Cryoglobulinemia

What is Cryoglobulinemia?

Cryoglobulins are special types of proteins that become solid or clump together when it’s colder than the human body temperature (37 degrees Celsius). These proteins can either be built of other proteins, known as immunoglobulins, along with complement components or just immunoglobulins alone. They lodge themselves inside blood vessels of moderate to small size all across the body, causing harm to the blood vessels’ interiors and damaging organs. This condition is known as cryoglobulinemia.
People with symptoms like skin ulcers, joint pain, kidney inflammation, nerve disorders, and a type of rash called purpura should be suspected to have cryoglobulinemia.

Cryoglobulinemia can be categorized into three main types based on the composition of their immunoglobulins.

Type I: In this type, the cryoglobulins are made up of only one type of immunoglobulin, mainly IgG or IgM. It usually occurs in people having disorders of B-cells, which are a type of white blood cell. These disorders usually include diseases like multiple myeloma, Waldenström macroglobulinemia, chronic lymphocytic leukemia, or conditions that produce a lot of one type of protein, known as monoclonal gammopathies, such as MGUS.

Type II: This, along with type III, falls into the category of mixed cryoglobulinemia, characterized by the presence of different kinds of immunoglobulins. It is often related to autoimmune diseases, cancers, or infections, especially hepatitis C virus (HCV) infection. Its immunoglobulin is not made up of only one type.

In type II, the cryoglobulins are a mixture of a single type of IgM (or IgG or IgA) which has an association with rheumatoid factor (RF) activity, combined with a variety of immunoglobulin types.

Commonly, type II cryoglobulinemia is linked with the following conditions:

– HCV infection, which is the most common cause for mixed cryoglobulinemia and vasculitis related to cryoglobulins.
– Vaccines.
– Hepatitis B virus (HBV) infection.
– HIV.
– Autoimmune diseases, primarily systemic lupus erythematosus (SLE), Sjögren syndrome, and adult-onset Still disease.
– Disorders of lymphocytes (kind of white blood cells).

Around 10% cases of this type do not have any known cause and are therefore referred to as “essential mixed cryoglobulinemia.”

Type III: The cryoglobulins in type III are a mix of all types of IgG and IgM, each of a different type. This condition most often occurs due to autoimmune disorders, sometimes associated with infections, generally hepatitis C virus.

What Causes Cryoglobulinemia?

Cryoglobulin is a type of protein that’s usually found in low amounts in healthy people. Scientists believe that these low levels show that the immune system is actively working to keep this protein in check through the use of special proteins with certain activity.

Often, the main factor that increases the risk of having too much cryoglobulin, a condition known as cryoglobulinemia, is drug use. Indeed, 90% of the instances where the blood vessels become inflamed due to cryoglobulin, a condition known as cryoglobulinemic vasculitis, are connected to hepatitis C infections. Here, the antibodies against the hepatitis C virus cause the formation of immune complexes, which leads to the activation of the immune response and as a result, causes blood vessel inflammation.

Additionally, cryoglobulinemia is also linked to diseases characterized by an overproduction of certain types of proteins, such as multiple myeloma, Waldenstrom macroglobulinemia, or MGUS, and diseases related to the damage of kidneys of unknown origin. Cryoglobulinemia is also associated with connective tissue diseases, such as lupus and Sjogren syndrome.

Risk Factors and Frequency for Cryoglobulinemia

Cryoglobulinemia is a rare condition, affecting approximately 1 in 100,000 people, with more cases seen in Southern Europe. It’s more common in people with certain conditions like HIV, Hepatitis C (HCV), and those who have both HIV and HCV. It’s also associated with autoimmune diseases like lupus (SLE) and Sjögren syndrome, as well as blood cancers like multiple myeloma and lymphoma.

This condition mostly affects adults and is seen more in females. Types of cryoglobulinemia vary, and geography also plays a role in its prevalence, since it is related to the spread of HCV and other associated diseases. Since it’s linked to many different factors, its occurrence is influenced by a mix of genetic factors, the environment, and infections.

