OVERVIEW

What is Cryoglobulinemia?

Some immunoglobulins in human blood precipitate at temperatures below 37°C but dissolve again at 37°C. These immunoglobulins, which reversibly precipitate upon cold exposure, are referred to as cryoglobulinemia.

This term is often used interchangeably with cryoglobulinemic vasculitis or cryoglobulinemic syndrome, as they essentially mean the same thing.

What is the Incidence of Cryoglobulinemia?

Due to its association with multiple causes and various clinical syndromes, there is no definitive data on its incidence or prevalence. It most commonly occurs in individuals aged 45–65.

What are the Types of Cryoglobulinemia?

Cryoglobulinemia can be classified into the following three types:

• Type I Cryoglobulinemia: Monoclonal, primarily consisting of a single immunoglobulin, most commonly IgG or IgM, and rarely IgA or free light chains. It is mainly associated with hematologic disorders and is the least common type.
• Type II Cryoglobulinemia: Mixed type, composed of two or more immunoglobulins, typically a monoclonal IgM with rheumatoid factor activity combined with polyclonal IgG. The most common cause is hepatitis C virus infection. Other causes include hepatitis B, HIV, systemic lupus erythematosus, Sjögren's syndrome, lymphoproliferative disorders, or may be idiopathic.
• Type III Cryoglobulinemia: Polyclonal type, involving a mixture of polyclonal IgG (all subtypes) and polyclonal IgM. It most commonly occurs secondary to autoimmune diseases (especially systemic lupus erythematosus and Sjögren's syndrome), but some cases are also caused by hepatitis C.

SYMPTOMS

What are the common manifestations of cryoglobulinemia?

• Hyperviscosity syndrome: Dizziness, headache, stroke, confusion; mainly seen in type I cryoglobulinemia, often caused by Waldenström macroglobulinemia, multiple myeloma, etc.
• Skin changes: Symmetric purpura-like lesions, possibly with pigmentation. Cyanosis and urticaria upon cold exposure; may also present with vesicles, ulcers, or Raynaud's phenomenon.
• Arthralgia: Involvement of hands and knees; distal small joints are more commonly affected. Pain may worsen with cold exposure.
• Myalgia and fatigue: Often occurs with arthralgia. Rarely, gastrointestinal smooth muscle involvement may cause abdominal pain. Intestinal obstruction is very uncommon.
• Kidney: Manifestations of glomerulonephritis, such as proteinuria and hematuria. Severe cases may lead to nephrotic syndrome or acute renal failure, often accompanied by hypertension.
• Nervous system: Peripheral nerve involvement, causing sensory abnormalities like burning pain, tingling, crawling sensations, or numbness. Motor nerve involvement may result in weakness, reduced or absent tendon reflexes. Rarely, central nervous system involvement can cause bleeding or stroke. Sensory abnormalities are usually more severe and frequent than motor nerve issues.
• Liver: Primarily due to underlying diseases affecting the liver.
• Lungs: A few patients may develop pulmonary fibrosis or infiltrative lesions.
• Systemic symptoms: Low-grade fever, fatigue, infections, dry mouth, dry eyes, etc.
  The root cause is vasculopathy due to cryoglobulin deposition in small arteries. When blood vessels of related organs are affected, corresponding organ damage and symptoms occur.

CAUSES

How is cryoglobulinemia caused?

The pathogenesis of cryoglobulinemia is mostly related to anti-complement activity, which triggers immune responses and tissue damage by activating the complement system, primarily leading to small vessel injury.

Abnormally elevated cryoglobulins can be classified as primary or idiopathic based on their origin. The former is asymptomatic and often detected only during routine tests, while the latter is commonly associated with immunoproliferative disorders, infectious diseases, etc.

Various factors can contribute to cryoglobulinemia, such as:

• Viral infections: Hepatitis C, hepatitis B, HIV, EBV, cytomegalovirus, etc.;

• Bacterial infections: Subacute infective endocarditis, Lyme disease, acute streptococcal infections, syphilis, Q fever, etc.;

• Fungal and parasitic infections: Coccidioidomycosis, leishmaniasis, malaria, etc.;

• Hematologic disorders: Waldenström macroglobulinemia, lymphoma, chronic lymphocytic leukemia, cold agglutinin disease, etc.;

• Rheumatic diseases: Sjögren's syndrome, systemic lupus erythematosus, primary biliary cholangitis, etc.

