Amyloidosis

Introduction to amyloidosis Amyloidosis (AL) is a clinical syndrome in which the deposition of amyloid in various organs of the body is caused by various reasons, resulting in the gradual decline of the function of the affected organs. Includes a group of diseases. Amyloid deposition in the tissue is called amyloidosis, also known as amyloidosis. Amyloid is a protein-like substance. It can be dyed brown when it is iodine. It is blue after adding sulfuric acid. It is similar to the reaction when starch is iodine, so it is called amyloidosis. Amyloidosis is a large amount of various soluble fiber soluble protein (amyloid) tissue that damages normal tissue function. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people Mode of infection: non-infectious Complications: Diabetes insipidus Congestive heart failure in children Congestive heart failure Atelectasis

Cause of amyloidosis

Physical and chemical factors (25%)

In animal experiments, bacterial toxins such as Escherichia coli endotoxin, as well as anti-toxin, serum, nucleic acid, plasma globulin, metformin, colloidal sulfur, thiouracil, mucopolysaccharide and gamma rays can be used to make starch. A model of degeneration, but the most commonly used is casein. 5 ml of casein 5 ml is given to rabbits subcutaneously, twice a week, and amyloidosis occurs 3 months later.

Immunity factor (20%)

Amyloid deposits are often associated with chronic or recurrent infections or inflammatory diseases such as tuberculosis, leprosy, syphilis and other diseases, but the incidence rates vary widely from country to country. It is reported that India is about 3/4 (150/). 200) secondary amyloidosis is caused by tuberculosis, while in North America, tumor-like leprosy with amyloidosis is more common in Africa, India, Southeast Asia, South America, etc., the incidence rate is 3% to 33%, others such as Chronic osteomyelitis, burns, paraplegia with hemorrhoids, chronic pyelonephritis, schistosomiasis, cystic fibrosis and other diseases are also more common with this disease, subcutaneous injection of heroin (diacetin morphine) caused by chronic suppurative skin infection, and reported secondary Amyloidosis is associated with human immunodeficiency virus infection, which supports the amyloid being the result of an antigen-antibody reaction, the direct deposition of an antigen-antibody complex, or an excess of antigen-antibody reaction when the amyloid is By-products in antibody synthesis, some studies have also pointed out that complement plays an important role in this process. In addition, some patients with autoimmune diseases can also see amyloidosis, the most common being For wet arthritis, it has been reported that 1000 patients with rheumatoid arthritis died after 3.1 years of follow-up after 3 years of amyloidosis; followed by ankylosing spondylitis, systemic lupus erythematosus, progressive sclerosis, Still disease, silver Scab arthritis, Reiter syndrome, nodular polyarteritis, Sjogren's syndrome (sjogren's syndrome), Behcet's disease, ulcerative colitis, Crohn's disease, and Wipple's disease. Some scholars believe that amyloid is a physiological substance, there is a trace amount in normal human body, and it increases with age. Once T cell function declines and B cell function is hyperactive, amyloid production is excessive, which leads to pathology. Change; or B cell function is defective, resulting in abnormal light chain, due to its low solubility and easy to deposit in the tissue, resulting in amyloidosis, experiments show that when the thymus congenital hypoplasia, the induction time of amyloidosis is shortened, indicating The importance of T cell function in the pathogenesis.

Genetic factors (15%)

Clinically, amyloidosis is common in certain hereditary diseases such as familial Mediterranean fever, familial amyloid polyneuropathy, familial amyloid cardiomyopathy, central nervous system disorders such as Alzheimer's disease, Down syndrome and hereditary Hemorrhagic amyloidosis, etc., and it is believed that amyloidosis has a certain relationship with heredity.

Tumor (5%)

Many patients with malignant tumors often develop amyloidosis, such as Hodgkin's disease, malignant lymphoma, immunoblastic lymphadenopathy, heavy chain disease, and rectal, lung, liver, kidney, and esophageal cancer. transsexual.

Other factors (5%)

Excessive increase in AH protein caused by long-term hemodialysis may also be associated with secondary amyloidosis.

Pathogenesis

The exact pathogenesis of amyloidosis is unclear. It is generally believed that normal people continue to have a small amount of amyloid production, which is continuously eliminated by the body's dissolution mechanism. The two achieve dynamic equilibrium without the deposition of amyloid in the body. The amyloid deposits only when the amyloid is produced too much, or is eliminated too little, or both.

In all amyloidosis, fibrin has a serum proprotein, which is caused by external stimuli to be excessively produced by prodrugs that can be deposited or degraded into amyloid fibrils, resulting in increased serum concentrations, or In some cases, mutations in the amyloid precursor protein cause a fundamental structural change, which is a factor that causes amyloidosis. For example, in secondary amyloidosis, an external stimulus causes the macrophage to produce IL. -1, IL-1 stimulates hepatocytes to produce large amounts of SAA, which on the one hand is catabolized and on the other hand is degraded to AA protein. In mice sensitive to amyloid, it can be seen after administration of exogenous SAA. It is rapidly blended into the amyloid fibrils, and in vitro, the use of natural 2-M purified from normal human serum or urine leads to the formation of amyloid fibrils, presumably in dialysis-related amyloidosis. In the kidney, patients with renal insufficiency have abnormally elevated 2-MG in serum, and today's dialysis membrane fails to reduce its concentration, which causes abnormally elevated serum 2-MG to create conditions for the occurrence and development of amyloidosis. In familial polyneuropathy, because a single amino acid substitution variant formed prealbumin normal degradation process can not valid, or may by altered morphology resulting variant prealbumin deposited as amyloid fibrils.

