Primary mixed cryoglobulinemic vasculitis
Introduction
Introduction to primary mixed cryoglobulinemia vasculitis Essential mixed cryoglobulinemia (EMC) is also known as purpura-joint pain-coldglobulinemia syndrome. Clinically characterized by purpura skin lesions, joint pain, anemia, kidney damage and hypergammaglobulinemia. Meltzer (1966) systematically described the disease on the basis of Wintrobe (1933) and Iener (1947). At the same time, it was also found that malignant tumors such as myeloma can also be associated with cryoglobulinemia. The same clinical features of the disease. In addition, such as subacute bacterial endocarditis, leprosy, hemolytic anemia, acute glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome can also be associated with cryoglobulinemia And cryoglobulinemia associated with these diseases is called secondary cryoglobulinemia. basic knowledge Sickness ratio: 0.0001% Susceptible people: no special people Mode of infection: non-infectious Complications: Crohn's disease
Cause
The cause of primary mixed cryoglobulinemia vasculitis
(1) Causes of the disease
The etiology and pathogenesis of this disease are still not very clear. In recent years, it has been found that the incidence of this disease is higher in patients with hepatitis B virus infection, but it is certain that it is an autoimmune rheumatism, an autoimmune reaction in the body. The formed mixed cryoglobulin plays a decisive role in the pathogenesis. The so-called cryoglobulin refers to a protein complex that can undergo reversible agglutination at low temperatures. The main component is immunoglobulin, which also contains a small amount of fibrinogen and lipid. Protein, collagen, complement and other serum protein components, from the immunochemical aspects of cold globulin into three types: type I is a monoclonal cold globulin type, containing two or more monoclonal antibodies, including IgA , IgG and IgM; type II is a combination of monoclonal and polyclonal cold globulin, including IgM-IgG, IgA-IgG and IgG-IgG, etc.; type III mixed polyclonal cryoglobulin, including IgA-IgG And IgM-IgG-IgA, primary cryoglobulinemia mainly includes type II, type III cold globulin, mixed type cryoglobulin is a condensed rheumatoid factor (RF), which contains IgM, acts as an antibody, can Dok The Fc segment antigenic determinant of IgG binds to form an immune complex and immunoinflammatory reaction occurs. Occasionally, IgA in mixed cryoglobulin acts as an antibody, and can react with the Fc segment antigenic determinant of polyclonal IgG, mixed with cryoglobulin. The IgG component is a polyclonal antibody and does not have the biological function of rheumatoid factor. Its condensation concentration depends on the IgM contained, but the condensation set must be involved in IgG. If IgG forms a complex with a specific antigen, IgG is particularly susceptible to interaction with IgM, thereby demonstrating that IgG acts as an antigen for mixed cryoglobulin condensation, but this antigen must be altered by the appropriate antigen and IgG to show its appearance.
(two) pathogenesis
The mechanism of action of cryoglobulin pathogenesis is not well understood. Studies have shown that cryoglobulin is deposited as an immune complex on the blood vessel wall, activating the classical pathway of complement and the alternative pathway, causing small blood vessels to produce immune vasculitis, resulting in affected blood vessels. Tissue ischemia at the site, and also due to vascular endothelial cell dysfunction and increased blood viscosity, red blood cell agglutination, coagulation and platelet dysfunction, etc. aggravate tissue ischemia, resulting in a series of clinical symptoms, this mechanism is secondary cold Globulinemia may be the same in diseases such as systemic lupus erythematosus. The pathogenic effect of mixed cold globulin depends on its cold tolerance and ability to bind complement. The condensable cryoglobulin is easy to deposit at room temperature. The pathogenic effect and the immunopathological damage caused by the mixed cold globulin which is easy to bind to complement are also strong.
Skin biopsy showed leukocyte rupture vasculitis, the pathological changes were subcutaneous capillaries, small arteries, venous vascular endothelial cell swelling, inflammatory degeneration and necrosis, surrounded by neutrophil infiltration, sometimes accompanied by fibrin deposition, An inflammatory lesion similar to the skin can also be seen in the biopsy of the internal organs.
