Cryoglobulins are the immunoglobulins that precipitate in vitro at temperatures < 37°C and redissolve after rewarming. Cryoglobulinemia refers to the presence of cryoglobulins in serum. Cryoglobulinemic disease or cryoglobulinemic vasculitis is used to describe patients with symptoms related to the presence of cryoglobulins.

Early diagnosis and treatment are important as the patient can develop kidney failure, respiratory distress, and advanced neuropathy and can cause death if left untreated. Treating the underlying cause is mainly important to control cryoglobulinemia. Symptomatic treatment includes NSAIDs, Corticosteroids, and immunosuppressives are required to reduce the symptoms. In severe cases, plasmapheresis and intravenous steroids are preferred.

Cryoglobulinemia: Causes

Cryoglobulinemia is divided into various types based on the components of the cryoprecipitate −

  • In Type I, there is isolated monoclonal immunoglobulin, generally either IgM or IgG.

  • In Type II cryoglobulins a mixture of monoclonal IgM and polyclonal IgG.

  • In Type III cryoglobulins mixture of polyclonal IgM and IgG and other forms of cryoglobulinemia have also been reported.

The condition mainly occurs between 45 to 60 years of age. Viral infections such as HCV, HBV, and HIV, autoimmune diseases such as primary Sjogren’s syndrome, SLE, and rheumatoid arthritis, and some malignancies such as B cell lymphoproliferative disorders are more commonly involved in the accumulation of cryoglobulins in the serum.

The patients usually present with a triad of purplish discoloration of the skin, pain in the joints, and weakness. In severe cases, the patients present with kidney failure, and respiratory distress which may cause death.

Cryoglobulinemia: Symptoms

The patient with cryoglobulinemia mainly presents with the following symptoms that include −

  • Most patients present with cutaneous purpura that is purplish discolored patches seen on the skin due to internal bleeding. This is mainly seen in patients with cryoglobulinaemic vasculitis

  • Joint pain in the hands, knees, and wrists

  • Weakness and fatigue

  • Neurological symptoms such as headache, confusion, blurring or loss of vision, bleeding from the nose, and hearing loss. These symptoms are more common in patients with hyperviscosity syndrome and usually develop in patients with type I cryoglobulinemia associated with hematological neoplasia

  • In patients with renal involvement present with protein and blood in the urine and mother symptoms of kidney involvement

  • If there is gastrointestinal involvement the patient presents with pain abdomen, fever, and bloody stools

  • When the lungs are involved, the patient presents with a cough, difficulty in breathing, and chest tightness

Cryoglobulinemia: Risk Factors

Several factors play an important role in the development of claudication which includes −

  • More common in older adults

  • Women are more affected than the males

  • A patient with a history of Chronic infection with the hepatitis C virus (HCV), is the major risk factor for the development of this condition.

  • People with autoimmune disorders such as lupus, rheumatoid arthritis, and primary Sjogren's syndrome have an increased risk of developing cryoglobulinemia.

  • Cryoglobulinemia can be associated with certain types of cancers, such as multiple myeloma and lymphoma.

  • Chronic infections, such as HIV and hepatitis B, have been associated with an increased risk of developing cryoglobulinemia.

  • Genetics also have been known to increase the risk

  • Exposure to certain environmental factors such as cold temperatures, certain medications, and chemicals may increase the risk of developing cryoglobulinemia.

Cryoglobulinemia: Diagnosis

The diagnosis of cryoglobulinemia is mainly done based on history and some of the tests may be required for confirmation and to rule out underlying causes.

  • Levels of serum cryoglobulins should be checked. Blood is collected in prewarmed syringes and tubes, transported, clotted, and centrifuged at 37–40°C, ensuring that the temperature never falls below 37°C. The serum is stored at 4°C for up to 7 days. Precipitation of type I cryoglobulins usually occurs within hours. Mixed cryoglobulins, particularly type III, can need days to precipitate. Cryoglobulin should be assayed serially when there is a high degree of suspicion of disease.

  • Complete blood count

  • Renal function tests to look for renal involvement

  • Liver function tests

  • Serum rheumatoid factor, antibodies, and serum HCV-RNA detection are required

  • Testing for other viruses hepatitis B virus, HIV

  • Antinuclear antibodies, anti-DNA, anti-Ro/La, and anticitrullinated antibodies have to be checked to look for autoimmune diseases.

  • Skin biopsy and renal biopsy are advised in some patients

Cryoglobulinemia: Treatment

The treatment of cryoglobulinemia is based on the underlying cause of the condition.

Conservative treatment includes −

  • Treat the underlying cause which is causing the cryoglobulin precipitate.

  • Cytotoxic agents such as cyclophosphamide are required in some patients.

  • Anti-viral such as Interferon and Ribavirin is used to treat the viral infections.

  • Rituximab is used in the refractory case and acts by targeting a specific type of white blood cell called B cells, which produce cryoglobulins.

  • Treating the underlying cause. If cryoglobulinemia is caused by an underlying condition such as hepatitis C, treating that condition may help to alleviate the symptoms of cryoglobulinemia.

  • Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressive drugs are used to reduce inflammation and improve joint pain, skin rashes, and other symptoms.

  • Aggressive Therapy that includes plasmapheresis to remove the circulation cryoglobulins and Intravenous steroids are required on patients with renal failure and advanced neuropathy.

Cryoglobulinemia: Prevention

Some of the measures that can help to prevent cryoglobulinemia include &miinus;

  • Avoiding drug use as Hepatitis C can also be transmitted through intravenous drug use, so avoiding drug use or seeking help to quit drug use can help to prevent this infection.

  • Practicing proper hygiene, such as washing hands regularly, can help to prevent the spread of infectious diseases that can lead to cryoglobulinemia

  • Vaccines for hepatitis B and C can help to prevent these viral infections

  • Hepatitis B and C can be transmitted through sexual contact, so practicing safe sex can help to prevent these infections.

Maintaining a healthy balanced diet, regular physical exercises, and avoiding exposure to harmful chemicals or toxins can help to promote overall health and reduce the risk of developing cryoglobulinemia.


Cryoglobulinemia is a condition that refers to the precipitation of cryoglobulins in the serum. Various causes have been known to cause cryoglobulinemia. Hepatitis C viral infection is the main cause. Other causes include hep b infection, HIV, certain autoimmune disorders such as Sjogren’s syndrome, Rheumatoid arthritis and SLE, and certain malignancies.

The patient mainly presents with purpura, joint pain, weakness, fatigue, pain abdomen, loose stools, and difficulty in breathing. In severe cases, death can occur due to renal failure and advanced neuropathy.

The diagnosis can be done by measuring the serum levels of cryoglobulins. Other investigations like CBC, renal function test, liver function test, testing for hep B and C infections, HIV testing and serum RA factors, Antinuclear antibodies, anti-DNA, anti-Ro/La, and anticitrullinated antibodies.

The treatment of cryoglobulinemia involves, treating the underlying cause, Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressive drugs are used to reduce inflammation and improve joint pain, skin rashes, and other symptoms. Plasmapheresis and Rituximab are used in advanced cases where the other treatments are not helpful.

Dr. Durgesh Kumar Sinha
Dr. Durgesh Kumar Sinha


Updated on: 17-Apr-2023


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