• Cryoglobulinemia is a rare illness, affecting about 1 in 100,000 people and is more prevalent in Southern Europe.
• It’s found in 15% to 20% of people with HIV, 40% to 65% of those with HCV, and over 90% of people with both HIV and HCV.
• It’s associated with autoimmune diseases like lupus and Sjögren syndrome, as well as blood cancers like multiple myeloma and lymphoma.
• More commonly seen in adults and females.
• 5% to 25% of cases are of type 1 cryoglobulinemia.
• The prevalence of the condition varies by region, correlating with the spread of HCV and other related diseases.
• Genetic, environmental, and infectious influences all play a role in its occurrence.

Signs and Symptoms of Cryoglobulinemia

Cryoglobulinemia is a medical condition that can be identified by a history of certain health issues. These could include autoimmune diseases, specific infections such as Hepatitis B and C or HIV, certain blood diseases, cold sensitivity resulting in skin ulcers, and symptoms indicating nerve damage due to insufficient blood flow.

Some common symptoms of cryoglobulinemia are joint pain, purplish skin spots (purpura), skin ulcers, a specific type of kidney disease (glomerulonephritis), and peripheral neuropathy. It’s important to pay closer attention if these symptoms are accompanied by a clonal hematologic disorder, a type of blood disease.

Cryoglobulinemia can present itself in different ways and can be categorized into different types as follows:

• Type I Cryoglobulinemia: Mostly presents with symptoms related to blood vessels like skin necrosis, livedo reticularis (a purplish, lacy skin rash), and ischemia (insufficient blood supply). Skin issues are the most common, occurring in about 70 to 85% of cases. Early treatment of these skin abnormalities can help prevent more severe conditions like gangrene.
• Type II/III (mixed) Cryoglobulinemia: Commonly related to underlying symptoms like fatigue, joint pain, and muscular pain. Purpura (skin spots), which can be palpable or felt under the skin, and sensory changes due to peripheral neuropathy are also common. A combination of the commonly seen symptoms which include purpura, arthralgias (joint pain), and weakness, is referred to as the “Meltzer triad”, and is detected early in about 80% of the patients. The most common symptom here is purpura, often seen on the legs but can spread to the torso and upper body. These symptoms usually last for 1-2 weeks, with recurrent episodes occurring 1-2 times a month.

Testing for Cryoglobulinemia

To identify cryoglobulinemia – a condition where abnormal proteins in the blood clump together – two significant indicators are used. These include measuring cryoglobulin, a protein that clumps together when cold, and checking for a low C4 complement level, which is a part of your immune system. This pair is often found in cases of cryoglobulinemia.

The laboratory process for detecting cryoglobulins requires collecting about 10 to 20 mL of blood, which is then prepared at a specific temperature without adding any anticoagulants. The blood is spun in a machine to separate the components and then placed in a refrigerator so the cryoglobulin can form a sediment. In type I cryoglobulinemia, this process often takes between 24 hours up to 5 days, while type II and type III takes around 5 to 7 days to appear as a sediment.

The amount of cryoglobulin in the blood compared to the total blood volume is known as the cryocrit. Usually, people without cryoglobulinemia have a cryocrit close to zero, and having a cryocrit of more than 0.5% to 1% or a concentration greater than 50 mcg/mL is deemed significant. It’s important to mention that the usefulness of a cryocrit test is limited as its results may not always be reliable or repeatable. However, a drop in the cryocrit over time could suggest successful treatment.

Depending on the type of cryoglobulinemia, the cryocrit levels can vary. In type II, it’s usually between 2% and 7%, and in type III, it’s about 1% to 3%. Type I, which is linked with certain immune system diseases, tends to have a higher cryocrit than type II, which almost never shows signs of overly thick blood. However, the cryocrit doesn’t reflect the severity of the disease, and the presence of symptoms should determine treatment. Even if the cryocrit is high, patients without symptoms usually don’t require any treatment.

