Materiały źródłowe

• #1 Cryoglobulinemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557606/

  Cryoglobulinemia is a rare medical condition characterized by the presence of abnormal proteins called cryoglobulins in the blood, which precipitate or clump together at low temperatures. […] These cryoglobulins, composed of immunoglobulins and sometimes complement components, deposit in small- to medium-sized blood vessels throughout the body, causing endothelial injury and end-organ damage. […] Chronic immune stimulation and lymphoproliferation lead to increased production of higher levels of mono-, oligo-, or polyclonal immunoglobulins, which subsequently form cryoglobulins. […] These cryoglobulins circulate in the blood and can precipitate, forming immune complexes that deposit in small- to medium-sized blood vessels, leading to vascular occlusion and inflammation. […] The deposition triggers an inflammatory response, causing endothelial cell injury and attracting immune cells such as lymphocytes and macrophages to the site.

• #2 Cryoglobulinemic vasculitis: pathophysiological mechanisms and diagnosis – PubMed

  https://pubmed.ncbi.nlm.nih.gov/33186245/

  Cryoglobulins (CG) are immunoglobulins that precipitate in the cold, and dissolve at 37C. In vivo, in cold exposed tissues and organs, they can induce vasculitis and occlusive vasculopathy after deposition on vascular endothelium under low temperature and high concentration conditions. […] The mechanisms of vascular lesions of pathogenic CG in function of CG type and their characteristics are better defined. […] The importance of looking for underlying diseases, especially hepatitis C virus status in mixed CG, is reminded.

• #3 Cryoglobulins: An Important but Neglected Clinical Test

  http://www.annclinlabsci.org/content/36/4/395.full

  Cryoglobulins (CRs) are special serum immunoglobulins that precipitate at temperatures 37C, but mostly at 0 4C, and that dissolve when re-warmed to 37C. The majority (95%) of CRs are immune complexes (IC) that contain rheumatoid factor (RF). Such CRs are known as mixed cryoglobulins to differentiate them from the CRs with monoclonal bands that do not contain RF or antigen-antibody complexes. The antigens present in the mixed complexes may include RNA and proteins (eg, hepatitis C virus proteins). A small fraction of CRs (5%) comprise pure monoclonal gammopathies, which have poor solubility at low temperatures because of their unique amino acid sequences. […] Mixed cryoglobulins, because of their decreased solubility in serum, tend to precipitate in the small vessels (venules, capillaries, arterioles) of the different tissues, causing a special type of vasculitis (cryoglobulinemic vasculitis). The histological hallmark of this condition is leukocytoclastic vasculitis secondary to vascular deposition of circulating CR immune-complexes and complement, together with leukocytes. Cryoglobulinemic vasculitis may involve many organs, particularly the skin, peripheral nervous system, and kidneys. The deposition of CR in and around the wall of the capillaries can lead to ischemia, infarction, and purpura. Not all patients with mixed CR develop clinical symptoms of vasculitis. CR vasculitis may or may not be accompanied by inflammatory infiltrates, typically lymphocytes. Purpura is more frequent in patients with a low cryocrit. Type II cryoglobulinemia is more associated with vasculitis. As discussed later, hepatitis C (HCV) is highly associated with type II cryoglobulinemia.

• #4 Cryoglobulinemia – Wikipedia

  https://en.wikipedia.org/wiki/Cryoglobulinemia

  Cryoglobulins consist of one or more of the following components: monoclonal or polyclonal IgM, IgG, IgA antibodies, monoclonal, or 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. […] 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).

• #5 Cryoglobulins: An Important but Neglected Clinical Test

  https://www.annclinlabsci.org/content/36/4/395.full

  Cryoglobulins (CRs) are special serum immunoglobulins that precipitate at temperatures 37C, but mostly at 0 4C, and that dissolve when re-warmed to 37C. The majority (95%) of CRs are immune complexes (IC) that contain rheumatoid factor (RF). Such CRs are known as mixed cryoglobulins to differentiate them from the CRs with monoclonal bands that do not contain RF or antigen-antibody complexes. The antigens present in the mixed complexes may include RNA and proteins (eg, hepatitis C virus proteins). A small fraction of CRs (5%) comprise pure monoclonal gammopathies, which have poor solubility at low temperatures because of their unique amino acid sequences. […] Mixed cryoglobulins, because of their decreased solubility in serum, tend to precipitate in the small vessels (venules, capillaries, arterioles) of the different tissues, causing a special type of vasculitis (cryoglobulinemic vasculitis). The histological hallmark of this condition is leukocytoclastic vasculitis secondary to vascular deposition of circulating CR immune-complexes and complement, together with leukocytes. Cryoglobulinemic vasculitis may involve many organs, particularly the skin, peripheral nervous system, and kidneys. The deposition of CR in and around the wall of the capillaries can lead to ischemia, infarction, and purpura. Not all patients with mixed CR develop clinical symptoms of vasculitis. CR vasculitis may or may not be accompanied by inflammatory infiltrates, typically lymphocytes. Purpura is more frequent in patients with a low cryocrit. Type II cryoglobulinemia is more associated with vasculitis. As discussed later, hepatitis C (HCV) is highly associated with type II cryoglobulinemia.

