NORD is very grateful to Vincent Agnello, MD, Lahey Clinic, Burlington, Massachusetts and VA Medical Center, Bedford, Massachusetts, for assistance in the preparation of this report.
Synonyms of Mixed Cryoglobulinemia
- Cryoglobulinemic Vasculitis
- Essential Mixed Cryoglobulinemia
- Type I Cryoglobulinemia
- Type II Cryoglobulinemia
- Type III Cryoglobulinemia
Mixed cryoglobulinemia is a rare disorder characterized by the presence of cryoglobulins in the blood. Cryoglobulins are abnormal proteins that thicken and clump together at cold temperatures, usually below 98.6 degrees Fahrenheit (the average human body temperature). However, the exact temperature at which this occurs may vary from one person to another. When these proteins clump together, they can restrict blood flow to joints, muscles, and organs. Eventually, damage or inflammation of affected blood vessels and surrounding tissue can develop, a condition known as vasculitis. Small blood vessels are usually affected, but occasionally larger blood vessels are involved. Common symptoms include skin lesions, joint pain (arthralgia), and weakness, but specific symptoms can vary greatly from one person to another and can potentially involve multiple organ systems. Mixed cryoglobulinemia is believed to be an immune-mediated disorder (in which the immune system response to chronic infection causes damage to various tissues) or an autoimmune disorder (in which the immune system mistakenly attacks the body’s own tissue). Many cases of mixed cryoglobulinemia are associated with chronic infection with the hepatitis C virus. In rare cases, no underlying cause for the disorder can be identified (essential mixed cryoglobulinemia).
Cryoglobulinemia involves dysfunction of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against infectious agents. The T cell system (cell-mediated immune response) contributes to fighting several viruses, some bacteria and yeast and fungi. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g. saliva). There are five classes of immunoglobulins (Ig) known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Any substance that triggers a response by the immune system is known as an antigen.
Cryoglobulinemia is generally broken down in three subtypes. In type I cryoglobulinemia, cryoglobulins are made up of a specific immunoglobulin, usually IgM. Type I cryoglobulinemia is usually associated with an underlying disorder, specifically certain types of cancer. Type II and type III cryoglobulinemia are known as mixed cryoglobulinemia. In these disorders, cryoglobulins are abnormal immune complexes. An immune complex is formed when an antibody attaches to an antigen. Unlike type I cryoglobulinemia, the cryoglobulins in type II and type III contain rheumatoid factor, which is an autoantibody (i.e. an antibody that attacks the body own tissue). The distinction between type II and type III cryoglobulinemia is mostly technical and deals with whether the rheumatoid factor is monoclonal or polyclonal. The clinical pictures of type II and III cryoglobulinemia are similar. This report primarily deals with mixed cryoglobulinemia.
The symptoms and physical findings of mixed cryoglobulinemia can vary greatly from one individual to another. Many different organ symptoms can be potentially become involved. Some individuals will only exhibit one manifestation of the disorder; others will exhibit symptoms of multiple organ systems.
Most affected individuals develop purplish discoloration of the skin due to bleeding underneath the skin from small blood vessels (purpura). Numerous small lesions the size of pinpricks (petechaie) may develop. Larger lesions or bruising (ecchymoses) can also occur. The lower extremities are most often affected. Purpuric lesions are most common after an affected individual has been standing or sitting for long periods of time (orthostatic purpura). In some cases, open sores (ulceration) and hives (urticarial) may also develop. Loss of tissue (necrosis) on the extremities (e.g. fingers and toes) can also occur.
Although joint pain (arthralgia) is very common in individuals with cryoglobulinemia, joint inflammation (arthritis) occurs far less frequently. Additional nonspecific symptoms are common including mild to severe itching, mild to severe pain, abdominal pain, muscle weakness, muscle pain (myalgia), and abnormal enlargement of the lymph nodes (lymphadenopathy). In some cases, abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) may occur.
Cryoglobulinemia can be associated with a kidney (renal) disease known as membranoproliferative glomerulonephritis (MPGN) type I characterized by a specific pattern of injury to the kidney most likely caused by deposition of cryoglobulins in the kidney. MPGN type I can be a severe complication, eventually leading to kidney failure.
Affected individuals may experience damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and painful or burning sensations that usually begin in the feet and sometimes the arms. These sensations may worsen at night (nocturnal exacerbation). Peripheral neuropathy may cause muscles weakness in legs and arms.
Affected individuals may also develop an abnormally dry mouth (xerostomia) and abnormally dry eyes (xerophthalmia), a combination which is sometimes referred to as Sicca syndrome. Numbness and tingling and a lack of blood flow to the fingers/or toes when exposed to cold temperatures (Raynaud’s phenomenon) may also occur. Internal bleeding and abnormal blood clot formation has also been reported.
