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]], [[acrocyanosis|blue discoloration of the arms or legs (acrocyanosis)]], necrosis, ulcers, and [[livedo reticularis]]; spontaneous [[Epistaxis|nose bleeds]], [[arthralgia|joint pain]], [[membranoproliferative glomerulonephritis]]; and cardiovascular disturbances such as shortness of breath, [[hypoxemia|inadequate levels of oxygen in the blood (hypoxemia)]], and [[congestive heart failure]].<ref name="pmid24575538" /><ref name="pmid28507447" />
| | * Peripheral neuropathy – Numbness, tingling, or weakness in hands and feet. |
| | | * Dizziness or confusion – Due to reduced blood supply to the brain. |
| === Types II and III cryoglobulinemic disease === | | 4. Kidney Involvement |
| | | * Glomerulonephritis – Inflammation of the kidneys, leading to proteinuria, hematuria, and hypertension. |
| Types II and III (or mixed or variant) cryoglobulinemic disease may also present with symptoms and signs of blood hyperviscosity syndrome and deposition of cryoglobulins within blood vessels but also include those attributable to cryoglobulinemic vasculitis. "[[Meltzer's triad]]" of palpable [[purpura]], [[arthralgia|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 (see attached photograph); 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]], [[Raynaud phenomenon]] (i.e., episodic painful reductions in blood flow to the fingers and toes).<ref name="pmid28507447" /><ref name="pmid27799164">{{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 |url = |doi-access = free }}</ref> 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.<ref name="pmid27799164" /> The hematological, infectious, and autoimmune diseases underlying type II cryoglobulinemic disease and the infectious and autoimmune diseases underlying type III cryoglobulinemic disease are also critical parts of the disease's clinical findings.
| | 5. Systemic Symptoms |
| | | * Chronic fatigue |
| == Mechanism==
| | * Fever |
| | | * Weight loss |
| === Cryoglobulins ===
| | == '''Diagnosis''' == |
| | | Diagnosis of cryoglobulinemia involves a combination of clinical evaluation, laboratory tests, and imaging studies. The following tests help confirm the condition: |
| Cryoglobulins consists of one or more of the following components: [[Monoclonal antibody|monoclonal]] or [[Polyclonal antibodies|polyclonal]] [[IgM]], [[IgG]], [[IgA]] antibodies, monoclonal [[Immunoglobulin light chain|κ]], or [[Immunoglobulin light chain|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 which 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:
| | * Cryoglobulin Test – Detects the presence of cryoglobulins in the blood. |
| * Monoclonal IgM-based cryogloblin occurs in cases of [[Waldenström's macroglobulinemia]] and the pre-malignant precursors to this cancer, [[plasma cell dyscrasia#IgM MGUS|IgM monoclonal gammopathy of undetermined significance]] and [[plasma cell dyscrasia#smoldering Waldenstrom's macroglobulinemia|smoldering Waldenstrom's macroglobulinemia]].<ref name="pmid24575538" /> | | * Rheumatoid Factor (RF) – Often positive in Type II and Type III cryoglobulinemia. |
| * 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 syndrome]]s and [[chronic myelogenous leukemia]].<ref name="pmid17289231" /> 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.<ref name="pmid24575538" /><ref name="pmid25399942" /> | | * Complement Levels – Low C4 levels suggest immune complex activation. |
| * 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]], [[Acute proliferative glomerulonephritis|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 disease]]s, and others.<ref name="pmid17289231" /> In these mixed-protein depositions, the monoclonal or polyclonal IgM typically possesses [[rheumatoid factor]] activity and therefore binds to the [[Antibody#CDRs, Fv, Fab and Fc regions|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).<ref name="pmid25399942" /> | | * Hepatitis C and Hepatitis B Testing – To check for viral infections. |
