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.[1]

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:

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.[2] Cryoglobulinemia associated with a particular disease (lymphoproliferative disorder, autoimmune disease, infectious disease) is known as secondary cryoglobulinemia.

In a French study of 36 patients with type I cryoglobulinemia, skin or vasomotor symptoms were present in 75%; nephropathy in 30%; and neuropathy in 47%. The underlying B cell disease was a nonmalignant monoclonal gammopathy in 36% and hematologic malignancy in 64%.Treatments included fludarabine and rituximab-based regimens. Five-year survival was 82%.[3]

In another study, of 64 patients with type I cryoglobulinemia vasculitis (CryoVas), Terrier et al identified 28 patients with monoclonal gammopathy of unknown significance and 36 with hematologic malignancy. Type I monoclonal CryoVas was characterized by severe cutaneous involvement (necrosis and ulcers) in almost 50% the patients, as well as high serum cryoglobulin levels. Survival rates were 97% at 1 year; 94% at 3 years; 94% at 5 years; and 87% at 10 years. Treatments included alkylating agents, rituximab, thalidomide or lenalinomide, and bortezomib. Clinical response rates ranged from 80-86%.[4]

In a study of patients with type II cryoglobulinemia, peripheral blood mononuclear cells from 18 patients were separated into CD3+ (T cells), CD19+ (B cells), and CD14+ (monocytes) and analyzed for the presence of negative-strand HCV RNA and for HCV nonstructural protein 3 (NS3). Negative-strand HCV RNA was detected in 6 patients, most frequently in B cells (3 patients), followed by T cells (2 patients) and monocytes (2 patients). NS3 protein was also detected in 6 patients: 5 were positive in T cells, 3 in B cells, and 3 in monocytes.[5]


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.[6, 7, 8] Alteration in protein conformation with temperature changes also leads to decreased solubility and subsequent vasculitic damage.[9, 10] 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.[11]

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 kidney injury). 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.[2, 12, 13, 14]

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.[13, 15, 16, 17]



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 over 18 years in their medical center in New York.[18] The prevalence of essential mixed cryoglobulinemia is reported as approximately 1:100,000.

The reported relative frequencies of the different types of cryoglobulinemia vary. Brouet et al reported the following frequencies: type I, 25%; type II, 25%; and type III, 50%.[19]


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 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.[20] 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.[21]

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.[22, 23, 24]


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


The mean age reported is 42-52 years.


Specific clinical manifestations associated with type I cryoglobulinemia are related to hyperviscosity and thrombosis, as would be expected given the usual high concentrations of immunoglobulins and limited interference with complement function. These manifestations include the following:

Specific clinical manifestations associated with types II and III cryoglobulinemia include the following:

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.[39, 25]

Cutaneous manifestations

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%).[19, 25, 18, 26]

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.[27] See the image below.

View Image

Rash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.

Musculoskeletal manifestations

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.[28, 29, 25]

Renal manifestations

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.[19, 30, 31]

Pulmonary manifestations

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.[32, 33, 34, 35]


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.[36, 25, 37, 38]

Other manifestations

Patients with cryoglobulinemia may also present with the following:


Skin manifestations include the following:

Pulmonary manifestations include the following:

Gastrointestinal manifestations include the following:

Renal manifestations include the following:

Joint manifestations include the following:

Nervous system manifestations include the following:

Fever is another manifestation.


Disease associations vary with the type of cryoglobulinemia, as follows:

Infections associated with cryoglobulinemia include the following:

Other disorders associated with cryoglobulinemia include the following:

Cryoglobulinemia may occur as a familial or idiopathic disorder. Finally, cases have been reported following vaccination (eg, with pneumococcal vaccine).

Laboratory Studies

To evaluate for serum cryoglobulins, the blood specimen must be collected 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:

Repeat centrifugation is performed 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).

Additional laboratory findings in cryoglobulinemia include the following:

Other studies to consider are as follows:

Imaging Studies


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).[18] 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.[41]

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. See the image below.

View Image

Renal biopsy sample that shows membranoproliferative glomerulonephritis in a patient with hepatitis C–associated cryoglobulinemia (hematoxylin and eos....