Other laboratory tests that can help evaluate cryoglobulinemia include immunochemical analysis, urinalysis, and tests for viral infections. Sometimes, a biopsy, or a sample of tissue from affected organs, is necessary for further evaluation. In some cases, doctors may use testing methods like electromyography (EMG) or imaging studies to confirm the presence of cryoglobulinemia.

Around half of the patients with cryoglobulinemia who also have the Hepatitis C Virus (HCV) may experience kidney issues, usually 3 to 5 years after the appearance of purplish spots on the skin. The most common complication is a specific type of kidney inflammation. A kidney biopsy can be used to determine the extent of the disease.

Treatment Options for Cryoglobulinemia

The treatment for cryoglobulinemia, a health condition related to abnormal proteins in the blood, largely depends on the specific type of disorder a patient has and how severe their symptoms are. Often, treatment focuses on addressing any underlying issues such as autoimmune conditions or infections. If a person has a more severe type of cryoglobulinemia, the common treatments involve steroids and a drug called rituximab. The plan of treatment usually includes measures like plasmapheresis, which is a procedure where the blood is filtered and returned to the body, and immunosuppression, which involves taking medications to lower the body’s immune response.

The most common cause of mixed cryoglobulinemia is Hepatitis C (HCV) infection. Treatment approaches have recently changed with the advent of direct antiviral therapy. Nowadays, HCV-positive patients with cryoglobulinemia usually start treatment with specific antiviral drugs such as sofosbuvir, velpatasvir, glecaprevir, or pibrentasvir. Studies show that this treatment works for nearly all patients, although there is a relapse rate of about 13%. Antiviral medications are necessary to eliminate the risk of viral infection, especially for patients who are on immunosuppressive treatment.

The severity of the disease guides the treatment approach. In mild cases, physicians usually do not prescribe immunosuppressive treatment but focus on addressing the underlying cause of the disease. In moderate-to-severe cases, the focus is on treating the main symptoms with immunosuppressive therapy, which usually starts once a steady state is achieved. This typically involves the use of drugs such as high-dose glucocorticoids and rituximab.

Rituximab has been shown to be effective in helping manage cryoglobulinemia by improving symptoms, reducing factors contributing to the illness, and eliminating disease-causing cells. However, this drug may cause side effects, such as serious episodes of inflammation of the blood vessels (vasculitis), sudden allergic reactions, and an increase in HCV virus levels. As a result, its use requires monitoring, especially for patients with a dormant Hepatitis B Virus (HBV) infection. For severe cases of the disease, rituximab is often required as part of long-term treatment.

In severe cases, a procedure called apheresis is often necessary. Apheresis quickly reduces the amount of abnormal proteins and viral particles in the blood, primarily addressing issues of blood thickness (hyperviscosity). However, this treatment may lead to an increase in abnormal protein synthesis, and to counteract this, drugs like cyclophosphamide or steroids are often used. Apheresis procedures, combined with steroid and cyclophosphamide, have shown high success rates in patients with kidney involvement due to cryoglobulinemia.

Patients undergoing treatment for cryoglobulinemia should be closely monitored. This includes regular check-ups, monitoring of blood pressure and creatinine levels, and observations of skin involvement. Vaccinations against diseases like influenza, pneumococci, varicella zoster, and COVID-19 are recommended for patients due to their weakened immune systems. However, vaccination should ideally be done before starting steroid or immunosuppressive drugs. If patients are already undergoing treatment, vaccination should be delayed to optimize response.

What else can Cryoglobulinemia be?