Renal biopsy may have extensive proliferative glomerulonephritis, glomerular basement membrane thickening with neutrophil infiltration, focal nephritis and membrane proliferative nephritis, but sometimes hyperplasia The change is mainly caused by the deposition of immunoglobulins involved in cryoglobulin deposition in the vascular glomerular intima. In many cases, capillary endothelial proliferation and acidophilic sedimentation in the basement membrane are found, especially in acute renal failure. Patients with large basement membrane eosinophils and complete capillary occlusion, basement membrane fragmentation, similar to membrane proliferative nephritis, and some cases of concomitant focal fibrinoid necrosis Renal arteritis, renal tubular and renal parenchymal injury is mild, some cases can be seen in the renal interstitial plasma cells and lymphocytes infiltration, accompanied by fibrosis, a few cases of capillary endothelial cells can be seen in the inclusion body crystal.
Electron microscopy showed cold-crystallized inclusion bodies and cellulose and tubular structures in subendothelial sediments. Immunopathology revealed IgM, IgG and C3 deposition in the embolus and in the vessel wall. These substances also deposited on the basement membrane. It is distributed in a granular form, thus demonstrating the role of immunity in the pathogenesis of this disease.
Prevention
Primary mixed cryoglobulinemia vasculitis prevention
Avoid cold stimulation, keep warm, patients with purpura in the lower limbs should reduce standing time, early diagnosis, early treatment.
Complication
Primary mixed cryoglobulinemia vasculitis complications Complications Crohn's disease
The disease can overlap with Sjogren's syndrome, Hashimoto's thyroiditis, Crohn's disease, etc., and systemic infections such as tuberculosis and Gram-negative bacilli infection may be combined in the later stages of the disease.
Symptom
Primary mixed cryoglobulinemia angiitis symptoms common symptoms abdominal pain cryoglobulinemia diarrhea polyclonal cryoglobulinemia kidney damage proteinuria upper gastrointestinal bleeding myalgia morning stiffness joint pain
In the early stage of the disease, most patients only showed finger or toe Raynaud when they were cold or exposed to cold water. However, in these cases, the typical Raynaud phenomenon of pale-cyan-purple red did not occur, but more cases appeared. Hairpin is the main performance process. With the development of the disease, physical pain can occur in cold fashion, numbness, joint pain or muscle pain, and even purple or purple skin pattern.
1. Skin, mucosal damage is most commonly recurrent and non-thrombocytopenic purpura, no itching, often distributed in the lower extremities, especially around the ankle, but also in the nose, ears, mouth and other exposed parts, cyanosis is intermittent Attacks occur in batches. Each episode lasts for several days to one week. Most cases can be recurrent for many years. After remission, local pigmentation can be left. Skin lesions can sometimes occur in skin lesions such as tendons.
Although cold, trauma, exercise, long-term standing or acute infection can induce skin damage, its symptoms are not related to the ambient temperature, and its symptoms are more common in summer than in winter, although cryoglobulinemia is still developing progressively. However, the purple sputum can be relieved by itself. In many cases, cold urticaria can be repeated. The performance of these skin mucosa can sometimes be the only symptom of disease activity.
2. Joint polyarticular pain is another common early manifestation of this disease. Any joint in the body can be affected, but the hand and ankle joints are the most common, sometimes the symptoms may be accompanied by myalgia, even without joint symptoms. Mild myalgia and fatigue may also occur. The symptoms of joint muscles are sometimes not parallel to the whole condition, and may disappear as the disease progresses. This joint lesion often has no obvious morning stiffness.
3. More than half of patients with kidney damage have renal involvement, some of them have edema, a large amount of proteinuria and hypertension, most patients with renal damage appear acute, chronic glomerulonephritis, a few patients may have acute nephritis Even soon developed into uremia, kidney damage is sometimes asymptomatic, many patients with kidney damage are found through routine tests or follow-up during the process of proteinuria, hematuria, pyuria and red blood cell cast, urine protein is mainly white Protein, while the urine light chain and this-week protein are not high, so the kidney and its function should be routinely examined during the examination of this disease.