• #6 Cryoglobulins: An Important but Neglected Clinical Test

  http://www.annclinlabsci.org/content/36/4/395.full

  Low affinity rheumatoid factors (often K light chains) are natural polyreactive antibodies present in human serum that have specificity for IgG. The normal role of RF in the immune response is unclear but it probably aids in immune complex clearance by making complexes larger and activating complement. The RF cross-reacts with other autoantigens and binds to microorganisms covered with specific IgG antibodies, leading to agglutination and complement activation. It is postulated that HCV infects circulating B lymphocytes, stimulating them initially to synthesize polyclonal IgM RF. However, unknown factors induce a shift to abnormal proliferation of a single clone of B cells that produces monoclonal IgM-K RF, leading to type II mixed cryoglobulinemia. […] HCV is considered to be both a hepatotropic and lymphotropic virus. About 30-50% of patients with CR type II eventually develop non-Hodgkins lymphoma. Moreover, HCV-related proteins and replicative particles were detected on the peripheral lymphocytes. The HCV envelope protein E2, which is able to bind to CD81 molecule expressed on B-lymphocytes, may be involved in the first steps of HCV-driven autoimmune and lymphoproliferative phenomena. Interestingly, translocation along with Bcl-2 activation has been demonstrated in B-lymphocytes of many HCV-related cryoglobulinemias. Mixed cryoglobulinemia, renal syndromes, lymphoproliferative disorders, Sjogren syndrome, porphyria cutanea tarda, and neuropathies are all strongly associated with HCV infection. The monoclonal CR in type II can be used as a marker to predict the development of lymphomas and ulcerative-necrotic vasculitis in other disorders (eg, HIV, Sjogrens disease).

• #7 Cryoglobulinemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/329255-overview

  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. […] Alteration in protein conformation with temperature changes also leads to decreased solubility and subsequent vasculitic damage. […] 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.

• #8 Cryoglobulinemia | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/816098/all/Cryoglobulinemia

  Exact mechanism of cold insolubility in these cryoproteins is unknown. Hypotheses include reduced concentrations of sialic acid and galactose in the Fc region of Ig as well as steric conformation changes due to temperature variation. […] An underlying lymphoproliferative disorder causes monoclonal B-cell proliferation. B cells produce CG, which precipitates, causing hyperviscosity and vessel damage. […] B-cell hyperactivation or hyperproliferation (from HCV or another chronic inflammatory state) produces Ig with rheumatoid factor activity, which leads to immune complex formation. Immune complex deposition and subsequent complement activation causes small vessel damage. […] Chronic immune stimulation or lymphoproliferation resulting in the increased production of CGs.

• #9 Cryoglobulins: An Important but Neglected Clinical Test

  https://www.annclinlabsci.org/content/36/4/395.full

  The solubility of proteins depends on many factors, such as the protein concentration, hydrophobicity, size, and surface charge, as well as the solution temperature, pH, and ionic strength. Changes in the primary structure of the variable portion of Ig, and reduced concentrations of sialic acid and galactose in the Fc region of Ig, may be related to decreased solubility of CRs. Because of the high molecular weight of CR complexes (ie, mixed CR), they are less soluble and tend to precipitate at cold temperatures in vitro and in vivo. Production of IgM-RF complexes represents a crucial factor in the pathophysiology of cryoprecipitation. The formation of cryo-aggregates upon exposure to cold may be the triggering factor for vasculitis; however this does not explain why tissues (eg, kidney, nerves) that are distant from the site of exposure to cold may be affected. One explanation, suggested by in vitro studies, is that alterations of chloride concentration may influence CR structure and aggregation.

• #10 Cryoglobulinemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/329255-overview

  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. […] Types II and III, also known as the mixed cryoglobulinemias, are associated with chronic inflammatory states such as systemic lupus erythematosus (SLE), Sjgren syndrome, and viral infections (particularly HCV).

• #11 Cryoglobulinemic Disease

  https://www.cancernetwork.com/view/cryoglobulinemic-disease

  Cryoglobulinemia refers to the presence of cryoglobulins (immunoglobulins that precipitate at variable temperatures 37C [98.6F]) in serum. […] Cryoglobulinemic organ damage may be produced by two different etiopathogenic mechanisms (accumulation of cryoglobulins and autoimmune-mediated vasculitic damage); […] Type I cryoglobulinemia mainly leads to tissue damage through the occlusion of blood vessels, leading to ischemia. The proximate cause of the occlusions is the precipitation of cryoglobulins from the serum and their accumulation in the microcirculation. […] This vascular occlusion is usually accompanied by high cryoglobulin concentrations and may be clinically associated with hyperviscosity syndrome and cold-induced necrotic acral lesions. […] Immune complex-mediated vasculitis is the key etiopathogenic pathway of damage in MC. The monoclonal IgM component of MC generates large immune complexes containing IgG and complement proteins.

• #12 Cryoglobulinemia and cryoglobulinemic vasculitis: etiological aspects and pathophysiological associations | Golovach | Modern Rheumatology Journal

  https://mrj.ima-press.net/mrj/article/view/997/0?locale=en_US

  The pathogenetic role of cryoglobulins in inducing vasculitis is associated with both leukocyte recruitment to the vessels and deposition of immune complexes, with complement system activation and microvascular damage. […] The pathogenesis of MCG is associated with B-cell lymphoproliferation, autoantibody production, immunoglobulin synthesis, rheumatoid factor activity and the subsequent formation of cryoprecipitated immune complexes in conjunction with ineffective cryoglobulin clearance by monocytes and/or macrophages.

• #13 Cryoglobulinemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557606/

  In addition, the immune complexes activate the complement system, further contributing to inflammation and tissue damage. […] For mixed cryoglobulinemia there is a role of genetic factors like the presence of BAFF (B-lymphocyte activating factor) and Fc receptor variants, especially in Hepatitis C infected individuals. […] It is hypothesized that Hepatitis C envelope protein E2 can bind with the B lymphocyte CD81 receptor, thereby acting as an antigenic stimulus. […] This leads to the formation of antibodies and the resulting antigen-antibody complexes that get deposited in vessel walls. […] Few cases of sustained vasculitis despite viral clearance indicate that the B cell clones persist despite antigen clearance. […] It was also observed that B cell-activating factor (BAFF) levels increase despite the completion of antiviral treatment in patients with HCV leading to relapses.