| | | * Kidney Function Tests – Includes urinalysis and serum creatinine levels. |
| == Diagnosis == | | * Tissue Biopsy – Skin or kidney biopsy may reveal cryoglobulin deposits and vasculitis. |
| Cryoglobulinemia and cryoglobulinemic disease must be distinguished from [[cryofibrinogenemia]] or cryofibrinogenemic disease, conditions which involve the cold-induced intravascular deposition of circulating native fibrinogens.<ref name="pmid23519183">{{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 |url = }}</ref><ref name="pmid28390781">{{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 |issue = |pages = 24–28 |year = 2017 |pmid = 28390781 |doi = 10.1016/j.ejim.2017.04.001 |url = }}</ref> The cryoglobulins in [[Blood plasma|plasma]] or [[serum (blood)|serum]] 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.<ref name="pmid28390781" /> Cryofibrinogenemia is occasionally found in cases of cryoglobulinemic disease.<ref name="pmid27734332">{{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 |url = }}</ref> 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 [[Thrombophilia|hypercoagulable states]].<ref name="pmid27734332" />
| | == '''Treatment''' == |
| | | The treatment of cryoglobulinemia depends on the severity of symptoms and the underlying cause. |
| [[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#serology|hepatitic 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 cryfibrinogenemia, 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 cases clinical findings.<ref name="pmid24575538" /><ref name="pmid27799164" /><ref name="pmid27734332" />
| | 1. Management of Underlying Disease |
| | | * If associated with Hepatitis C, antiviral therapy is the primary treatment. |
| == Treatment == | | * Blood cancers such as multiple myeloma require chemotherapy or immunotherapy. |
| | | * Autoimmune-related cryoglobulinemia is treated with immunosuppressive medications. |
| All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.<ref name="pmid27799164" /><ref name="pmid23519183" />
| | 2. Immunosuppressive Therapy |
| | | For patients with severe symptoms, treatment may include: |
| === Asymptomatic cryoglobulinemia ===
| | * Corticosteroids – Reduce inflammation in cryoglobulinemic vasculitis. |
| | | * Rituximab – A monoclonal antibody targeting B-cells, used in Type II and Type III disease. |
| 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 that 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 their composition of immunoglobulin type(s) and complement component(s) and examined for the presence of the premalignant and malignant diseases associated with Type I disease as well as the infectious and autoimmune diseases associated with type II and type III disease.<ref name="pmid27799164" /> A study conducted in Italy on >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.<ref name="pmid24418294">{{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 |url = }}</ref> 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.<ref name="pmid24418294" />
| | * Cyclophosphamide or Azathioprine – Used in refractory cases. |
| | | 3. Plasma Exchange (Plasmapheresis) |
| === Severely symptomatic cryoglobulinemic disease ===
| | * Used in severe cases with life-threatening hyperviscosity, kidney failure, or severe vasculitis. |
| | | * Removes circulating cryoglobulins to prevent organ damage. |
| 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 [[Mesenteric ischemia|intestinal ischemia]], intestinal perforation, [[cholecystitis]], or [[pancreatitis]], causing acute abdominal pain, general malaise, fever, and/or [[hematochezia|bloody bowel movements]]; vasculitis-driven pulmonary disturbances (e.g., [[hemoptysis|coughing up blood]], [[acute respiratory failure]], X-ray evidence of diffuse [[pulmonary infiltrate]]s caused by [[Pulmonary hemorrhage#Diffuse alveolar hemorrhage|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 [[corticosteroid]]s (e.g., [[dexamethasone]]) and/or [[immunosuppressive drug|immunosuppressive]] drugs. Cases where no underlying disease is known are also often treated with the latter corticosteroid and immunosuppressive medications.<ref name="pmid24575538" /><ref name="pmid17289231" /><ref name="pmid23519183" />