Cryoglobulinemia is a medical condition that requires a detailed examination, as its symptoms are very similar to other types of blood vessel inflammation diseases that impact smaller to medium-sized blood vessels. When doctors are considering a diagnosis of cryoglobulinemia, they also need to consider the following conditions that can have similar indicators:

• ANCA-associated vasculitis, like Wegener’s granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis
• IgA vasculitis, previously known as Henoch-Schönlein purpura
• Small blood vessel skin inflammation
• Hypersensitivity vasculitis
• Inflammation of blood vessels that can accompany conditions such as lupus, rheumatoid arthritis, and Sjögren’s syndrome

Additionally, they need to consider conditions related to blood clotting and blockages, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Moreover, patients with long-term HCV or Hepatitis C infections may show similar symptoms such as joint pain and a type of kidney inflammation, even if they do not have cryoglobulinemia. For this reason, more tests are required to make a confirmed diagnosis.

What to expect with Cryoglobulinemia

When looking at the future outlook or prognosis of cryoglobulinemia, which is a medical condition where abnormal proteins in the blood cause clumps to form in cold temperatures, it’s important to take into account the patient’s overall health and any other conditions they may have. There’s a particular connection with type 1 cryoglobulinemia and blood diseases, which are often already present in these patients. However, simply having these abnormal proteins in the blood doesn’t necessarily mean a higher chance of death.

About 70% of people diagnosed with cryoglobulinemia are still alive 10 years after experiencing noticeable symptoms, and roughly half are still alive 10 years after diagnosis. The outlook largely depends on any other health conditions the person has and how severe they are, along with how effective the treatment is. Recent tests with a type of treatment called “CD-20 antibody rituximab” have shown promising results, and it’s increasingly being used.

When cryoglobulinemia is associated with the Hepatitis C virus (HCV), it can lead to a serious condition called vasculitis. This condition has an approximately 25% mortality rate over five years. The outcome usually depends on the health of key organs like the liver, kidneys, central nervous system (brain and spinal cord), heart and digestive system. Issues with blood vessels connected to these organs can heavily impact the prognosis. In particular, kidney failure is more likely in patients with HCV-related cryoglobulinemia, compared to those with a mixed type of the condition.

Possible Complications When Diagnosed with Cryoglobulinemia

People with cryoglobulinemia can experience complications that affect their health outlook. These complications, research has found, can lower a patient’s chances of survival. Common issues include kidney failure and the gradual formation of a disorder where your body produces too many lymphocytes, a type of white blood cell.

One type of non-aggressive cancer of the lymph nodes related to Hepatitis C Virus (HCV) can be successfully treated with direct viral medications alone. However, with more aggressive cancers, the use of antiviral medication during the time around chemotherapy is still debated.

Kidney complications are quite common among patients with cryoglobulinemia, particularly those that are HCV positive. These typically happen 3 to 5 years after the appearance of purple spots on the skin, and most often present as a form of kidney disease known as membranoproliferative glomerulonephritis. To assess the extent of the disease, a kidney biopsy can be carried out. The overall health outlook for this condition is not very good. Mild effects on the kidney can be managed with antiviral medication, while serious effects may warrant treatment with medication that suppress the immune system, along with steroids and a procedure to remove harmful substances from your blood (apheresis). But even if there’s a long-term response to antiviral treatment, the affected organs often take a while to recover.

Preventing Cryoglobulinemia

To manage a medical condition called cryoglobulinemia, it’s very important for patients to understand and follow treatment guidelines, as well as to prevent worsening of the condition. Regular check-ups with a doctor are crucial in keeping track of how the condition is progressing, sticking to the treatment plan, and noticing early signs of the condition getting worse or causing complications.

Starting treatment early is key in preventing damage to organs that could be caused by this condition. Patients need to also make certain changes in their lifestyle, like avoiding exposure to cold weather and injuries, and reducing alcohol intake, as these can make their symptoms worse. Patients who have mild symptoms, like joint pain and tiredness, can take certain drugs that reduce inflammation and pain to help relieve their conditions.

Patients also need to be aware of the possible complications of cryoglobulinemia, which can affect the kidneys and nerves. If patients notice new symptoms, they should seek medical help immediately. Giving patients the right information about their condition and teaching them how to manage it themselves can help improve the result of the treatment and increase their overall quality of life.