• #14

  https://step2.medbullets.com/rheumatology/120645/mixed-cryoglobulinemia

  Hyperviscosity syndrome resulting from cryoglobulins (single or mixed immunoglobulins) in the blood […] Pathogenesis […] proteins, mainly immunoglobulins, precipitate at cold temperatures […] IgM antibody (but different from cold agglutinin disease) deposition […] often against anti-hepatitis C IgG […] precipitated clumps can block blood vessels.

• #15 A Case of Cryoglobulinemia after Successful Hepatitis C Virus Treatment

  https://clinmedjournals.org/articles/jcnrc/journal-of-clinical-nephrology-and-renal-care-jcnrc-6-050.php?jid=jcnrc

  Mixed cryoglobulinemia is associated with HCV in 70% to 90% of cases. Less than 100 cases of mixed cryoglobulinemic vasculitis following SVR after HCV infection have been reported in the literature. Although not determined, the mechanism of the immune response in such cryoglobulinemic vasculitis may involve impaired cryoglobulin clearance from past infection or persistent inactive HCV antigens.

• #16 Prevalence of cryoglobulinemia and cryoglobulinemic vasculitis in chronically HCV-infected Brazilian patients | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-avance-resumen-prevalence-cryoglobulinemia-cryoglobulinemic-vasculitis-in-S1665268119303370

  Cryoglobulinemia is one of the most frequent extrahepatic manifestations of chronic hepatitis C virus (HCV) infection and it may evolve to cryoglobulinemic vasculitis (CryoVas) which is a systemic vasculitis that affects small-sized vessels. […] Cryoglobulinemic vasculitis (CryoVas) is a systemic vasculitis that affects predominantly small-vessels, especially in the skin, joints, peripheral nerves and kidneys. […] Cryoglobulinemia is the consequence of the chronic proliferation of B-cells, that produces pathogenic IgG and IgM immunoglobulin (Ig) isotypes with rheumatoid factor activity. […] Almost 80% of CryoVas cases are secondary to chronic HCV infection, but lymphoproliferative disorders, autoimmune diseases and other infections are also possible etiologies for cryoglobulinemia and CryoVas.

• #17 Mechanisms Involved in the Pathogenesis of Cryoglobulinemia in Patients with Chronic Hepatitis C and Other Causes of Chronic Liver Diseases | SpringerLink

  https://link.springer.com/chapter/10.1007/978-4-431-68255-4_54

  The purpose of this study was to investigate the mechanisms involved in the pathogenesis of cryoglobulinemia (CG) in patients with chronic liver diseases. […] CG was found in 54% of patients with hepatitis C, 14% of patients with hepatitis B, and in 32% of patients with chronic LD. […] However, CG was found more often in patients with HCV infection, and in 30% of noncirrhotic patients with chronic hepatitis C, suggesting that liver injury is not the only cause of CG. […] Furthermore, CG became undetectable in 10/25 patients treated with interferon. […] In conclusion, mechanisms by which CG are generated are probably multifactorial. Our results suggest that HCV may be responsible for the production of CG independently of the severity of liver damage.

• #18 Cryoglobulins: An Important but Neglected Clinical Test

  https://www.annclinlabsci.org/content/36/4/395.full

  Low affinity rheumatoid factors (often K light chains) are natural polyreactive antibodies present in human serum that have specificity for IgG. The normal role of RF in the immune response is unclear but it probably aids in immune complex clearance by making complexes larger and activating complement. The RF cross-reacts with other autoantigens and binds to microorganisms covered with specific IgG antibodies, leading to agglutination and complement activation. It is postulated that HCV infects circulating B lymphocytes, stimulating them initially to synthesize polyclonal IgM RF. However, unknown factors induce a shift to abnormal proliferation of a single clone of B cells that produces monoclonal IgM-K RF, leading to type II mixed cryoglobulinemia. […] HCV is considered to be both a hepatotropic and lymphotropic virus. About 30-50% of patients with CR type II eventually develop non-Hodgkins lymphoma. Moreover, HCV-related proteins and replicative particles were detected on the peripheral lymphocytes. The HCV envelope protein E2, which is able to bind to CD81 molecule expressed on B-lymphocytes, may be involved in the first steps of HCV-driven autoimmune and lymphoproliferative phenomena. Interestingly, translocation along with Bcl-2 activation has been demonstrated in B-lymphocytes of many HCV-related cryoglobulinemias. Mixed cryoglobulinemia, renal syndromes, lymphoproliferative disorders, Sjogren syndrome, porphyria cutanea tarda, and neuropathies are all strongly associated with HCV infection. The monoclonal CR in type II can be used as a marker to predict the development of lymphomas and ulcerative-necrotic vasculitis in other disorders (eg, HIV, Sjogrens disease).