| | 4. Supportive Care |
| | | * Avoid cold exposure – Prevents precipitation of cryoglobulins. |
| === Type I cryoglobulinemic disease === | | * Pain management – NSAIDs or acetaminophen for joint and muscle pain. |
| 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 macroglobulonemia).<ref name="pmid27799164" /><ref name="pmid23519183" />
| | * Antihypertensive medications – For patients with renal involvement. |
| | | == '''Complications''' == |
| === Type II and III cryoglobulinemic disease === | | If left untreated, cryoglobulinemia can lead to serious complications, including: |
| | | * Permanent nerve damage due to peripheral neuropathy. |
| 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.<ref name="pmid28507447" /> The most effective therapy for hepatitis C-associated cryoglobulinemic disease consists of a combination of anti-viral drugs, [[Peginterferon-alfa|pegylated INFα]] and [[ribavirin]]; depletion of [[B cell]]s 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.<ref name="pmid24575538" /><ref name="pmid27799164" /> 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 drug]]s to the therapeutic regimen may improve results.<ref name="pmid27799164" /> 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.<ref name="pmid24575538" /><ref name="pmid27799164" />
| | * Kidney failure from glomerulonephritis. |
| | | * Severe skin ulcers and gangrene due to vascular obstruction. |
| == See also == | | * Life-threatening infections in immunosuppressed patients. |
| | | == '''Prognosis''' == |
| | The outlook for patients with cryoglobulinemia varies depending on the underlying cause and the effectiveness of treatment. Patients with mild disease often have a good prognosis, while those with severe organ involvement may require long-term medical care. |
| | == '''Prevention''' == |
| | There is no direct way to prevent cryoglobulinemia, but reducing risk factors can help: |
| | * Early treatment of infections such as Hepatitis C. |
| | * Regular monitoring in patients with autoimmune diseases or hematologic disorders. |
| | * Avoidance of cold exposure for individuals with known cryoglobulinemia. |
| | == '''See Also''' == |
| | * [[Cryoglobulin]] |
| * [[Cryofibrinogenemia]] | | * [[Cryofibrinogenemia]] |
| * [[Cryoglobulinemic purpura]]
| |
| * [[Cryoglobulinemic vasculitis]] | | * [[Cryoglobulinemic vasculitis]] |
| * [[Dysfibrinogenemia]]
| |
| * [[Hematopoietic ulcer]]
| |
| * [[Hyperviscosity syndrome]] | | * [[Hyperviscosity syndrome]] |
| * [[Paraproteinemia]] | | * [[Autoimmune disease]] |
| * [[Plasma cell dyscrasias]] | | * [[Multiple myeloma]] |
| | | * [[Hepatitis C]] |
| == References == | | == '''External Links''' == |
| | |
| {{Reflist}}
| |
| | |
| == External links ==
| |
| {{Medical resources | | {{Medical resources |
| | DiseasesDB = 3207 | | | DiseasesDB = 3207 |
| | ICD10 = {{ICD10|D|89|1|d|80}} | | | ICD10 = {{ICD10|D|89|1|d|80}} |
| | ICD9 = {{ICD9|273.2}} | | | ICD9 = {{ICD9|273.2}} |
| | ICDO = | | | MedlinePlus = 000540 |
| | OMIM =
| | | eMedicineSubj = med |
| | MedlinePlus = 000540
| | | eMedicineTopic = 480 |
| | eMedicineSubj = med | | | MeshID = D003449 |
| | eMedicineTopic = 480 | |
| | MeshID = D003449 | |
| }} | | }} |
|
| |
| {{Commons category|Cryoglobulinemia}} | | {{Commons category|Cryoglobulinemia}} |
|
| |
| {{Immunoproliferative immunoglobulin disorders}} | | {{Immunoproliferative immunoglobulin disorders}} |
| {{authority control}}
| | [[Category:Hematologic disorders]] |
| | | [[Category:Autoimmune diseases]] |
| [[Category:Hepatitis C virus-associated diseases]] | | [[Category:Infectious disease-related disorders]] |
| [[Category:Medical diagnosis]] | | [[Category:Medical emergencies]] |
| [[Category:Medical signs]] | | [[Category:Vasculitis]] |
