Overview of Cold Globulins
Cryoglobulins are immunoglobulins that precipitate on exposure to cold and re-dissolve on exposure to warmth. Three different types of cryoglobulins are known: type I, a monoclonal immunoglobulin usually seen in myeloproliferative abnormalities such as multiple myeloma and Waldenström’s macroglobulinemia; type II, primary cryoglobulinemia, in which the cryoglobulin consists of both polyclonal IgG and monoclonal rheumatoid factor; and type III, mixed polyclonal cryoglobulins, in which both IgG and rheumatoid factor are polyclonal. In the past type II or primary cryoglobulinemia was thought to be secondary to EBV and hepatitis B virus infection. However, it is now clearly recognized that most cases are associated with hepatitis C virus infection. Type III or mixed polyclonal cryoglobulins are commonly associated with autoimmune diseases such as lupus erythematosus, dry syndrome and hematologic malignancies as well as hepatitis C virus infection. In primary cryoglobulinemia, 80% to 95% of patients have circulating antibodies to hepatitis C virus and RNA expression of the virus in plasma. It is a disease of cryoglobulinemia or cryofibrinogenemia (CFE) with femoral gluteal skin lesions, with a clinical and immunologic presentation that is distinct from that of the usual cryoglobulinemic vasculitis, and with a long, recurrent course.
Etiology
The etiology of CFE is not fully understood, except in relation to cold stimuli; patients with CGE may have an idiopathic, chronic course without any triggers or visceral damage, while patients with CFE have a prolonged course without visceral lesions and often have a primary form of the disease. Mixed cryoglobulinemia has the dual pathogenic effects of immune complexes and condensation, which can cause vasculitis damage in addition to cyanosis and reticular cyanosis caused by increased blood viscosity.
The disease is prevalent in obese young and middle-aged women, and the lesions are confined to the femoral buttocks. This is due to the low skin temperature in this area and the localized hypertrophy of subcutaneous fat, which meets the conditions required for CG (cryoglobulin) precipitation and activation of complement. Although the skin temperature of the fingers is low, it is not suitable for complement activation, so lesions rarely occur.
Symptoms
Clinical features of cryoglobulinemic vasculitis include leukocyte-crushing vasculitis and purpuric rash. Systemic manifestations include arthralgia, arthritis, lymphadenopathy, hepatosplenomegaly, and peripheral nephropathy, as well as hypocomplementemia (especially reduced C4 levels), and rheumatoid factor positivity. 20% to 60% of patients have manifestations of renal disease, which is more commonly seen in type II cryoglobulinemia. Renal biopsy shows proliferative glomerulonephritis, with subendothelial deposits seen by immunofluorescence, diffuse IgM deposition in the capillary pore ring, and endothelial thrombus consisting of cryoglobulin deposits as typical manifestations. Clinically, polymorphic skin lesions occurring above the outer femur and buttocks are common, with a long course and may recur. It develops in the cold season and subsides in the summer. It occurs in young and middle-aged women, especially in those who are obese in the femoral and buttocks area. It is divided into the following three types according to different clinical manifestations:
1. Erythema multiforme
The damage is a slightly elevated symmetrical bright red edematous erythema with a dark red or purplish-red center and a clear boundary, which can be enlarged to the surrounding area and merge with each other, showing a polypoid erythema. The process is slow. Conscious light itch or light tenderness. It is accompanied by reticular erythema.
2. Cyanotic vasculitis
The damage is greenish purple or greenish brown reticular erythema, partly dark purple infiltrative reticular erythema, with mild vesiculation, crusting, and desquamation on the surface and shallow scar in the center. The rash is unilateral or symmetrically distributed. Cyanosis or Raynaud’s phenomenon on hands and feet. Duration of the disease is prolonged. Self-conscious pain.
3. Erythema nodosum
The damage is dark purple or reddish brown bean-sized to finger-sized erythema and nodules, symmetrically distributed. The skin of the hands and feet tends to be blue-purple.