It should be noted that hematologic disorders mainly cause type I cryoglobulinemia, which has relatively distinct clinical manifestations and outcomes.

Rheumatologists primarily deal with mixed cryoglobulinemia (types II and III), which is mostly caused by hepatitis C infection. A minority of cases are linked to hepatitis B, primary (idiopathic) causes, or other etiologies.

DIAGNOSIS

How is cryoglobulinemia diagnosed?

For cases presenting with non-thrombocytopenic purpura, joint or muscle pain that appears or worsens upon cold exposure, with or without nephritis, primary cryoglobulinemia should be highly suspected. The diagnosis can be confirmed by detecting positive cryoglobulins in the body.

However, other secondary causes of cryoglobulinemia must be ruled out, such as multiple myeloma, lymphoma, and primary macroglobulinemia.

Initial screening tests may reveal mild anemia, elevated erythrocyte sedimentation rate (ESR), and significantly reduced complement C4 levels, while C3 levels are usually normal. Type II or III cryoglobulinemia may show elevated rheumatoid factor.

Although cryoglobulin testing is not always mandatory in clinical practice, a positive result confirms the diagnosis. The specific testing method is as follows:

• Collect 10–20 ml of blood and incubate in a 37°C water bath for 30–60 minutes.
• Separate the serum and store it at 4°C for 7 days.
• Observe daily. If precipitation forms, it confirms cryoglobulin deposition. The precipitate is typically washed 3–6 times with cold saline to exclude other possible substances.
• The precipitate must then redissolve at 37°C.
• Note: Anticoagulants must not be used, as they may cause false-negative results.

Different cryoglobulin concentrations may indicate different types of cryoglobulinemia: Type I often exceeds 5 mg/ml; Type III is usually below 1 mg/ml; and Type II is typically above 1 mg/ml. Cryoglobulin typing can be performed.

Etiological diagnosis is also crucial. After clinical suspicion, possible underlying causes should be investigated, as they often determine treatment. Tests may include screening for hepatitis C, hepatitis B, and hematological disorders.

Finally, tissue biopsy is an important diagnostic measure:

• Skin biopsy of purpura typically shows leukocytoclastic vasculitis under light microscopy, with occasional cryoglobulin deposits in skin vessels. IgM immunofluorescence may reveal immunoglobulin and complement deposition in vessel walls.
• Renal histology shows membranoproliferative glomerulonephritis in over 80% of patients, with thickened glomerular basement membranes and cellular proliferation. Some light microscopy findings may show cryoglobulin deposits. IgM immunofluorescence is also highly specific.
  Electron microscopy may reveal granular deposits in subendothelial glomerular basement membranes (GBM) within infiltrating macrophages.

TREATMENT

Which department should I visit for cryoglobulinemia?

Typically, this condition is treated in the rheumatology/immunology or hematology departments. In rare cases of acute kidney failure, patients may seek care in the nephrology department.

How is cryoglobulinemia treated?

• Type I cryoglobulinemia treatment: Patients receive treatment when symptoms appear, primarily targeting the underlying disease. For example, the International Working Group recommends bortezomib as the first-line treatment for patients associated with Waldenstrom macroglobulinemia.
• Others: Treatment depends on the underlying cause. If caused by hepatitis C, antiviral therapy is the definitive measure. During antiviral treatment, plasmapheresis or rituximab may be used. If caused by a hematologic disorder, the primary blood disease is treated first, followed by plasmapheresis or rituximab therapy.

DIET & LIFESTYLE

What should patients with cryoglobulinemia pay attention to in daily life?

• Since cold can trigger worsening symptoms, keeping warm is an important measure to alleviate symptoms.

• Regular exercise can improve overall health.

• There are no special dietary requirements.

PREVENTION

None