Introduction
Background
Cryoglobulins are single or mixed immunoglobulins that undergo reversible precipitation at low temperatures. Several types of cryoglobulins have been identified, and the potential clinical manifestations vary by cryoglobulin type.
Cryoglobulinemia is characterized by the presence of cryoglobulins in the serum. This may result in a clinical syndrome of systemic inflammation (most commonly affecting the kidneys and skin) caused by cryoglobulin-containing immune complexes.
Cryoglobulinemia may be classified based on cryoglobulin composition with the Brouet classification, which is as follows:
- Type I cryoglobulinemia, or simple cryoglobulinemia, is the result of a monoclonal immunoglobulin, usually immunoglobulin M (IgM) or, less frequently, immunoglobulin G (IgG), immunoglobulin A (IgA), or light chains.
- Types II and III cryoglobulinemia (mixed cryoglobulinemia) contain rheumatoid factors (RFs), which are usually IgM and, rarely, IgG or IgA. These RFs form complexes with the fragment, crystallizable (Fc) portion of polyclonal IgG. The actual RF may be monoclonal (in type II cryoglobulinemia) or polyclonal (in type III cryoglobulinemia) immunoglobulin. Types II and III cryoglobulinemia represent 80% of all cryoglobulins.
Cryoglobulinemia may also be classified based on the association of the syndrome with an underlying disease. Cryoglobulinemia without an associated disease has been known as essential, or idiopathic, cryoglobulinemia. However, the discovery of a close association between hepatitis C virus (HCV) and mixed cryoglobulinemia has cast doubt on the existence of essential, or idiopathic, cryoglobulinemia.1 Cryoglobulinemia associated with a particular disease (lymphoproliferative disorder, autoimmune disease, infectious disease) is known as secondary cryoglobulinemia.
Pathophysiology
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.2,3,4 Alteration in protein conformation with temperature changes also leads to decreased solubility and subsequent vasculitic damage.5,6 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.7
Some of the sequelae of cryoglobulinemia are thought to be related to immune-complex disease (eg, glomerulonephritis, chronic vasculitis), but not all persons with cryoglobulinemia present with these manifestations. Individuals with cryoglobulinemia may have intravascular cryoglobulin deposits, a reduced level of complement, and complement fragments (C3a, C5a) that act as chemotactic mediators of inflammation; however, the pathophysiologic process of this disease has not been fully explained. Other sequelae are directly related to cryoprecipitation in vivo, including plugging and thrombosis of small arteries and capillaries in the extremities (gangrene) and glomeruli (acute renal failure). Circulating large–molecular-weight cryoprotein complexes, even when unprecipitated in vivo, can lead to clinical hyperviscosity syndrome.
Type I cryoglobulins are usually monoclonal IgM and, less frequently, IgG, IgA, or light chains. Type I cryoglobulins rarely have RF activity and do not activate complement in vitro. This disorder is typically related to an underlying lymphoproliferative disease and, as such, may be clinically indistinguishable from Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. Type I cryoglobulinemia may result in hyperviscosity due to high levels of circulating monoclonal cryoglobulin, leading to physical obstruction of vessels. Concentrations may reach up to 8 g/L. In addition, nonobstructive damage may be mediated by immune complex deposition and subsequent inflammatory vasculitis.
Types II and III, also known as the mixed cryoglobulinemias, are associated with chronic inflammatory states such as systemic lupus erythematosus (SLE), Sjögren syndrome, and viral infections (particularly HCV). In these disorders, the IgG fraction is always polyclonal with either monoclonal (type II) or polyclonal (type III) IgM (rarely IgA or IgG) with RF activity (ability to bind IgG). B-cell clonal expansion, particularly RF-secreting cells, is a distinctive feature in many of these disease states.1,8,9,10
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.9,11,12,13
Frequency
United States
Cryoglobulins are reported in otherwise healthy individuals, so the true prevalence of the disease is unknown. Overall, cryoglobulinemia is thought to be rare. However, cryoglobulinemia may be underestimated based on the medical literature (perhaps because of the various clinical presentations); Gorevic et al evaluated only 126 cases of cryoglobulinemia from 1960-1978 in their medical center in New York.14 The prevalence of essential mixed cryoglobulinemia is reported as approximately 1:100,000.
The reported relative frequencies of the different types of cryoglobulinemia vary. A well-known publication by Brouet et al (1974) reports the following frequencies: type I, 25%; type II, 25%; and type III, 50%.15
International
The prevalence of mixed cryoglobulinemia is related to the endemic presence of HCV infection. Therefore, the prevalence varies from country to country. The incidence of HCV infection in mixed cryoglobulinemia in the Mediterranean Basin is 90%.
