AUTHOR AND EDITOR INFORMATION

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• Workup
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• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

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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 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. 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}

Sex

The female-to-male ratio is 3:1.

Age

The mean age reported is 42-52 years.

CLINICAL

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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
  • 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}
  • 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.^{31, 21, 32, 33}
  • 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.
• 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.^{34, 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
• 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
  • Bacterial - Endocarditis, streptococcal infections, syphilis, Lyme disease, leprosy, Q fever
  • 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)

DIFFERENTIALS

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Other Problems to be Considered

Consider an active infection (ie, viral, bacterial, fungal, parasitic) or a systemic vasculitic process, particularly with evidence of skin lesions, renal disease, or both.

WORKUP

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Lab Studies

• Evaluation for serum cryoglobulins
• • The blood specimen must be obtained in warm tubes (37°C) in the absence of anticoagulants.
  • Allow the blood sample to clot before removal of serum with centrifugation (at 37°C).
  • The period required for the serum sample to incubate (at 4°C) depends on the type of cryoglobulin present, as follows:
  • • Type I tends to precipitate within the first 24 hours (at concentrations >5 mg/mL).
    • Type III cryoglobulins may require 7 days to precipitate a small sample (<1 mg/mL).
  • Repeat centrifugation to determine cryocrit (volume of precipitate as a percentage of original serum volume).
  • Cryoglobulin concentration may be determined via spectrophotometric analysis. Specific immunologic assays may be used to identify cryoglobulin components (immunoglobulins, light chains, clonality).
• Urinalysis: Abnormalities may represent evidence of renal disease.
• Complete blood cell count: Leukocytosis may be a manifestation of concomitant infection or leukemia. Anemia may be present.
• Serum chemistry: Patients with renal insufficiency may present with elevated serum creatinine levels and electrolyte abnormalities.
• Liver function studies: Liver function studies may reveal evidence of underlying hepatitis; obtain hepatitis serology.
• RF: RF is positive in types II and III.
• Antinuclear antibody (ANA): ANA is indicated upon clinical suspicion of underlying connective-tissue disease (SLE, Sjögren syndrome).
• Erythrocyte sedimentation rate (ESR): Elevations may be secondary to rouleaux formation.
• Complement evaluation (CH50, C3, C4): Patients may display hypocomplementemia (especially low C4 levels).
• Other studies: Consider serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and quantitative immunoglobulin upon suspicion for underlying gammopathy.
• Serum viscosity: Measure serum viscosity if symptoms warrant.
• Further diagnostic laboratory tests: Consider further testing based on the level of suspicion for other associated disease.

Imaging Studies

• A chest radiograph may reveal interstitial involvement or pleural effusions.
• CT imaging may be considered upon high suspicion of underlying malignancy.
• Transesophageal echocardiography should be obtained if bacterial endocarditis is suspected.
• Angiography may be considered to evaluate for evidence of vasculitis.

Procedures

• Tissue biopsy may be required for diagnosis when patients with vasculitis, renal disease, or both are evaluated.
• Electromyography and nerve conduction studies may be used to confirm neuropathy when history or physical examination findings are suggestive.
• Further diagnostic procedures (eg, bone marrow biopsy, liver biopsy) usually depend on coexistent disease, especially HCV infection.

Histologic Findings

Skin: Purpura are histologically characterized by dermal vasculitis that extends variably to the subcutaneous interstitial space. HCV-associated proteins have been found in vasculitic skin biopsy samples, suggesting a role for these antigens in pathogenesis of the lesions.

Other organs: Autopsy studies have revealed unsuspected vasculitis of multiple organs (heart, lung, gastrointestinal tract, central nervous system, liver, muscle, adrenals).¹⁴ Histologic evaluation of affected lung, kidney, and muscle reveals eosinophilic material in the lumen of small vessels with frequent extension into the vessel intima and inflammation of the vessel wall.³⁵

Although biopsy samples generally exhibit inflammatory vascular changes (eg, leukocytoclastic vasculitis in patients with vasculitic purpura), intraluminal cryoglobulin deposits may be observed, especially in renal glomeruli.