4. Two-thirds of patients with digestive system may have different degrees of enlargement of the liver, or with splenomegaly, and more patients with abnormal liver function. Most of these patients are usually asymptomatic and severe. Due to liver disease or even cirrhosis, portal hypertension, or rapid progressive liver failure, liver biopsy often shows varying degrees of hepatitis, vasculitis, cirrhosis and fibrosis, plasma cells and lymphocytes infiltration, in these patients The positive rate of serum hepatitis B virus surface antigen and antibody is very high. Gastrointestinal vasculitis has non-localized abdominal pain. In case of cold, it may induce abdominal pain or increase, sometimes patients may have upper gastrointestinal bleeding or blood in the stool, fecal occult blood test is positive; mesenteric Insufficient arterial blood supply can cause diarrhea or constipation, and atypical peptic ulcer can occur in individual patients.
5. About one-third of patients with nervous system may have central nervous system symptoms. Type III is more common than patients with type I and II. It is characterized by encephalopathy, cranial nerve palsy, pyramidal tract sign, myelitis and extrapyramidal system. These lesions are mainly caused by the deposition of cryoglobulin in the blood vessel wall of the central nervous system, causing inflammation of the central vasculature, causing congestion, hemorrhage and inflammatory cell infiltration at the site, and nerve demyelination. Some patients may also have Multiple asymmetric peripheral neuropathy, early manifestations of paresthesia, dyskinesia, muscle atrophy, muscle weakness and electromyography abnormalities.
6. Other diseases can also affect the heart, manifested as myocarditis, coronary arteritis, transient pericarditis and arrhythmia, but the incidence is low, often asymptomatic, pulmonary involvement can be expressed as pulmonary interstitial Fibrosis and mild pleurisy, in some cases, adrenal cortex and pancreas involvement, often found through pathological examination, sometimes with superficial lymphadenopathy or lower extremity lymphadenopathy.
Examine
Examination of primary mixed cryoglobulinemia vasculitis
1. Patients with blood routine and erythrocyte sedimentation rate have mild anemia, white blood cells may be slightly elevated or decreased, blood viscosity is increased, red blood cells are arranged in a string of money, and most patients have increased erythrocyte sedimentation rate.
2. More than half of patients with urinary routine may have proteinuria, hematuria, casts and pus cells.
3. About 2/3 of the biochemical tests may have abnormal liver function, elevated serum GPT and elevated bilirubin. When renal function is involved, BUN may increase, serum potassium and CO2CP decrease, and protein electrophoresis shows Gamma globulin is elevated.
4. Immunological examination of serum IgG, IgM increased, sometimes IgA increased, complement decreased, a small number of patients may have rheumatoid factor and anti-nuclear antibody positive, some patients with low cellular immunity.
Serum cryoglobulin determination is the specific examination of the disease, taking 5 ml of fasting venous blood at room temperature, placed in a clean ordinary test tube, without anticoagulant, immediately placed in a 37 ° C water bath for 1 ~ 2h to solidify, and then Centrifuge at 37 ° C, 3000 r / min, the serum obtained was centrifuged once again under the same conditions to ensure the absence of blood cells in the serum. The serum obtained after the second centrifugation was transferred to a 5 ml graduated centrifuge tube at 4 ° C in a refrigerator. Incubate for 72 hours. The serum after cold incubation is centrifuged at 4200 °C for 3 min at 3200 r/min. If there is a precipitate, the above serum is removed, and the cryoglobulin is precipitated: washed with 4 ° C physiological saline, and then centrifuged again. Washing, repeated 3 to 5 times, until the final protein is not detected in the washing supernatant, and then the purified cryoprecipitate is dissolved in an appropriate amount of 0.05 mmol / L, pH 8.2 barbital buffer cryoglobulin quantification and Immunochemical analysis, determination of IgM, IgG, IgA and C3 contained in cryoglobulin, cold globulin greater than 14mg / L is positive, but should be noted due to various ethnic groups, regional and laboratory conditions are different, cryoglobulin determination The value is not completely uniform and should be based on actual conditions. Status determination standard value.