• #19 Relationship Between Cryoglobulinemia-associated Nephritis and HCV – Page 2

  https://www.medscape.com/viewarticle/580491_2

  It is presently believed that HCV infects B lymphocytes while infecting hepatocytes due to the shared expression of CD81 receptors. Lymphocytes that are chronically stimulated by HCV are prone to widespread autoantibody production related to HCV-induced lowering of the cell-activation threshold. This favors the development of a number of immune manifestations associated with HCV infection, which are variously assembled in clinical pictures we collectively call the 'HCV syndrome’. […] The pathogenetic implication of HCV in the formation, transport and removal from the circulation of cryoprecipitable immune complexes (ICs) in MC has been studied extensively in recent years. […] Pathogenesis of tissue injury in mixed cryoglobulinemia. HCV infects B lymphocytes while infecting hepatocytes due to the common expression of the CD81 receptors. A HCV-dependent gene translocation able to protect cells against apoptosis sustains the oligoclonal monotypic lymphoproliferation that occurs in mixed cryoglobulinemia.

• #20 Mixed cryoglobulinemia | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-25

  Chronic stimulation of the lymphatic system exerted through viral epitopes, autoantigen production, and/or molecular mimicry mechanism has been suggested by the presence, in HCV-positive patients, of anti-GOR antibodies, which are cross-reactive autoantibodies directed to both HCV core and a nuclear antigen named GOR. […] Another important pathogenetic factor is the interaction between HCV E2 protein and CD81 molecule, a quite ubiquitary tetraspannin present on B-cells surface; the consequence may be the strong and sustained polyclonal stimulation of B-cell compartment. […] It is possible to hypothesize that during chronic HCV infection, several factors (including the interaction between HCV E2 protein and CD81 molecule, the high viral variability, and the persistent infection of both hepatic and lymphatic cells) may favor a sustained and strong B-cell activation. […] The consequent B-lymphocyte expansion is responsible for autoantibody production, including the cryoglobulins. […] Given its biological characteristics, HCV may be involved in a wide number of autoimmune and lymphoproliferative disorders.

• #21 Relationship Between Cryoglobulinemia-associated Nephritis and HCV – Page 2

  https://www.medscape.com/viewarticle/580491_2

  Under the trigger effects of chronic HCV infection, oligo- or monoclonal IgM sharing rheumatoid activity is synthesized, thus favoring the appearance in the circulation of ICs (formed by HCV, anti-HCV polyclonal IgG and the monoclonal IgM itself), which is critical for tissue (especially renal) deposition because of the particular affinity of monoclonal IgM to fibronectin and other mesangial components. […] Therefore, the pathogenetic scenario of the disease is dominated by the following: Chronic stimulation by HCV infection, sustaining the synthesis of IgM rheumatoid factor and, consequently, of cryoprecipitable ICs; The abnormal kinetics and easy deposition of the HCV-containing ICs; A subclinical smoldering lymphoproliferative disorder.

• #22 Cryoglobulinemia: Better Treatments With Brighter Outcomes

  https://www.cancernetwork.com/view/cryoglobulinemia-better-treatments-brighter-outcomes

  The review by Retamozo and colleagues provides a comprehensive overview of the etiology, pathogenesis, and clinical manifestations-as well as the treatment-of different types of cryoglobulinemia. […] The exact pathogenesis accounting for the association with HCV infection has been recently determined and involves a viral protein-induced stimulation of liver and immune cells. […] The cryoglobulinemic Igs bind the viral core proteins, leading to their precipitation. […] These immune complexes lead to vascular damage that, in turn, results in the frequent purpura, joint symptoms, and generalized weakness experienced by most patients.

• #23 HCV, Mixed Cryoglobulinemia and Malignant Lymphoproliferation | IntechOpen

  https://www.intechopen.com/chapters/44874

  HCV core protein, in the presence of high levels of circulating gC1q-R, can exacerbate the inflammatory state by activating the complement cascade, thus determining endothelial cell activation and initiating an in situ inflammatory response. […] From a biological point of view, the clinical response to antiviral therapy consists of a significant reduction in soluble gC1q-R in association with increased levels of C4d and a lower viral load. […] Viral persistence represents a continuous stimulus for the host immune system, leading to B-cell selection and clonal expansion as evidenced by the synthesis of IgM autoantibodies with RF activity (IgM-RF), which characterizes MC. […] This process seems to occur in a microenvironment such as that provided by intraportal lymphoid follicles due to distinct selection events probably supported by cytokine signaling, thereby sustaining B-cell activation and proliferation.

• #24 Cryoglobulins: An Important but Neglected Clinical Test

  https://www.annclinlabsci.org/content/36/4/395.full

  Mixed CRs (the majority of CRs) are associated with viral infections, including HIV, HBV, and HCV. In acute viral hepatitis of various etiologies, CRs appear in the acute period of the disease triggered by the viruses. The CR-precipitate mostly is type II, containing monoclonal IgM (RF), and polyclonal IgG in addition to the viral proteins and viral RNA. […] Considering the high frequency of positive CR tests in patients with HCV, the percentage of those with severely symptomatic vasculitis appears low. Circumstances that predispose HCV-infected patients to develop mixed cryoglobulinemic vasculitis remain unclear, but the hosts immune response genes may play a role. Based on multivariate analysis, four independent factors appear to be associated with the presence of CR; female gender, alcohol consumption, HCV genotype II or III, and extensive liver fibrosis. In general, patients with cryoglobulinemia tend to have more severe arthralgia and elevated liver enzymes, compared to patients without cryoglobulinemia.

• #25 Frontiers | Non-hepatitis-associated mixed cryoglobulinemia with polyclonal plasma cells disease and alcoholic cirrhosis: A rare case report

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1014261/full

  Mixed cryoglobulinemia refers to the serum presence of a variety of cryoglobulins, which are defined as immunoglobulins that precipitate at temperatures of < 37°C. The most common cause of mixed cryoglobulinemia is hepatitis C virus (HCV), while other infections, including hepatitis B virus (HBV) and HIV infections, and lymphoproliferative and autoimmune disorders have also been associated with the disease. [...] Treatment should be modulated according to the underlying etiopathogenesis and the severity of clinical presentation. There are three broad strategies in the treatment of cryoglobulinemia: conventional immunosuppression, antiviral treatments, and biological therapies, and studies found that both combined or sequential antiviral therapies and targeted biological treatments might be more effective than monotherapy.