TREATMENT

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Medical Care

The goal of therapy is to treat underlying conditions, as well as to limit the precipitant cryoglobulin and the resultant inflammatory effects. Thus, HCV testing is required. HCV-antibody or HCV-RNA testing may be diagnostic. If HCV test results are negative and clinical suspicion remains high, these tests may be performed on the cryoprecipitate. Asymptomatic cryoglobulinemia does not require treatment. Some authors recommend intervening as little as possible except when faced with severe deterioration of renal or neurologic function. Secondary cryoglobulinemia is best managed with treatment of the underlying malignancy or associated disease. Otherwise, cryoglobulinemia is treated simply with suppression of the immune response. A paucity of controlled studies evaluating the relative efficacy of various therapies limits the use of existing data.

• Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used in patients with arthralgia and fatigue.
• Immunosuppressive medications (eg, corticosteroid therapy and/or cyclophosphamide or azathioprine) are indicated upon evidence of organ involvement such as vasculitis, renal disease, progressive neurologic findings, or disabling skin manifestations.
• Plasmapheresis is indicated for severe or life-threatening complications related to in vivo cryoprecipitation or serum hyperviscosity. Concomitant use of high-dose corticosteroids and cytotoxic agents is recommended for reduction of immunoglobulin production. Some authors recommend using concomitant cytotoxic medications or corticosteroids to reduce a rebound phenomenon that may develop after plasmapheresis.
• Pegylated interferon alfa (IFN-alfa) combined with ribavirin has demonstrated efficacy in patients with cryoglobulinemia associated with hepatitis C, and efficacy in patients with chronic myelogenous leukemias and low-grade lymphomas has been reported. The details of therapy and the recommended approach vary based on the clinical setting, and expert opinion should be sought.
• Small and uncontrolled studies suggest the anti-CD20 chimeric monoclonal antibody rituximab is effective in controlling disease manifestations such as vasculitis, peripheral neuropathy, arthralgias, low-grade B-cell lymphomas, renal disease, and fever.^{36, 37} Rituximab therapy has been used predominately in HCV-related mixed cryoglobulinemia refractory to or unsuitable for corticosteroids and antiviral (IFN-alfa) therapy. Rituximab therapy is reportedly well tolerated in this patient population; however, treatment results in increased titers of HCV-RNA of undetermined significance. The National Institutes of Health has launched a large trial of rituximab in the treatment of mixed cryoglobulinemia.

Consultations

• Rheumatologist or clinical immunologist
• Nephrologist upon evidence of renal disease (ie, hypertension, abnormal findings on urinalysis)
• Hematologist upon evidence of underlying hematological disease or for plasmapheresis
• Gastroenterologist or hepatologist for patients with underlying hepatitis

MEDICATION

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The overall aim of therapy is treatment of any underlying condition and general suppression of the immune response. Mild anti-inflammatory medications (eg, NSAIDs) are effective in mild cases, and corticosteroid therapy is reserved for the more severe or refractory cases. Patients who require potent immunosuppression or other more aggressive therapies for severe disease should be treated by a specialist. Cyclophosphamide may be used as a steroid-sparing agent or administered concomitantly in severe cases of vasculitis, particularly in patients with renal disease. Azathioprine is commonly used as a steroid-sparing agent, and chlorambucil has also been used for severe vasculitis.

Drug Category: Nonsteroidal anti-inflammatory drugs

NSAIDs such as ibuprofen, naproxen, and indomethacin have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. NSAIDs may have additional mechanisms, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions. NSAIDs are used to reduce the resultant inflammatory response of cryoglobulin precipitation.

Drug Category: Corticosteroids

These medications are used to reduce the resultant immune response from cryoglobulin precipitation, particularly in patients with more severe symptoms or some evidence of organ damage.

Drug Category: Immunosuppressive agents

These are commonly used as steroid-sparing agents.

Drug Category: Interferons

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. IFN-alfa is generally administered subcutaneously.

Drug Category: Antiviral agents

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Drug Category: Antineoplastic agents

These agents inhibit cell growth and proliferation.

FOLLOW-UP

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Further Inpatient Care

• Admit the patient to an inpatient medical service upon evidence of active vasculitis involving renal, cardiopulmonary, or neurologic systems that requires use of aggressive immunosuppressive therapy.
• Patients who develop end-organ compromise secondary to active vasculitis may need to be monitored in an intensive care unit setting.