Clinical significance of cryoglobulin:
1 cold globulin is a kind of immune complex, which can provide a diagnostic basis for immune complex diseases.
2 Many infectious diseases (such as hepatitis B) and autoimmune diseases (such as systemic lupus erythematosus), the appearance and disappearance of cryoglobulin are obviously related to the activity and remission of the disease, and the evaluation of the condition and prognosis is certain. significance.
3 As a simple method for isolation and purification of immune complexes, it provides conditions for the verification of antigens, antibodies and other components, and has certain theoretical significance.
When the central nervous system develops lesions, there may be EEG, brain CT and brain MRI abnormalities. When the heart is involved, most patients may have abnormal ECG, and some patients may show pulmonary interstitial changes.
Diagnosis
Diagnosis and differential diagnosis of primary mixed cryoglobulinemia vasculitis
diagnosis
For cases of non-thrombocytopenic purpura that appear or worsen in the event of cold, joint muscle pain, with or without nephritis, the possibility of primary cryoglobulinemia should be highly suspected, and then the body is tested for cold globulin. The disease can be diagnosed, but secondary cryoglobulinemia caused by the following diseases, such as multiple myeloma, lymphoma, primary macroglobulinemia, subacute bacterial endocarditis, should be excluded. Infectious mononucleosis, sarcoidosis, systemic lupus erythematosus and rheumatoid arthritis, etc. Finally, immunological examination to determine the presence of IgM in cold globulin, IgG, IgA and C3 is more conducive to the determination of immunity Learning type.
Differential diagnosis
1. Primary cold urticaria This disease is an autosomal dominant hereditary disease, partly acquired. The patient has neither cold cold blood nor cold agglutinin and cold globulin. Measles may be caused by the release of histamine from mast cells due to cold stimulation. This disease does not cause joint pain, nephritis and other symptoms during the onset of the disease.
2. Cold hemolysin syndrome This syndrome is caused by the form of cold hemolysin (essentially IgG antibody) in the body, which binds to red blood cells and causes hemolysis at the temperature below 20 °C. The clinical features are chills, high fever, headache, abdominal pain, nausea, vomiting, bronchial asthma, high blood pressure, tachycardia, systemic cold urticaria and soy sauce hemoglobinuria accompanied by acute hemolytic anemia. The Donath-Landsteiner test for the identification of cold hemolysin is positive, usually the titer is positive from 1:2 to 1:64, the Coomb test is positive, generally no joint symptoms, nephritis and other systemic manifestations, the body cold globulin is not high, rheumatoid factor And anti-nuclear antibodies were negative, and the level of complement was normal.
3. Cold agglutinin syndrome This syndrome is an excessively high concentration of agglutinin in the body, which binds to red blood cells during cold stimulation and causes acute hemolysis syndrome. It is confirmed by immunological examination that the cold agglutinin belongs to the light chain type IgM antibody. It has cold globulin properties, usually interacts with I antigen, and can cause hemolysis under complement-mediated action. The cold agglutinin syndrome is acute, subacute and chronic. The first two types are secondary to certain viruses. Infection, such as infectious mononucleosis, rubella, lymphoma, etc., while the chronic type is idiopathic, the common feature of the three types is spontaneous agglutination of superficial intravascular red blood cells in the cold hind limbs, nose, ears, etc. When the temperature of the affected part rises, the hair becomes disappeared. The blood biochemical examination can find that the blood is automatically coagulated below 20 °C. The Coomb test is positive at 37 °C, and the complement can occur after mild acidification of the blood at 20-30 °C. Dependent anemia, peripheral blood has hemolytic anemia, reticulocytes increase, white blood cells can increase or decrease, thrombocytopenia, other hemolysis tests are also positive, a few cases of protein electrophoresis can be in Vice- protein peak area appears.
In short, cold hemolysin syndrome and cold agglutinin syndrome are cold hemolytic anemia, primary cryoglobulinemia is an immune complex vasculitis disease, no hemolytic anemia, easier to identify.
