Cryoglobulinaemia

Cryoglobulins are antibodies that show reversible precipitation at low temperatures. It is postulated that the resultant aggregates and immune complexes outstrip reticuloendothelial-clearing activity and tissue damage results from immune complex deposition and complement activation.¹ Manifestations vary according to type and range from acrocyanosis and retinal haemorrhage to hypertension and renal disease.¹

There are several types and variable clinical pictures. The Brouet classification² is:

• Type I or simple cryoglobulinaemia, is caused by monoclonal antibody, usually IgM, but less often IgG, IgA or light chains.
• Type II and type III cryoglobulinaemia are called mixed cryoglobulinaemia. They contain rheumatoid factor (RF), which is usually IgM. The RF is monoclonal in type II and polyclonal in type III cryoglobulinaemia.

• Essential mixed cryoglobulinaemia occurs in about 1 in 100,000 people.
• It usually presents between about 40 and 60 years of age with a female preponderance of 3:2.
• In people with hepatitis C infection (HCV), the prevalence of cryoglobulinaemia is 40 to 50%.³
• The relative proportions are roughly:
  • type I =25%
  • type II =25%
  • type III =50%

Features

Type I cryoglobulinaemia presents with:

• Acrocyanosis
• Retinal haemorrhage
• Severe Raynaud's phenomenon
• Arterial thrombosis

Types II and III cryoglobulinaemia produce:

• Arthralgias and arthritis in the proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, knees, and ankles
• Immune-complex glomerulonephritis
• Vascular purpuric lesions

The approximate frequencies are:

• Cutaneous symptoms of purpura, distal necrosis, cold urticaria, and ulceration (50-100%)
• Joint disease (35-70%)
• Renal disease (10-60%)
• Raynaud's phenomenon (30-50%)
• Neurological symptoms including paraesthesia and peripheral neuropathy (10-30%)
• Abdominal pain (2-25%)
• Sicca (10-15%)
• Acrocyanosis (10%)
• Haemorrhage (5-10%)
• Arterial thrombosis (1%)

Meltzer's triad is purpura, arthralgia, and weakness.

Signs

Skin:

• Ischaemic necrosis
• Palpable purpura
• Scarring of tip of nose, pinna, fingertips, and toes
• Acrocyanosis

Lungs:

• Rhonchi
• Pleural effusion

Gastrointestinal:

• Haemorrhage
• Hepatomegaly or signs of cirrhosis with palmar erythema and spider naevi
• Splenomegaly

Renal disease may present as:

• Diffuse glomerulonephritis with nephrotic syndrome
• Hypertension

Neurological:

• Peripheral neuropathy
• Visual disturbances

Fever can also occur.

• Cryoglobulinaemia may occur with a specific disease such as a lymphoproliferative disorder, autoimmune or infectious disease, or it can be idiopathic when it is called essential cryoglobulinaemia.
• It can run in families and rarely after vaccination, especially against pneumococcus.

Type I occurs in lymphoproliferative disorders including multiple myeloma and Waldenström's macroglobulinemia.

Type II and III occur in lymphoproliferative disorders including chronic lymphocytic leukaemia as well as chronic liver disease, infections, and connective tissue diseases.

Infections include:

• Viral - Hepatitis A, hepatitis B, hepatitis C, HIV, Epstein-Barr virus, cytomegalovirus, adenovirus.
• Bacterial - Endocarditis, streptococcal infections, syphilis, Lyme disease, leprosy, Q fever
• Fungal - Coccidioidomycosis
• Parasitic - Malaria, toxoplasmosis, others

• Systemic lupus erythematosus (SLE)
• Rheumatoid arthritis
• Sjogren syndrome

Vasculitis includes:

• Polyarteritis nodosa
• Henoch-Schönlein purpura

The differential diagnosis includes looking for the underlying cause of the cryoglobulinaemia:

• Antiphospholipid syndrome
• Chronic lymphocytic leukaemia
• Cirrhosis
• Glomerulonephritis
• Goodpasture's syndrome
• Haemolytic uraemic syndrome
• Hepatitis A, B or C
• Non-Hodgkin's lymphoma
• Multiple myeloma
• Polyarteritis nodosa
• Sarcoidosis
• Systemic lupus erythematosus
• Waldenström's macroglobulinaemia.

Hepatitis C infection is very common in those with HIV and a study has suggested that it is the HCV that is important and not the HIV.⁶ This may be a reflection of the efficacy of HAART⁷ (highly active antiretroviral therapy).

• Check for serum cryoglobulins. The blood must be kept warm and then serum incubated at 4 °C. Type I tends to precipitate within the first 24 hours but type III may take a week. Correct handling is essential for reliable diagnosis.⁸
• FBC: leucocytosis may occur with infection or leukaemia. There may be anaemia.
• Urinalysis may show evidence of renal disease.
• U&E: in case of renal disease.
• LFTs: may show hepatitis. If so get serology for hepatitis.
• Rheumatoid Factor: RF is positive in type II and III.
• Antinuclear antibody: if SLE suspected.
• ESR will be elevated with rouleaux formation.
• Complement levels may be reduced, especially C4.
• Electrophoresis of serum and urine if there is suspicion of an underlying gammopathy.

Further tests will be required if other diseases are suspected.

Non-drug

Sufferers must avoid cold environments.

Drug

• The aim is to limit precipitation of cryoglobulin and the inflammation that results. Asymptomatic cryoglobulinaemia does not require treatment unless there is renal or neurological damage.
• Secondary cryoglobulinaemia is managed by treating the underlying disease. Otherwise treatment is suppression of the immune response.
• Non-steroidal anti-inflammatory drugs (NSAIDs) are used for arthralgia and fatigue.
• Immunosuppressive agents such as corticosteroids and/or cyclophosphamide or azathioprine are used when there is evidence of organ involvement such as vasculitis, renal disease, progressive neurological features, or severe skin disease. However, it is suggested that immunosuppression should be restricted to palliative care as it may facilitate viral replication.³
• Plasmapheresis can be used for severe or life-threatening complications in combination with steroids and immunosuppression.⁹
• Interferon-alfa (IFN-a) works in patients with cryoglobulinaemia associated with hepatitis C and possibly chronic myelogenous leukemias and low-grade lymphomas. The first line treatment for cryoglobulinaemia with HCV is pegylated interferon-alpha and ribavirin.³
• Ritumaxib appears to be safe and effective.¹⁰

• Stroke, convulsion or coma
• Blindness
• Myocardial infarction
• Pericarditis
• Congestive heart failure
• Respiratory distress
• Gastrointestinal haemorrhage
• Acute renal failure
• Cutaneous necrosis or gangrene

Prognosis depends on the underlying cause like lymphoproliferative disorders, hepatitis B or C. Renal involvement has an adverse effect. In one study¹¹ the median time from diagnosis to death was just over 3 years.