Cryoglobulinemia
Cryoglobulinemia | |
---|---|
Other names | Cryoglobulinaemia, cryoglobulinemic disease |
Specialty | Hematology |
Cryoglobulinemia is a medical condition in which the blood contains large amounts of
Cryoglobulins typically
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
Classification
Since the first description of cryoglobulinemia in association with the clinical triad of skin
Type | Composition | Percent of cases | Association with other diseases |
---|---|---|---|
Type I | Monoclonal IgG, IgM, IgA, or their κ or λ light chains
|
10–15% | Hematological diseases, particularly |
Type II | Monoclonal IgM plus polyclonal IgG or, rarely, IgA | 50–60% | Infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection; hematological diseases particularly B cell disorders; autoimmune diseases[7][8] |
Type III | Polyclonal IgM plus polyclonal IgG or IgA | 25–30% | systemic lupus erythematosus and rheumatoid arthritis; infectious diseases particularly HCV infection[7][8]
|
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.[9] Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease.[8] The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity.[9]
More recent high resolution 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 isotypes of circulating monoclonal immunoglobulin(s) are in transition to type II disease.[7][10]
Signs and symptoms
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:[citation needed]
- a) increase blood viscosity thereby reducing blood flow to tissues to cause the epistaxis;
- 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;
- c) in type II and type III disease, deposit on the endothelium of blood vessels and activate the blood complement system to form pro-inflammatory elements such as C5a thereby initiating the systemic vascular inflammatory reaction termed cryoglobulinemic vasculitis.[2][9]
Purpura seen in cryoglobulinemia may also be referred to as cryoglobulinemic purpura.[11]
Essential cryoglobulinemic disease
The signs and symptoms in the increasingly rare cases of cryoglobulinemic disease that cannot be attributed to an underlying disease generally resemble those of patients suffering Type II and III (i.e., mixed) cryoglobulinemic disease.[9][12]
Type I cryoglobulinemic disease
Signs and symptoms due to the cryoglobulins of type I disease reflect the
Types II and III cryoglobulinemic disease
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. "
Mechanism
Cryoglobulins
Cryoglobulins consists of one or more of the following components:
- Monoclonal IgM-based cryoglobulin occurs in cases of smoldering Waldenstrom's macroglobulinemia.[2]
- Monoclonal IgG or, rarely, IgA, κ light chain, or λ light chain cryoglobulins occur in cases of 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.[7] 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.[2][3]
- 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 temporal arteritis, polymyositis, Henoch–Schönlein purpura, pemphigus vulgaris, sarcoidosis, inflammatory bowel diseases, and others.[7] 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).[3]
Diagnosis
Cryoglobulinemia and cryoglobulinemic disease must be distinguished from
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 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 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 cases clinical findings.[2][13][16]
Treatment
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.[13][14]
Asymptomatic cryoglobulinemia
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.[13] 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.[17] 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.[17]
Severely symptomatic cryoglobulinemic disease
People affected by the severest, often life-threatening, complications of cryoglobulinemic disease require urgent
Type I cryoglobulinemic disease
Treatment of Type I disease is generally directed towards treating the underlying pre-malignant or malignant disorder (see
Type II and III cryoglobulinemic disease
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
See also
- Cryofibrinogenemia
- Cryoglobulinemic vasculitis
- Dysfibrinogenemia
- Hematopoietic ulcer
- Hyperviscosity syndrome
- Paraproteinemia
- Plasma cell dyscrasias
References
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- ^ "Cryoglobulin" at Dorland's Medical Dictionary
- ^ PMID 17289231.
- ^ PMID 17289231.
- ^ PMID 28507447.
- PMID 8034987.
- ISSN 0002-9343.
- ^ "Overview of cryoglobulins and cryoglobulinemia". www.uptodate.com. Retrieved August 31, 2017.
- ^ PMID 27799164.
- ^ PMID 23519183.
- ^ PMID 28390781.
- ^ S2CID 39645385.
- ^ PMID 24418294.