February 7, 2017

Cryoglobulins are proteins found in the blood that precipitate (clump together) in the cold and cause inflammation and organ damage. However, these proteins can occasionally be present in low levels in the blood without any symptoms. When there are symptoms due to the cryoglobulins, the disease is called “cryoglobulinemia.”

Immunoglobulins are the class of proteins that make antibodies in response to foreign substances – antigens introduced into the body. In the case of cryoglobulinaemia, the abnormal immunoglobulins form complexes – cryoglobulins and precipitate (leach) out of the blood at cold temperatures. This causes restricted tissue blood flow and systemic inflammation, which leads to many clinical signs and symptoms including skin lesions, arthralgia (joint pain), arthritis, vascular purpura (purple skin marks), livedo (marbling pattern), and bleeding conditions.

Types of Cryoglobulinemia

Cryoglobulinemia may be classified based on cryoglobulin composition with the Brouet classification, which is as follows –

Cryoglobulinemia is basically classified into three types, Type-I, Type-II, and Type-III.

  • Type I Cryoglobulinemia – This is caused by monoclonal immunoglobulin. This type is usually related to cancerous conditions of the blood or the immune systems.
  • Types II Cryoglobulinemia – This is caused by IgM, IgG and IgA monoclonal immunoglobulin. These types of Cryoglobulinemia are most commonly found in people who have chronic inflammatory conditions like hepatitis C.
  • Types III Cryoglobulinemia – This disease is caused by IgM and IgG polyclonal immunoglobulin.

Cryoglobulinaemia is thought to be rare. Essential mixed cryoglobulinaemia occurs in about 1 in 100,000 people. Most cases of cryoglobulinaemia have an underlying cause. The type of cryoglobulinaemia found in patients is roughly 25% with type I, 25% with type II and 50% with type III.

Each type is associated with different diseases and disorders, which may include cancer involving white blood cells, infections, autoimmune disorders, rheumatic diseases, vasculitis, kidney disease, hepatitis C virus infection, and peripheral neuropathy. More than 90% of people with cryoglobulinemia also have a hepatitis C infection. Hepatitis C virus infection is primarily acquired by needle sharing and tainted blood products, and only rarely transmitted sexually. Treatment of the underlying hepatitis C virus infection may be an effective therapy for an associated peripheral neuropathy


  • Hyper-Viscosity– Cryoglobulins circulates in blood and become thick and precipitate at low body temperature. The cause of change in physical characteristics at low temperature is not known.
  • Antibodies– Cryoglobulins are proteins that function as antibodies. Cryoglobulin increases in autoimmune disease.
  • Infection- Cryoglobulin is found in higher concentration in hepatitis C infection.
  • Blood Cancers– Cryoglobulin is abnormally increased in patient suffering with lymphoma and multiple myeloma
  • Connective Tissue Disease– Concentration of Cryoglobulin is at higher level in patients suffering with connective tissue disorder like lupus.

Risk Factors

Infections associated with cryoglobulinemia include the following:

  • Viral – Hepatitis A, B, and C (see Differentials); HIV; Epstein-Barr virus (EBV); cytomegalovirus (CMV); adenovirus; chikungunya
  • Bacterial – Endocarditis, streptococcal infections, syphilis, Lyme disease, leprosy, Q fever, brucellosis
  • Fungal – Coccidioidomycosis
  • Parasitic – Malaria, toxoplasmosis, others


Most people with cryoglobulins have no symptoms other than elevated levels on lab tests. When symptoms are present, they are most commonly fatigue, joint pain, numbness or weakness, and a rash that looks like red spots or purple bruises, usually over the lower legs.

Other symptoms and signs may include –

  • Change of the color of hands and/or feet (from normal to white to a purplish-blue color) with cold, called “Raynaud’s Phenomenon”
  • Weight loss
  • High blood pressure
  • Swelling of ankles and legs
  • Skin ulcers and gangrene
  • Enlarged liver or spleen
  • Numbness, tingling or weakness
  • Kidney damage

Specific Symptoms of Cryoglobulinemia –

  • Skin- Purple bruises, rash and skin ulcer
  • Skeletal System- Joint pain, muscle ache, ankle swelling (edema feet) and Raynaud’s phenomenon
  • Nervous System- Peripheral neuropathy, numbness and weakness
  • Respiratory System- Dyspnea or short of breath
  • Kidney- Glomerulonephritis causes hematuria, proteinuria and kidney failure
  • Cardiovascular System- Hypertension
  • Gastrointestinal System- Enlarged liver and spleen


Complications include –

  • Bleeding in the digestive tract (rare)
  • Heart disease (rare)
  • Infections of ulcers
  • Kidney failure
  • Liver failure
  • Skin death
  • Death
  • Ischemic Changes– Serum Cryoglobulin causes thick precipitation of serum at low temperatures. Increased blood viscosity eventually start slowing the blood flow or blocks the smaller vessels. The reduced blood supply to tissue and organs causes ischemia (lack of blood supply) and numerous complications including renal failure.
  • Tissue and Organ Damage– Cryoglobulinemia is a disease, which damages the tissue secondary to ischemia. Blocking of blood supply to normal tissue and organ causes ischemia.


Medications –

  • Rituximab is an effective drug and has fewer risks than other medicines.
  • Cyclophosphamide is used in life-threatening conditions where rituximab is not working or available. This medicine was used often in the past.
  • A treatment called plasmaphereis is also used. In this his procedure, blood plasma is taken out of blood circulation and abnormal cryoglobulin antibody proteins are removed. The plasma is replaced by fluid, protein, or donated plasma.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used in patients with arthralgia and fatigue.

Alternative Treatment