• #26 HCV, Mixed Cryoglobulinemia and Malignant Lymphoproliferation | IntechOpen

  https://www.intechopen.com/chapters/44874

  For many years, an infectious agent was thought to be the etiologic factor underlying MC. This hypothesis gained significant support from the study of Meltzer and Franklin, in which the pathogenetic role of a hepatotropic virus was suggested. […] Currently, HBV is considered as a causative agent of MC only in about 5% of cases. […] In the early 1990s, after the identification of HCV as the major etiologic agent of non-A, non-B hepatitis, several authors reported the high prevalence of anti-HCV antibodies in MC patients. […] This correlation was subsequently confirmed by the detection of HCV genomic sequences, especially in the cryoprecipitates versus the corresponding supernatants. […] The intrinsic mechanism by which HCV promotes cryoglobulin production remains unclear. […] According to this scheme, cryoglobulins may be considered the result of these interactions and the presence of IgM molecules with RF activity a crucial event in the cryoprecipitating process.

• #27 Hepatitis C virus-related mixed cryoglobulinemia: Is genetics to blame?

  https://www.wjgnet.com/1007-9327/full/v19/i47/8910.htm

  Mixed cryoglobulinemia (MC) is the extrahepatic manifestation most strictly correlated with hepatitis C virus (HCV) infection; it is a benign autoimmune and lymphoproliferative disorder that evolves to lymphoma in 5%-10% of cases. MC is reputed to be a multistep and multifactorial process whose pathogenicity is still poorly understood. […] The pathogenesis of MC is still poorly understood, although it is certain that several subsequent events contribute to disease onset, when they occur in a favorable host genetic substrate. […] The reasons why only some chronically infected HCV patients develop MC and why only some of these exhibit systemic symptoms, the so-called MC syndrome (MCS), are unknown. […] One of the most obvious explanations, the genetic factor, has only recently been seriously contemplated, when the impact of this disease on chronic HCV infection and its role in predisposing to lymphoid malignancies has been recognized.

• #28 Hepatitis C virus-related mixed cryoglobulinemia: Is genetics to blame?

  https://www.wjgnet.com/1007-9327/full/v19/i47/8910.htm

  Since then, several studies have tried to clarify the complex pathogenesis of MC and the most recent have focused on genetics. […] Together with genetic predisposition, epigenetic factors such as the expression of specific miRNAs can be a major contribution to the pathogenesis of HCV-related lymphoproliferative disorders. […] The identification of a characteristic genetic signature of cryoglobulinemic patients would be an important step toward a personalized approach in their clinical care. […] The above data are heterogeneous and sometimes even conflicting, thus, there is a clear need for multicenter studies including large numbers of patients, and the future application of the new genomic and proteomic wide-range technologies will surely assist in this direction.

• #29 Neuropathies associated with cryoglobulinemia | MedLink Neurology

  https://www.medlink.com/articles/neuropathies-associated-with-cryoglobulinemia

  Cryoglobulins are plasma proteins that precipitate on cooling and dissolve after rewarming. Cryoglobulinemia may arise in association with an identifiable cause like an infection (mainly hepatitis C virus infection), a lymphoproliferative disorder, or an autoimmune disease (such as Sjgren syndrome). […] Cryoglobulinemia may lead to a variety of systemic complications, including purpura, arthritis, glomerulonephritis, and peripheral neuropathy, which could be potentially disabling. […] In this review, the authors review the pathogenesis, management, and treatment of neuropathies associated with cryoglobulinemia. […] The pathophysiology of end-organ injury by cryoglobulins depends on the type of cryoglobulin, the immunoglobulin concentration, and whether the tissue temperature can go low on exposure, such as with the skin and distal peripheral nerves. An occlusive vasculopathy of venules and arterioles by large cryoglobulin aggregates is the main mechanism in type I cryoglobulinemia, especially when the paraprotein is of IgM type. On the other hand, cryoglobulinemic vasculitis is the main mechanism in type II cryoglobulinemia. Cryoglobulinemic vasculitis is caused by deposition of immune complexes containing rheumatoid factor and complement components on the endothelial cells in the setting of exposure to cold temperature that triggers a local inflammatory reaction, including inflammatory cells and cytokines.

• #30 Clinical and Serological Profiles in Cryoglobulinemia: Analysis of Isotypes and Etiologies

  https://www.mdpi.com/2077-0383/13/20/6069

  Our findings underscore the significant role of RD in CG syndrome, particularly in MCG, with a notable 58% prevalence of RD in our CG cohort. This exceeds the previously reported 30% in non-infectious CG cases, potentially reflecting enhanced detection of previously underdiagnosed conditions such as SjS. The established association between CG and RD, particularly with SjS and SLE, is important, even though it is less commonly reported in other RDs. Our findings contribute to the growing evidence supporting the necessity of CG evaluation in these patients. […] Our study identified a substantial proportion (22.6%) of patients presenting with vasomotor and skin-related manifestations, irrespective of etiology. This underscores the critical role of CG testing in everyday clinical practice for patients with unexplained skin abnormalities, even in the absence of a clear underlying etiology. Given their expertise in skin manifestations, dermatologists are often the first healthcare providers to evaluate skin changes. However, the heterogeneity in clinical presentation is a hallmark of CG, highlighting the necessity for CG evaluation across various specialties, including nephrologists, infectious disease specialists, hematologists, and neurologists, as early recognition of CG is essential.

