Cryoglobulinaemia

Cryoglobulinaemia is a rare blood vessel condition where abnormal proteins clump together in cold temperatures, potentially blocking blood flow and damaging organs throughout the body, particularly the kidneys and liver.

Table of contents

• What is cryoglobulinaemia?
• Types of cryoglobulinaemia
• Symptoms
• Causes and risk factors
• Complications
• Diagnosis
• Treatment
• Living with cryoglobulinaemia

What is cryoglobulinaemia?

Cryoglobulinaemia is a family of rare conditions classified as vasculitis, which means irritation and swelling of the blood vessels^[1]. The name literally means “cold antibody in the blood,” which refers to the chemical properties of the proteins that cause this disease^[12].

Cryoglobulins are abnormal proteins found in the blood. For people who have cryoglobulinaemia, these proteins clump together at body temperatures below 98.6°F (37°C)^[1]. These clumps can block blood flow, which can damage the skin, joints, nerves and organs, mainly the kidneys and liver^[1].

Cryoglobulinaemia is a rare condition. Researchers estimate that it affects about 1 out of every 100,000 people worldwide^[8]. However, the exact number of cases is not known because low levels of cryoglobulins can be present without causing symptoms^[8].

Types of cryoglobulinaemia

There are three types of cryoglobulinaemia, classified based on the composition of the abnormal proteins^[2]:

• Type 1: This type has one kind of abnormal protein, called monoclonal. Type 1 most often is linked to blood cancers such as multiple myeloma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia^[1]. Because type 1 cryoglobulins do not easily activate complement (part of the immune system), patients with type 1 are usually without symptoms until the level of cryoglobulinemia is sufficiently high to cause hyperviscosity syndrome (when blood becomes too thick)^[12].
• Type 2: This type has two types of abnormal protein, both monoclonal and polyclonal. Type 2 most often is linked to hepatitis C virus^[1]. Both types 2 and 3 are called mixed cryoglobulins because they contain rheumatoid factors, which are antibodies that bind to other antibodies^[12].
• Type 3: This type has a mix of polyclonal proteins. Type 3 most often is linked to autoimmune diseases such as rheumatoid arthritis^[1].

Symptoms

Some people have no symptoms of cryoglobulinaemia. For people who have symptoms, the symptoms might come and go^[1].

The most common symptoms include:

• Skin spots: Most people with cryoglobulinaemia get purple skin spots, called lesions or purpura, on their legs. On Black or brown skin, the spots might look black or brown. Some people also get open leg sores, called ulcers^[1].
• Joint pain: Symptoms like those of rheumatoid arthritis are common in cryoglobulinaemia^[1].
• Peripheral neuropathy: Cryoglobulinaemia can damage the nerves at the tips of the fingers and toes. This causes numbness and other problems^[1].

Other symptoms may include:

• Spasms in the blood vessels of the hands and feet with cold temperatures that cause them to turn blue (Raynaud’s phenomenon)^[8]
• Weight loss^[8]
• High blood pressure^[8]
• Swelling of the ankles and legs^[8]
• Fatigue and weakness^[8]
• Enlarged liver or enlarged spleen^[8]
• Kidney damage^[8]

Causes and risk factors

It is not clear what causes cryoglobulinaemia^[1]. The condition is a type of vasculitis, which is an autoimmune disease. Autoimmune disorders occur when the body’s immune system attacks healthy tissue by mistake^[8].

Cryoglobulinaemia has been linked to:

• Infections: Hepatitis C is the most common infection linked to cryoglobulinaemia. It is now evident that most patients diagnosed with type 2 or type 3 mixed cryoglobulinemia have the disease as an immune response to chronic hepatitis C infection^[12]. Other infections include hepatitis B, HIV, Epstein-Barr, toxoplasmosis and malaria^[3].
• Certain cancers: Some cancers of the blood, such as multiple myeloma, Waldenström macroglobulinemia and chronic lymphocytic leukemia, can cause cryoglobulinaemia^[3].
• Autoimmune diseases: Diseases in which the immune system attacks healthy tissues by mistake, called autoimmune diseases, increase the risk of getting cryoglobulinaemia. Examples are lupus, rheumatoid arthritis and Sjögren’s syndrome^[3].

Risk factors of cryoglobulinaemia may include:

• Sex: Cryoglobulinaemia happens more often in women than in men^[3].
• Age: Symptoms of cryoglobulinaemia most often begin in middle age, typically affecting people over the age of 50^[3].
• Other diseases: Cryoglobulinaemia is linked with diseases such as hepatitis C, HIV, multiple myeloma, Waldenström macroglobulinemia, lupus and Sjögren’s syndrome^[3].

Drug use is a prime risk factor for cryoglobulinaemia because more than 90% of cases are associated with hepatitis C infections. Hepatitis C is acquired by injection drug use (needle-sharing), tainted blood products, and probably rarely, sexual transmission^[12].

Complications

Left untreated, cryoglobulinaemia can cause permanent skin, tissue and organ damage, including^[8]:

• Skin infections or ulcers
• Skin death (necrosis)
• Kidney failure
• Liver failure

Diagnosis

Diagnosis of cryoglobulinaemia involves a blood test. The blood is kept at body temperature, 98.6°F (37°C), for a time. Then it is cooled before being tested. The sample must be handled this way to get correct results^[10]. Your healthcare provider will order a specific blood test that detects the presence of cryoglobulins in your blood^[8].

Learning the type of cryoglobulins you have can sometimes help determine the cause and how to treat it^[8]. Diagnosis involves measuring cryoglobulin levels along with low C4 complement levels^[2].

Other blood and urine tests also might be used to find the underlying cause^[10]. Your healthcare provider will ask about your medical history and perform a physical exam^[8].

Treatment

Treatment depends on the cause of cryoglobulinaemia and how severe it is. Watchful waiting might be a choice if you have no symptoms^[10]. Asymptomatic cryoglobulinaemia does not require treatment^[4].

Treatment may include:

• Medicines that calm the immune system: Corticosteroid therapy is considered for at least initial therapy in patients with more severe symptoms such as vasculitis, neurologic findings, severe skin disease, or kidney involvement^[11]. Treatment varies based on the severity and nature of the underlying disorder, with mixed cryoglobulinemia typically treated with steroids and rituximab^[2].
• Medicines that fight viral infections: Treatment may include antiviral medications, particularly for hepatitis C-related cryoglobulinemia^[10]. Treatment of the underlying hepatitis may be an effective therapy for this type of vasculitis^[12].
• Plasmapheresis: For severe symptoms, a treatment that swaps blood plasma for donor plasma or another fluid might be used^[10]. Plasmapheresis is indicated for severe or life-threatening complications related to in vivo cryoprecipitation or serum hyperviscosity^[11].
• NSAIDs: Nonsteroidal anti-inflammatory drugs may be used in patients with joint pain and fatigue^[11].

Treatment targets both the cryoglobulins and the underlying conditions. Secondary cryoglobulinaemia is best managed with treatment of the underlying malignancy or associated disease^[11].

Even with treatment, cryoglobulinaemia often returns. You might need regular follow-up visits with your health care professional to watch for its return^[10].

Living with cryoglobulinaemia

If you have cryoglobulinaemia, it is important to stay out of cold temperatures. Protect your fingers and toes. You may want to wear gloves when using the freezer or refrigerator^[10].

Check your feet daily for sores. Cryoglobulinaemia can make it harder for foot damage to heal^[10].

Living with cryoglobulinaemia requires a multidisciplinary approach to managing symptoms and improving overall well-being. Regular check-ups with healthcare providers are essential to monitor disease progression^[16].