Mortality/Morbidity
- General: Mortality and morbidity in individuals with cryoglobulinemia often depend on concomitant disease (eg, lymphoproliferative disorder, viral hepatitis); for example, the prognosis in patients with chronic hepatitis C infection depends on their response to treatment; manifested by their decrease in viral load. The overall prognosis is worse in persons with concomitant renal disease, lymphoproliferative disease, or plasma cell disorders. Mean survival is approximately 50% at 10 years after diagnosis. Morbidity due specifically to cryoglobulinemia may be significant, with infection and cardiovascular disease being major considerations. Hepatic failure may result from chronic viral hepatitis.
- Renal disease: Survival rates reported among patients with renal involvement vary from greater than 60% at 5 years of follow-up to 30% at 7 years of follow-up. The risk of renal failure appears to be greater in those with HCV-associated disease.16 The prognosis of renal disease in the more common type II cryoglobulinemia varies. Most patients experience a slowly progressive course punctuated by acute exacerbations, with up to one third of patients undergoing some degree of clinical remission. Bryce et al, in a prospective study, found only age (and no laboratory parameters) to be a significant predictor of mortality in type II cryoglobulinemic renal disease.17
- Lymphoproliferative disease: Lymphoproliferative disease is more common in individuals with cryoglobulinemia. Patients with mixed cryoglobulinemia may develop benign lymphoid infiltrates in the spleen and bone marrow. Less frequently, some patients develop B-cell non-Hodgkin lymphoma. The reported incidence of malignant lymphoma in mixed cryoglobulinemia varies widely, from less than 10% of patients to as high as 40%, with onset 5-10 years after disease diagnosis.18,19,20
Race
Cryoglobulinemia does not have a racial predilection.
Sex
The female-to-male ratio is 3:1.
Age
The mean age reported is 42-52 years.
Clinical
History
- Specific clinical manifestations associated with type I cryoglobulinemia are related to hyperviscosity and thrombosis, as would be expected given their usual high concentrations of immunoglobulins and limited interference with complement function. These manifestations include acrocyanosis, retinal hemorrhage, severe Raynaud phenomenon with digital ulceration, livedo reticularis, purpura, and arterial thrombosis.
- Specific clinical manifestations associated with types II and III cryoglobulinemia include joint involvement (usually, arthralgias in the proximal interphalangeal [PIP] joints, metacarpophalangeal [MCP] joints, knees, and ankles), fatigue, myalgias, renal immune-complex disease, cutaneous vasculitis, and peripheral neuropathy.
- Typical presentations and reported frequencies include the following:
- Cutaneous: These manifestations are nearly always present in cryoglobulinemia. Observed lesions have a predilection for dependent areas (particularly the lower extremities) and include erythematous macules and purpuric papules (90-95%), as well as ulcerations (10-25%).15,21,14,22 Lesions in nondependent areas are more common in type I cryoglobulinemia (head and mucosa), as are livedo reticularis, Raynaud phenomenon, and ulcerations. Nailfold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis.23
Rash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.
- Musculoskeletal: Symptoms such as arthralgias and myalgias are rare in type I cryoglobulinemia and are common in types II and III disease. Frank arthritis and myositis are rare. Arthralgias commonly affect the proximal interphalangeal and metacarpophalangeal joints of the hands, knees, and ankles. Musculoskeletal symptoms are described in more than 70% of persons with cryoglobulinemia.24,25,21
- Renal: Renal disease may occur secondary to thrombosis (type I cryoglobulinemia) or immune complex deposition (types II and III). The incidence of renal disease varies from 5-60%. Histologically, membranoproliferative glomerulonephritis is almost always the lesion in mixed cryoglobulinemia. Clinically, isolated proteinuria and hematuria are more common than nephrotic syndrome, nephritic syndrome, or acute renal failure. Renal involvement is one of the most serious complications of cryoglobulinemia and typically manifests early in the course of the disease (within 3-5 y of diagnosis). Failure to treat may result in renal failure.15,26,27
- Pulmonary: A reduction in forced expiratory flow rates and the presence of interstitial infiltrates revealed by chest radiographs are common in mixed cryoglobulinemia. Approximately 40-50% of patients are symptomatic with dyspnea, cough, or pleuritic pain. Severe pulmonary disease is rare.28,29,30,31
- Neuropathy: Neuropathy is common in types II and III disease (as determined with electromyographic and nerve conduction studies), affecting 70-80% of patients. Symptomatic disease was once reported as less common (5-40%); however, more recently, subjective symptoms have been reported up to 91% of patients. Sensory fibers are more commonly affected than motor fibers, with pure motor neuropathy in approximately 5% of patients.32,21,33,34
- Abdominal pain: Abdominal pain has been reported in 2-22% of patients. Vasculitis of the small mesenteric vessels that leads to acute abdomen has been reported.