• #31 Cryoglobulinemia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cryoglobulinemia/symptoms-causes/syc-20371244

  Cryoglobulinemia is a family of rare conditions, called vasculitis. Vasculitis causes irritation and swelling, called inflammation, of the blood vessels. […] Cryoglobulins are atypical proteins in the blood. For people who have cryoglobulinemia (kry-o-glob-u-lih-NEE-me-uh), these proteins may clump together at body temperatures below 98.6 F (37 C). […] These clumps can block blood flow. This can damage the skin, joints, nerves and organs, mainly the kidneys and liver. […] It’s not clear what causes cryoglobulinemia. It’s been linked to: […] Disease in which the immune system attacks healthy tissues by mistake, called autoimmune, increases the risk of getting cryoglobulinemia. Examples are lupus, rheumatoid arthritis and Sjogren syndrome. […] Cryoglobulinemia can affect the kidneys. The main symptoms are protein or blood in the urine. High blood pressure most often goes with the kidney symptoms. In time, kidney failure might happen.

• #32 Clinical and Serological Profiles in Cryoglobulinemia: Analysis of Isotypes and Etiologies

  https://www.mdpi.com/2077-0383/13/20/6069

  Cryoglobulinemia (CG) is marked by abnormal immunoglobulins (Ig) in serum, precipitating at temperatures below 37 °C. The precise biochemical mechanisms that precipitate cryoglobulin upon cold exposure have not been completely elucidated. Complement activation plays a significant role by attaching to endothelial cell receptors, thus aiding in the deposition of immune complexes and causing subsequent inflammation in small- and medium-sized vessels. The main mechanism contributing to CG is aberrant autoantibody production by plasma cells and B-cell clonal expansion. This process can be facilitated by lymphoproliferative disorders, persistent immune stimulation due to chronic infections, or autoimmune diseases. Consequently, CG is recognized as a condition encompassing a broad spectrum of potential etiologies, diverse pathogenic mechanisms, a wide array of phenotypic manifestations, and a pronounced interplay between infection, autoimmunity, and neoplastic processes.

• #33 Sjögren’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Sj%C3%B6gren%27s_disease

  Environmental and hormonal factors, in concert with an appropriate genetic background, are believed to trigger Sjgren’s disease, which dysregulates epithelial cells and allows aberrant homing and activation of dendritic cells (DCs), T cells, and B cells. […] Dysregulation of apoptosis (programmed cell death) is believed to play a role in the pathogenesis of a variety of autoimmune diseases, though its role in Sjgren’s disease is controversial. […] Both the Fas and Fas ligand proteins are overexpressed in primary Sjgren’s patients, while expression of BCL-1, which is known to downregulate apoptosis, was found significantly reduced in acinar and ductal epithelial cells of Sjgren’s patients compared to healthy people. […] The relationship of autoantibodies expressed in Sjgren’s syndrome with apoptosis is still being researched.

• #34 Cryoglobulinemia | UNC Kidney Center

  https://unckidneycenter.org/kidneyhealthlibrary/glomerular-disease/cryoglobulinemia/

  Cryoglobulins are proteins that are normally dissolved in blood, but become solid or gel-like at cold temperatures (less than 98.6 F). Cryoglobulinemia simply means that these abnormal proteins are in the blood. […] When these proteins are in their solid form they can physically block blood vessels throughout the body. They can also attach to antibodies to cause vasculitis (swelling of the blood vessels). […] Type I occurs at the same time as cancers of the blood and immune system. Multiple myeloma, chronic lymphocytic leukemia and Waldenstroms macroglobulinemia are all cancers of this type. […] Types II and III are associated with diseases that have chronic internal swelling. These diseases include autoimmune diseases such as systemic lupus erythematosus or Sjogrens syndrome, and viruses such as hepatitis C or HIV.

• #35 Cryoglobulinemia – UF Health

  https://ufhealth.org/conditions-and-treatments/cryoglobulinemia

  Cryoglobulins are antibodies. It is not yet known why they become solid or gel-like at low temperatures in the laboratory. In the body, these antibodies can form immune complexes that can cause inflammation and block blood vessels. This is called cryoglobulinemic vasculitis. This may lead to problems ranging from skin rashes to kidney failure. […] Severe cryoglobulinemia vasculitis involves vital organs or large areas of skin. It is treated with corticosteroids and other medicines that suppress the immune system. […] This disorder is due to a cancer of the blood or immune system such as multiple myeloma. Treatment is directed against the abnormal cancer cells that produce the cryoglobulin.

• #36

  https://link.springer.com/article/10.1007/s00277-024-05970-y

  A 42-year-old male was referred to the internal medicine department because of renal failure and persistent malaise after a recent SARS-CoV-2 infection. […] Type 1 cryoglobulinemia is usually associated with lymphoproliferative disorders and is characterized by various symptoms caused by cryoprecipitates occluding small blood vessels. […] This is, to our knowledge, the first case of type I cryoglobulinemia with proven precipitation of SARS-CoV-19 antibodies. COVID-19 induced cryoglobulinemia appears to have a mild disease course and to be self-limiting upon viral clearance. […] We believe it is important that physicians are aware of this rare complication of COVID-19 as it might be under-recognized. […] Our case highlights the appearance of a type I cryoglobulinemia triggered by COVID-19. The determination of the cryoglobulinemia as type I (i.e., monoclonal) renders this case unique, because cryoglobulinemia secondary to infection is usually a type II or III (i.e., polyclonal).