Immunologic abnormalitiesCG (cryoglobulin) is often elevated in patients with CGE. Patients with CFE have increased CF (cryofibrinogen) and decreased CH50 (50% complement hemolytic units). Some patients have a positive anti-complement test. Skin immunofluorescence examination of the vessel wall is negative.
Tests
1. Volumetric detection of cryoglobulins
2. Spectrophotometric detection of cryoglobulins
3. Other laboratory tests: blood sedimentation is often increased, serum immunoglobulin is usually elevated, complement, especially C4, is often decreased, and rheumatoid factor can be positive. Hepatitis A, B, and C viruses and other viral antigens such as EBV, cytomegalovirus, and human immunodeficiency virus can be detected, and sometimes there is pathogenetic evidence of associated bacterial infections such as staphylococcal infections.
Diagnosis
Skin purpura biopsy may show typical leukocytoclastic vasculitis. Neutrophil-predominant infiltrates and nuclear ruptures are seen around the walls of small blood vessels and in the walls of tubes. Sometimes there is erythrocytic exudate and characteristic hyaline emboli formation. Immunofluorescence revealed IgG or complement deposits in the vessel walls. The kidneys showed membranoproliferative glomerulonephritis characterized by proliferative lesions. Nephritis with massive mononuclear cell exudates and diffuse thickening of the basement membrane. It may also manifest as a proliferative mesangial. Glomerulonephritis, and in a few cases, focal proliferative glomerulonephritis. Sometimes questionable stromal inflammation and necrotizing arteriolitis are seen, and immune complexes formed with the participation of cryoglobulins and complement are seen deposited in the intima-media of the glomeruli at the lesion, and cryocrystals, inclusion bodies, and fibrinoid and tubular structures are seen on electron microscopy. Neural biopsy reveals extensive vasculitis with necrosis of the vessel wall and perivascular inflammatory cells, thickening of the vessel wall and narrowing of the lumen, loss of myelin sheaths, and axonal degeneration caused by cryoglobulins.
Differential diagnosis
The disease is not difficult to diagnose based on clinical features and immunologic abnormalities. However, it should be differentiated from cold erythema multiforme.
Cold erythema multiforme is often preceded by prodromal symptoms, and the characteristic iridescent erythema is often seen on exposed areas such as the hands, feet, and face, and is not accompanied by reticulocyanotic erythema.
The diagnosis of cryoglobulinemia should take into account the vasculitis of the patient’s skin as well as the systemic symptoms, especially if there are manifestations of hypocomplementemia, and especially if liver function tests are abnormal, and the patient should undergo tests related to hepatitis C virus infection. Skin biopsy may reveal leukocyte-crushing vasculitis. In order to detect cryoglobulins in serum, at least 20 ml of blood is required. To avoid interference from serum lipids, blood should be collected after fasting, and blood samples should be sent to the laboratory immediately, placed in a 37°C environment, and centrifuged and then the samples placed in the refrigerator at 4°C for at least one week, and if any cold deposits are found they should be immediately re-dissolved at 37°C. Cold deposits can also be used to detect hepatitis C virus antibodies and viral RNA.
Treatment
1. Pay attention to keep warm, avoid cold
When there is a primary disease, it should be treated promptly. There are no particularly effective drugs and treatments. It has been reported that a trial of vasoactive drugs, vitamin C, glucocorticoids or immunosuppressants such as cyclophosphamide may be effective.
2. Local symptomatic treatment
Some people try TDP (specific electromagnetic spectrum radiator) irradiation to get better therapeutic effect.
3. Traditional Chinese medicine
Warming Yang and activating blood circulation or activating blood circulation and removing blood stasis can be used, with the formula of Warming Yang and Activating Blood circulation Tang and Tao Hong and Four Substances Tang with additions and subtractions. To support the positive and fight against cold, use Ginseng Nourishing Rong Tang or tonifying Zhong Yi Qi Tang.