- Sicca symptoms have been reported in 4-20% of patients.21,28
- Acrocyanosis has been reported in up to 9% of patients.
- Arterial thrombosis has been reported in 1% of patients.
- Cutaneous: These manifestations are nearly always present in cryoglobulinemia. Observed lesions have a predilection for dependent areas (particularly the lower extremities) and include erythematous macules and purpuric papules (90-95%), as well as ulcerations (10-25%).15,21,14,22 Lesions in nondependent areas are more common in type I cryoglobulinemia (head and mucosa), as are livedo reticularis, Raynaud phenomenon, and ulcerations. Nailfold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis.23
- Meltzer triad, ie, purpura, arthralgia, and weakness, was first described in 1966 by Meltzer and Franklin in cases of essential mixed cryoglobulinemia. This triad is generally seen with types II and III cryoglobulinemia and is seen in up to 25-30% of patients.35,21
Physical
- Skin manifestations
- Ischemic necrosis (40% in type I, 0-20% in mixed types)
- Palpable purpura (15% in type I, 80% in mixed types)
- Livedoid vasculitis (1% in type I, 14% in type III)
- Cold-induced urticaria (15% in type I, 10% in type III)
- Hyperkeratotic spicules in areas exposed to cold
- Scarring of tip of nose, pinnae, fingertips, and toes
- Acrocyanosis
- Nailfold capillary abnormalities
- Pulmonary manifestations
- Dyspnea
- Cough
- Pleurisy
- Pleural effusions
- Bronchiectasis
- Gastrointestinal manifestations
- Abdominal pain (2-22%)
- Hemorrhage
- Hepatomegaly or signs of cirrhosis (ie, palmar erythema, abdominal wall collateral vessels, spider angiomata)
- Splenomegaly
- Renal manifestations
- Membranoproliferative glomerulonephritis described in all types (more common in type II)
- Intraluminal cryoglobulin deposition
- Hypertension
- Nephrotic-range proteinuria with resultant edema
- Joint manifestations
- Arthralgias (5% of type I, 20-58% of mixed)
- Frank arthritis and progressive joint deformity (distinctly rare)
- Nervous system manifestations
- Sensorimotor neuropathy
- Visual disturbances
- CNS involvement (rare, although pseudotumor cerebri and cerebral vascular events have been described)
- Other manifestations - Fever
Causes
- Disease associations variable based on type of cryoglobulinemia
- Type I is observed in lymphoproliferative disorders (eg, multiple myeloma, Waldenström macroglobulinemia).
- Types II and III are observed in chronic inflammatory diseases such as chronic liver disease, infections (chronic HCV infection), and coexistent connective-tissue diseases (SLE, Sjögren syndrome). Mixed cryoglobulinemia is rarely associated with lymphoproliferative disorders.
- Infection
- Viral - Hepatitis A, B, and C (see Differentials); HIV; Epstein-Barr virus (EBV); cytomegalovirus (CMV); adenovirus; chikungunya
- Bacterial - Endocarditis, streptococcal infections, syphilis, Lyme disease, leprosy, Q fever, brucellosis
- Fungal -Coccidioidomycosis
- Parasitic -Malaria, toxoplasmosis, others
- Autoimmune diseases
- SLE, rheumatoid arthritis, Sjögren syndrome
- Vasculitis -Polyarteritis nodosa (especially hepatitis B–associated), Henoch-Schönlein purpura
- Lymphoproliferative disorders - Waldenström macroglobulinemia, multiple myeloma, lymphoma, leukemia (eg, chronic lymphocytic leukemia, hairy cell leukemia)
- Renal diseases -Proliferative glomerulonephritis
- Liver diseases - Hepatitis A, B, and C (30-98% of patients with HCV infection have cryoglobulins, especially type II); cirrhosis
- Familial
- Essential
- Experimental - Postvaccination (eg, pneumococcal vaccine)
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Further Reading
Keywords
cryoglobulinemia, cryoproteinemia, cryoglobulins, immunoglobulins, essential cryoglobulinemia, simple cryoglobulinemia, type I cryoglobulinemia, type II cryoglobulinemia, type III cryoglobulinemia, mixed cryoglobulinemia, essential cryoglobulinemia, idiopathic cryoglobulinemia, hepatitis C virus, HCV, secondary cryoglobulinemia, glomerulonephritis, chronic vasculitis, cryoprecipitation, systemic lupus erythematosus, SLE, Sjögren syndrome, Sjögren's syndrome, hyperviscosity, thrombosis, acrocyanosis, retinal hemorrhage, Raynaud phenomenon, Raynaud's phenomenon, livedo reticularis, purpura, arterial thrombosis, multiple myeloma, Waldenström macroglobulinemia, Waldenström's macroglobulinemia, chronic liver disease