• #37 HCV, Mixed Cryoglobulinemia and Malignant Lymphoproliferation | IntechOpen

  https://www.intechopen.com/chapters/44874

  The unique clinical features of MC are the result of the biological activities of the immune complexes constituted by IgM-RF, anti-HCV IgG, viral antigens, and complement fractions. […] Thus, MC may be considered a low-grade, indolent, benign lymphoproliferative disease reflecting an antigen-dependent B-cell clonal expansion with potential evolution into a malignant phenotype. […] HCV-related malignant NHLs may accordingly derive from a benign lymphoproliferation such as MC and usually occur as low grade/indolent lymphomas but, over time, their phenotypes may become more aggressive. […] However, there are several further aspects that need to be clarified regarding the pathogenetic mechanisms of HCV-induced lymphomagenesis.

• #38 Cryoglobulinemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/329255-overview

  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.

• #39 HCV, Mixed Cryoglobulinemia and Malignant Lymphoproliferation | IntechOpen

  https://www.intechopen.com/chapters/44874

  The interaction between HCV and lymphocytes results in the modulation of cell functions. […] It has been postulated that the initial activation of these cells is followed by the emergence of a dominant clone that synthesizes a monoclonal RF, resulting in the development of type II MC after a transition phase in which an IgM clonal heterogeneity reflects a type II-type III variant. […] An important role in the nature of cryoprecipitating immune complexes is played by the complement system. […] These data support the hypothesis that an efficient engagement of C1q protein by cryoglobulins is a crucial factor in the pathogenesis of MC. […] The receptor for the globular domain of C1q (gC1q-R) directly interacts with HCV core protein, thereby altering host T- and B-cell immunity. […] Moreover, it was recently demonstrated that higher levels of soluble gC1q-R reflect a higher specific mRNA expression by the blood mononuclear cells of MC patients.

• #40 A Case of Cryoglobulinemia after Successful Hepatitis C Virus Treatment

  https://clinmedjournals.org/articles/jcnrc/journal-of-clinical-nephrology-and-renal-care-jcnrc-6-050.php

  Cryoglobulinemic vasculitis is a complex and destructive disease process that affects multiple organ systems. The pathophysiology includes formation of immune complex deposits that create an inflammatory response in various organs, yielding distinct presentations such as purpura, arthralgias, neuropathy, fever, and pulmonary vasculitis. […] Cryoglobulinemic vasculitis affects multiple organ systems due to an inflammatory cascade involving HCV antigen-stimulated B-cell polyclonal expansion followed by production of the cryoglobulins. These immune complexes precipitate at temperatures less than 37 °C, and thus deposit in the vascular endothelium. Cryoglobulins bind the C1qR receptor on endothelial cells, causing release of vasoactive peptides, activation of the classical complement pathway, and production of low levels of C4. […] The mechanism of the immune response in such cryoglobulinemic vasculitis may involve impaired cryoglobulin clearance from past infection or persistent inactive HCV antigens.

• #41 Prevalence of cryoglobulinemia and cryoglobulinemic vasculitis in chronically HCV-infected Brazilian patients | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-avance-resumen-prevalence-cryoglobulinemia-cryoglobulinemic-vasculitis-in-S1665268119303370

  After the discovery of the HCV as the main etiologic agent of CryoVas, an opportunity to control CryoVas manifestations with antiviral therapy emerged. […] Despite the initial success observed with interferon alpha (IFN) based antiviral treatment, HCV-associated CryoVas still remained a severe disease with a 5-year mortality rate of 25%. […] Even with the advent of novel therapies for hepatitis C with interferon-free agents, CryoVas is still a problem that may persist after the sustained virological response. […] The presence of cryoglobulins was associated with lower serum levels of all complement components evaluated (i.e. C2h, C3, C4 and CH100) even in the absence of CryoVas manifestations. […] When comparing HCV patients presenting cryoglobulinemia with those presenting CryoVas, low serum C4 levels were more frequently found in the latter.

• #42 HCV, Mixed Cryoglobulinemia and Malignant Lymphoproliferation | IntechOpen

  https://www.intechopen.com/chapters/44874

  HCV core protein, in the presence of high levels of circulating gC1q-R, can exacerbate the inflammatory state by activating the complement cascade, thus determining endothelial cell activation and initiating an in situ inflammatory response. […] From a biological point of view, the clinical response to antiviral therapy consists of a significant reduction in soluble gC1q-R in association with increased levels of C4d and a lower viral load. […] Viral persistence represents a continuous stimulus for the host immune system, leading to B-cell selection and clonal expansion as evidenced by the synthesis of IgM autoantibodies with RF activity (IgM-RF), which characterizes MC. […] This process seems to occur in a microenvironment such as that provided by intraportal lymphoid follicles due to distinct selection events probably supported by cytokine signaling, thereby sustaining B-cell activation and proliferation.

• #43 Clinical and Serological Profiles in Cryoglobulinemia: Analysis of Isotypes and Etiologies

  https://www.mdpi.com/2077-0383/13/20/6069

  Renal involvement and glomerulonephritis were observed in patients from various subgroups in our cohort. As previously reported, the presence of GN, especially in the context of elevated cryoglobulin levels, should prompt clinicians to consider CG as a potential underlying cause of renal involvement. Early recognition of renal involvement and initiation of appropriate treatment strategies are paramount to preventing further renal deterioration and complications. […] Our study also highlights the association between hematological disorders and type I CG, primarily characterized by the IgM subtype. This observation is consistent with earlier extensive studies, including the comprehensive analysis conducted by Kolopp-Sarda involving 1675 CG patients. Additionally, we observed that these patients display significantly higher levels of serum cryoglobulins than individuals with MCG.