Chronic inflammation of the liver (hepatitis) can occur in affected individuals, particularly those with hepatitis C-associated mixed cryoglobulinemia. Chronic hepatitis is often mild or moderate and may not cause any symptoms. Symptoms that can occur include fatigue and aching muscles or joints. Chronic hepatitis can eventually progress to cause scarring (cirrhosis) of the liver.
Less often, additional symptoms have been reported in individuals with mixed cryoglobulinemia including lung disease, widespread (diffuse) vasculitis, and certain endocrine disorders such as disorders of affecting the thyroid including autoimmune thyroiditis, hypothyroidism and thyroid cancer. Diffuse vasculitis is a severe, potentially life-threatening complication. When the gastrointestinal tract is involved, sudden, severe abdominal pain (acute abdomen) may be the initial symptom.
Diabetes mellitus type 2 occurs with greater frequency in individuals with hepatitis C infection with and without mixed cryoglobulinemia than it does in the general population. Whether individuals with mixed cryoglobulinemia have a higher risk of developing diabetes is not known. Some individuals with mixed cryoglobulinemia may develop cancer as a late complication of the disorder, specifically a type of B-cell lymphoma or a form of liver cancer known as hepatocellular carcinoma.
Mixed cryoglobulinemia is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunogic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of mixed cryoglobulinemia have not been conclusively identified.
Mixed cryoglobulinemia has been associated with various infectious agents and immune disorders. In the majority of cases, chronic infection with the hepatitis C virus is believed to play a role the development of the disorder. Mixed cryoglobulinemia affects approximately 30%-50% of individuals with chronic hepatitis C infection. However, only 10%-30% of those individuals actually develop symptoms of mixed cryoglobulinemia (although their blood contains abnormal cryoglobulins). Why some individuals with hepatitis C virus infection develop symptomatic mixed cryoglobulinemia and others do not, is not fully understood.
Additionally, mixed cryoglobulinemia has been associated with other disorders including systemic lupus erythematosus, Sjogren’s syndrome, human immunodeficiency virus (HIV), rheumatoid arthritis, and, in extremely rare cases, lymphoma. In less than 5% of cases, mixed cryoglobulinemia has been associated with infection with the hepatitis B virus. In rare cases, no underlying disorder can be identified in affected individuals. These individuals are referred to as having essential mixed cryoglobulinemia. The number of individuals diagnosed with essential mixed cryoglobulinemia has dramatically decreased since the association with the hepatitis C virus was established.
The symptoms of mixed cryoglobulinemia are caused by deposition of abnormal immune complexes (cryoglobulins) in the blood vessels and surrounding tissues of the body. These large immune complexes stick to the walls of the blood vessels restricting blood flow to various organs. In addition, they may cause an immune system response, in which white blood cells are sent to the affected blood vessels, causing inflammation and damage to the blood vessels and surrounding tissue.
Mixed cryoglobulinemia is believed to be a rare disorder, but the exact incidence and prevalence in the general population is unknown. Less than 1% of HCV-infected patients in Northern Europe and North America develop cryoglobulinemia while 2-5% of HCV-infected patients in South Europe develop the disorder. Mixed cryoglobulinemia most often presents in individuals between the ages of 40-60. Females are affected three times as often as males. Approximately 90% of cases of mixed cryoglobulinemia are associated with infection with the hepatitis C virus.
Symptoms of the following disorders can be similar to those of mixed cryoglobulinemia. Comparisons may be useful for a differential diagnosis.
There are numerous disorders that overlap, occur in conjunction with or have signs and symptoms that are similar to cryoglobulinemia. These disorders include Sjogren’s syndrome, rheumatoid arthritis, B-cell lymphomas, autoimmune hepatitis, systemic lupus erythematosus, Waldenstrom’s macroglobulinemia, multiple myeloma, hemolytic uremic syndrome, antiophospholipid syndrome, and polyarteritis nodosa. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of mixed cryoglobulinemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a blood test to detect the presence of cryoglobulins.
Clinical Testing and Workup
The key test for mixed cryoglobulinemia is a blood test. When a blood sample is taken, its temperature is 37 Celsius. It is essential that the sample remains at this temperature until it is placed in a room-temperature centrifuge. Usually, the sample will be stored in a water bath or a container that preserves the sample at body temperature. The sample may be required to be stored for 5-7 days. Eventually, the sample will be spun down in the centrifuge to separate out the cells. If cryoglobulinemia is present, this will cause a white precipitate to form that redissolves upon rewarming.
Additional routine viral and antibody tests may be performed such as a test to detect rheumatoid factor, which is positive in 80%-90% of cases.
In some cases, tests to measure the levels of certain proteins known as complement may be performed. Individuals with cryoglobulinemia often have low levels of complement (hypocomplementemia), especially low C4 levels. Blood tests can reveal characteristic low levels of complement, which can aid in a diagnosis of cryoglobulinemia.
Additional tests may be performed to detect underlying disorders potentially associated with cryoglobulinemia such as liver function tests that can reveal hepatitis C virus infection.