Medical Care

The goal of therapy is to treat underlying conditions, as well as to limit the precipitant cryoglobulin and the resultant inflammatory effects.[42] Thus, hepatitis C virus (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.[43]

Case reports have detailed the remission of hepatitis B–related cryoglobulinemic vasculitis with entecavir therapy.[44]

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.[45, 46] 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 has resulted in increased titers of HCV RNA of undetermined significance.

Rituximab was well tolerated and effective in a randomized controlled trial that compared rituximab with immunosuppressive therapy for HCV-associated cryoglobulinemic vasculitis in 24 patients in whom antiviral therapy had failed to induce remission. These researchers observed no adverse effects of rituximab on HCV plasma viremia or on hepatic transaminase levels.[60]


Medication Summary

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.

Ibuprofen (Advil, Motrin, Excedrin IB, Ibuprin)

Clinical Context:  NSAIDs are the DOC in patients with mild symptoms of arthralgia or fatigue. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Class Summary

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.

Prednisone (Sterapred)

Clinical Context:  DOC in patients with evidence of acute vasculitis.

Class Summary

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.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:  Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, interfering with growth of normal and neoplastic cells.

Azathioprine (Imuran)

Clinical Context:  Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Chlorambucil (Leukeran)

Clinical Context:  Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Class Summary

These are commonly used as steroid-sparing agents.

Interferon alfa-2b (Intron A)

Clinical Context:  Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Has antiviral activity in HCV infection.

Peginterferon alfa-2a (Pegasys)

Clinical Context:  Used in combination with ribavirin to treat patient with chronic HCV infection who have compensated liver disease and have not received IFN-alfa previously. Consists of interferon alfa-2a attached to a 40-kD branched PEG molecule. Predominantly metabolized by the liver.

Peginterferon alfa 2b (PEG-Intron)

Clinical Context:  Escherichia coli recombinant product. Used to treat chronic HCV infection in patients not previously treated with INF-alfa who have compensated liver disease. Exerts cellular activities by binding to specific membrane receptors on cell surface, which, in turn, may suppress cell proliferation and may enhance phagocytic activity of macrophages. May also increase cytotoxicity of lymphocytes for target cells and inhibit virus replication in virus-infected cells.

Class Summary

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

Ribavirin (Virazole)

Clinical Context:  Antiviral nucleoside analogs. Chemical name is 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, has little effect on the course of HCV infection. When used with IFN, significantly augments rate of sustained virologic response.

Class Summary

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.

Entecavir (Baraclude)

Clinical Context:  Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic hepatitis B infection. Available as tab and oral solution (0.05 mg/mL; 0.5 mg = 10 mL).

Class Summary

This agent inhibits the viral reverse transcriptase enzyme, which limits viral replication.

Rituximab (Rituxan)

Clinical Context:  Genetically engineered human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.

Immunomodulates response against malignant cells.

Class Summary

These agents inhibit cell growth and proliferation.

Further Inpatient Care

Further Outpatient Care

Inpatient & Outpatient Medications






Adam M Tritsch, MD, Resident Physician, Department of Internal Medicine, Eisenhower Army Medical Center, Fort Gordon, Georgia

Disclosure: Amgen Stocks None


Colin C Edgerton, MD, Clinical Assistant Professor, Department of Medicine, Medical College of Georgia; Clinical Assistant Professor, Department of Medicine, Uniformed Services University

Disclosure: Nothing to disclose.

Specialty Editors

Kristine M Lohr, MD, MS, Professor, Department of Internal Medicine, Interim Chief, Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Lawrence H Brent, MD, Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Disclosure: AbbVie Honoraria Speaking and teaching; Genentech Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Janssen Consulting fee Consulting

Alex J Mechaber, MD, FACP, Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Craig Ainsworth, MD Chief of Medical Residents, Department of Internal Medicine, Eisenhower Army Medical Center

Craig Ainsworth, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Robert John Oglesby, MD Chief of Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center; Associate Professor of Medicine, Uniformed Services University of the Health Sciences

Robert John Oglesby, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and Arthritis Foundation

Disclosure: Nothing to disclose.

Timothy M Straight, MD Instructor, Department of Medicine, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.


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Rash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.

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

Rash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.

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