Further Outpatient Care

• Outpatient management is reasonable in patients suspected of having mild vasculitis that is expected to respond to outpatient oral immunosuppressive therapy or in patients treated for vague symptoms of arthralgias, fatigue, or malaise without evidence of active vasculitis.

In/Out Patient Meds

• Consider the use of NSAIDs in patients with mild symptoms of arthralgias, fatigue, or malaise without evidence of vasculitis.
• Consider corticosteroid therapy for at least initial therapy in patients with more severe symptoms such as vasculitis, neurologic findings, severe cutaneous disease, or renal involvement or in those who otherwise meet criteria for inpatient medical care. These patients may require additional immunosuppressive therapy and are best treated by a specialist.

Transfer

• Consider transferring patients who meet criteria for admission to a facility able to accommodate patients who require possible subspecialty consultation with a rheumatologist, hematologist, gastroenterologist/hepatologist, or nephrologist.
• In patients with evidence of potential end-organ compromise, consider transfer to a facility able to accommodate intensive or critical care patients.

Deterrence/Prevention

• Avoidance of precipitating environmental factors such as cold temperatures

Complications

• Stroke, seizure, or coma
• Blindness
• Acute myocardial infarction
• Pericarditis
• Congestive heart failure
• Respiratory distress
• Gastrointestinal hemorrhage
• Acute renal failure
• Severe cutaneous necrosis or gangrene

Prognosis

• As discussed in Mortality/Morbidity, the prognosis in these patients depends on the presence of underlying diseases (eg, lymphoproliferative disorders, hepatitis B or C infection, connective-tissue disease), all of which increase the mortality rate over that of the healthy population and more accurately direct estimates of individual survival. Renal disease portends a poorer prognosis.

Patient Education

• Inform patients of the potential symptom complexes involved in the acute manifestations of cryoglobulinemia so medical therapy can be sought early to avoid potential organ damage.
• Patients with less severe disease that manifests primarily as arthralgias and fatigue benefit from understanding the precipitating factor (ie, cold temperatures, trauma). Avoidance and use of NSAIDs may reduce symptoms.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to recognize active vasculitis and to search for evidence of other organ involvement (renal)
• Failure to exclude infection as an etiology for disease manifestation (eg, hepatitis, endocarditis)
• Failure to identify underlying lymphoproliferative, hepatic, renal, or connective-tissue disease associated with typical clinical presentation

Special Concerns

• Pregnancy: Potential treatments may be contraindicated in pregnancy.
• Pediatric patients: Note dose limitations in pediatric patients.
• Geriatric patients: Be aware of potential underlying renal insufficiency prior to therapy in elderly patients. Elderly patients often require dose adjustments because of age-related alterations in pharmacokinetics and pharmacodynamics.

MULTIMEDIA

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Media file 1:  Rash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.
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Media type:  Photo

Media file 2:  Renal biopsy sample that shows membranoproliferative glomerulonephritis in a patient with hepatitis C–associated cryoglobulinemia (hematoxylin and eosin; magnified X 200).
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Media type:  Photo

REFERENCES

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3. Wang AC, Wells JV, Fudenberg HH. Chemical analyses of cryoglobulins. Immunochemistry. Jul 1974;11(7):341-5. [Medline].
4. Pastore Y, Lajaunias F, Kuroki A, Moll T, Kikuchi S, Izui S. An experimental model of cryoglobulin-associated vasculitis in mice. Springer Semin Immunopathol. 2001;23(3):315-29. [Medline].
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11. Sansonno D, Gesualdo L, Manno C, Schena FP, Dammacco F. Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology. May 1997;25(5):1237-44. [Medline].
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16. Beddhu S, Bastacky S, Johnson JP. The clinical and morphologic spectrum of renal cryoglobulinemia. Medicine (Baltimore). Sep 2002;81(5):398-409. [Medline].
17. Bryce AH, Kyle RA, Dispenzieri A, Gertz MA. Natural history and therapy of 66 patients with mixed cryoglobulinemia. Am J Hematol. Jul 2006;81(7):511-8. [Medline].
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Article Last Updated: Dec 4, 2007