The treatment of mixed cryoglobulinemia may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, kidney specialists (nephrologists), liver specialists (hepatologists), specialists in diagnosing and treating blood disorders (hematologists), and other healthcare professionals may need to systematically and comprehensively plan an affect individual’s treatment.
Initial treatment is directed against the underlying condition associated with the disorder, which in most cases will be infection with the hepatitis C virus. Affected individuals are treated with pegylated interferon usually in conjunction with ribavirin to eradicate the hepatitis C virus. This treatment often leads to significant clinical improvement.
Additional therapies are tailored to the individual patient based upon numerous factors including the severity and progression of the disease, specific organ involvement, any associated disorders, overall health, patient preference, and additional factors. These therapies may be used alone or in conjunction with one another.
Immunosuppressive drugs such as corticosteroids, cyclophosphamide, or azathioprine may be used in individuals with organ involvement including vasculitis, kidney disease, neurological symptoms, or disabling skin abnormalities. These drugs require careful monitoring because they can cause virus replication. Immunosuppressive drugs may be the initial therapy in individuals without a known underlying cause to their cryoglobulinemia (essential mixed cryoglobulinemia).
A newer immunosuppressive drug known as rituximab has been increasingly used for the major complications associated with mixed cryoglobulinemia (see Investigational Therapies below).
Additional treatment is symptomatic and can include non-steroidal anti-inflammatories drugs (NSAIDs) for the treatment of fatigue and arthralgia. Some individuals may be treated with a low antigen complement (LAC) diet. This diet is designed to promote the clearance of circulating immune complexes (cryoglobulins) from the blood. The LAC diet is best for individuals with mild mixed cryoglobulinemia and often used in conjunction with low doses of corticosteroids.
Researchers are studying the use of the immunosuppressive drug rituximab, which targets specific white blood cells known as B-lymphocytes, for the treatment of individuals with mixed cryoglobulinemia. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Initial studies have shown that the drug is safe and effective. Advantages of rituximab are that it avoids serious immunosuppression and side effects associated with other immunosuppressive agents. More research is necessary to determine the long-term safety and effectiveness of rituximab for the treatment of mixed cryoglobulinemia.
Some individuals who have severe mixed cryoglobulinemia may undergo a procedure known as plasmapheresis. These procedures are usually reserved for individuals who have not responded to other treatment options and are experiencing severe or life-threatening complications. Plasmapheresis involves removing unwanted substances (e.g. cryoglobulins) from the blood. Blood is removed from the patient and the solid blood cells are separated from the liquid plasma. The patient’s plasma is then replaced with donor human plasma or albumin, which is re-transfused, along with the patient’s original blood cells.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Mixed Cryoglobulinemia Resources
NORD offers an online community for this rare disease. RareConnect was created by EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders) to provide a safe space where individuals and families affected by rare diseases can connect with each other, share vital experiences, and find helpful information and resources. You can view these international, rare disease communities at www.rareconnect.org.
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Ferri C, Sebastiani M, Saadoun D, Cacoub P. Cryoglobulinemia and Hepatitis C Virus. In: EULAR Textbook on Rheumatic Diseases, Bijlsma JWJ, Burmester GR, da Silva JAP, Faarvang KL, et al., editors. 2009 BMJ Publishing Group LTD, London, England. pp. 795-802
Casato M, Agnello V. Mixed Cryoglobulinemia Syndrome Secondary to Hepatitis C Virus Infection. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:5.
Choudry M, Rao N, Juneja R. Successful treatment of cryoglobulinaemia with rituximab. Case Rep Nephrol Urol. 2012;2:72-77. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482085/
Iannuzzella F, Vaglio A, Garini G. Management of hepatitis C virus-related mixed cryoglobulinemia. Am J Med. 2010;123:400-408. http://www.ncbi.nlm.nih.gov/pubmed/20399313
Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008;3:25. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569912/
Bryce AH, Dispenzieri A, Kyle RA, et al. Response to rituximab in patients with type II cryoglobulinemia. Clin Lymphoma Myeloma. 2006;7:140-144. http://www.ncbi.nlm.nih.gov/pubmed/17026826
Morra E. Cryoglobulinemia. Hematology Am Soc Hematol Educ Program. 2005;368-372. http://www.ncbi.nlm.nih.gov/pubmed/16304405
De Rosa FG, Pucillo LP, Casato M, Agnello V. Myths, misconceptions and mixed cryoglobulinemia associated with HCV infection. Minerva Gastroenterol Dietol. 2002;48:319-329. http://www.ncbi.nlm.nih.gov/pubmed/16491057
Ferri C. Mixed Cryoglobulinemia. Orphanet Encyclopedia, December 2011. Available at: http://www.orpha.net/ Accessed on: May 19, 2013.
Tritsch AM, Ainsworth C, Edgerton CC, Oglesby RJ. Cryoglobulinemia. Emedicine Journal, January 18, 2012. Available at: http://emedicine.medscape.com/article/329255-overview Accessed on: May 19, 2013.
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