• #44 A Case of Cryoglobulinemia after Successful Hepatitis C Virus Treatment

  https://clinmedjournals.org/articles/jcnrc/journal-of-clinical-nephrology-and-renal-care-jcnrc-6-050.php?jid=jcnrc

  Cryoglobulinemic vasculitis is a complex and destructive disease process that affects multiple organ systems. The pathophysiology includes formation of immune complex deposits that create an inflammatory response in various organs, yielding distinct presentations such as purpura, arthralgias, neuropathy, fever, and pulmonary vasculitis. […] Cryoglobulinemic vasculitis is often precipitated by infectious etiologies and most commonly by hepatitis C virus (HCV) infection. […] Cryoglobulinemic vasculitis affects multiple organ systems due to an inflammatory cascade involving HCV antigen-stimulated B-cell polyclonal expansion followed by production of the cryoglobulins. These immune complexes precipitate at temperatures less than 37 °C, and thus deposit in the vascular endothelium. Cryoglobulins bind the C1qR receptor on endothelial cells, causing release of vasoactive peptides, activation of the classical complement pathway, and production of low levels of C4.

• #45 Frontiers | Non-hepatitis-associated mixed cryoglobulinemia with polyclonal plasma cells disease and alcoholic cirrhosis: A rare case report

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1014261/full

  The main clinical manifestations of mixed cryoglobulinemia include palpable purpura (it suggests the presence of some form of vasculitis), renal disease, arthralgia or arthritis, non-specific systemic symptoms (including weakness), peripheral neuropathy, and hypocomplementary syndrome (decreased C4 levels are usually most prominent). Studies suggested that treatment should be modulated according to the underlying etiopathogenesis and the severity of clinical presentation rather than merely symptomatic relief. […] Therefore, it is important to identify the etiology of renal impairment timely, which is closely related to the prognosis of patients with liver cirrhosis. If the etiology of renal dysfunction for the patient can be identified as mixed polyclonal cryoglobulinemia timely, we will clarify the direction of treatment and treat this cause first using conventional immunosuppression and biological therapies, ultimately improving the success rate of treatment and reducing the fatality rate. […] Early treatment of mixed cryoglobulinemia is important to alleviating multiple organ dysfunction, ultimately improving the success rate of therapy and reducing the fatality rate in a potentially life-saving therapy.

• #46 Neuropathies associated with cryoglobulinemia | MedLink Neurology

  https://www.medlink.com/articles/neuropathies-associated-with-cryoglobulinemia

  The mechanism of peripheral nerve damage seems to be vasculitic in both cryoglobulin-positive and cryoglobulin-negative patients, as supported by the clinical and morphological findings. […] The association of type II cryoglobulinemia with hepatitis C virus infection in neuropathic patients, as well as the occurrence of peripheral neuropathy in hepatitis C virus-infected patients without cryoglobulinemia, raised the issue as to whether the hepatitis C virus alone could play a direct role in the pathogenesis of neuropathy associated with cryoglobulinemia.

• #47 Neuropathies associated with cryoglobulinemia | MedLink Neurology

  https://www.medlink.com/articles/neuropathies-associated-with-cryoglobulinemia

  Cryoglobulins are plasma proteins that precipitate on cooling and dissolve after rewarming. Cryoglobulinemia may arise in association with an identifiable cause like an infection (mainly hepatitis C virus infection), a lymphoproliferative disorder, or an autoimmune disease (such as Sjgren syndrome). […] Cryoglobulinemia may lead to a variety of systemic complications, including purpura, arthritis, glomerulonephritis, and peripheral neuropathy, which could be potentially disabling. […] In this review, the authors review the pathogenesis, management, and treatment of neuropathies associated with cryoglobulinemia. […] The pathophysiology of end-organ injury by cryoglobulins depends on the type of cryoglobulin, the immunoglobulin concentration, and whether the tissue temperature can go low on exposure, such as with the skin and distal peripheral nerves. An occlusive vasculopathy of venules and arterioles by large cryoglobulin aggregates is the main mechanism in type I cryoglobulinemia, especially when the paraprotein is of IgM type. On the other hand, cryoglobulinemic vasculitis is the main mechanism in type II cryoglobulinemia. Cryoglobulinemic vasculitis is caused by deposition of immune complexes containing rheumatoid factor and complement components on the endothelial cells in the setting of exposure to cold temperature that triggers a local inflammatory reaction, including inflammatory cells and cytokines.

• #48 How do I Deal with Cryoglobulinemia?

  https://www.iomcworld.com/open-access/how-do-i-deal-with-cryoglobulinemia-111971.html

  The presence of cryoglobulins in the serum distinguishes cryoglobulinemia from other diseases. […] Cryoglobulinemia is a condition in which cryoglobulins are present in the bloodstream. […] Cryoglobulinemia is classified using a technique that was devised more than 40 years ago. It has the benefit of connecting with pathogenicity and clinical symptoms, which vary depending on the kind. […] The mechanism of cryoglobulin pathogenicity is better defined. HCV causes clonal B-cell growth, which produces monoclonal IgM molecules that attach to polyclonal IgG molecules, forming an RF. Immune complexes are formed when IgM interacts with anti-HCV IgG. These immune complexes link to endothelial cells’ C1q receptors, which enhances inflammatory cell recruitment and causes vasculitis. […] The etiology of cryoglobulins in type I, on the other hand, is tiny blood vessel blockage with a limited inflammatory response.

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