In the occurrence and development of amyloidosis, the intrinsic properties of proproteins determine their susceptibility. In vitro experiments confirmed that only certain light chain subtypes can be converted into amyloid fibrils, clinically only 15%-20 % of patients with multiple myeloma and light chain disease are accompanied by amyloidosis. For example, the Bence-Jones protein of the VI subgroup is prone to amyloid fibrils. This light chain has abnormal structural features, and the monoclonal light chain is The mechanism by which amyloid deposits are unclear, but in an in vitro bone marrow cell culture of a myeloma-associated amyloidosis patient, amyloid is present in macrophages but not in plasma cells. It is speculated that plasma cells synthesize light chain proteins, which are then processed by macrophages to produce amyloid.

Experimental observations have found that there are one or more surface-related proteases in normal human monocytes and murine peritoneal macrophages, which have the ability to break down SAA and AA proteins into smaller fragments, while secondary amyloid Monocytes of degenerative patients cannot degrade SAA in vitro, suggesting that dysfunction of monocytes is another factor leading to amyloidosis.

In addition, two factors are involved in the formation and development of amyloid fibrils, namely amyloid enhancer and regression factor, and the enhancement factor extracted from the mouse spleen before amyloidosis can shorten the starch induced by casein. At the time of degeneration, it has also been determined that there is a factor in the serum that promotes the dissolution of AA amyloid fibrils suspended in agar, but its exact role in the pathogenesis of amyloidosis is not known.

Little is known about the role of genetic factors in the susceptibility and tolerability of human amyloid deposits, even in the familial form of amyloidosis, the exact mechanism by which defective genetically manipulated amyloid deposits at specific sites It remains to be further clarified.

It is generally believed that the pathophysiological mechanism of amyloid protein-induced tissue damage may be due to the fact that when these proteins pass through the capillary wall, part of it is deposited on the vessel wall, and the rest diffuses outside the cell, causing local tissue hyperplasia and hypertrophy. Atrophy, leading to tissue damage, dysfunction of organs, in this process, various inflammatory mediators, various cytokines and growth factors in the body are involved, and play different degrees, but the exact mechanism still needs further In-depth study.

Amyloidosis prevention

prevention:

1. Because the cause of amyloidosis is unclear, there is no way to prevent primary amyloidosis.

2. Secondary amyloidosis can only initiate inflammatory diseases of amyloidosis, such as tuberculosis and rheumatoid arthritis, by prophylactic or effective treatment. If drugs can be used to control rheumatoid arthritis, the likelihood of developing secondary amyloidosis is reduced.

The etiology and pathogenesis of this disease are not yet clear. The main points of prevention are: First, actively prevent and treat chronic infectious diseases; second, do a good job in genetic counseling.

Amyloidosis complications Complications, diabetes insipidus, congestive heart failure, congestive heart failure, atelectasis

1. Combined with renal diabetes insipidus, hyperkalemia, renal failure.

2. Clinically, with congestive heart failure, and progressive, intractable seizures, heart failure caused by amyloidosis is difficult to treat, individual patients are extremely sensitive to digitalis, so that serious or even fatal arrhythmia occurs, if Involving the conduction system can lead to conduction block, atrial fibrillation, atrial flutter and ventricular arrhythmia, which is often a late manifestation of primary amyloidosis with a very poor prognosis.

3. Combined portal hypertension and esophageal variceal hemorrhage and spontaneous liver rupture, in addition, gallbladder and pancreas may also have amyloid deposits.

4. Combined with airway obstruction, dyspnea, atelectasis, pleural effusion, secondary infection.

Symptoms of amyloidosis Common symptoms Amyloidosis conduction block Liver dysfunction Protein urinary bleeding tends to diffuse mucosal fat of the larynx...

1. Clinical manifestations: Amyloidosis often involves multiple systems and multiple organs. The clinical manifestations depend on the degree of damage of the organs involved and the affected organs. The organs often invaded include kidney, heart, liver, gastrointestinal, tongue, spleen. The nervous system, the skin, etc., the affected organs appear as organ enlargement and dysfunction, for example, kidney involvement, manifested as diffuse disease of the kidneys, swelling, proteinuria, hematuria or nephrotic syndrome, eventually developing renal failure, heart Involved, manifested as cardiac hypertrophy, heart enlargement, conduction block, cardiac insufficiency, liver involvement, manifested as liver enlargement, liver dysfunction, tongue involvement, manifested as giant tongue, pain, difficulty in speaking, etc., in addition, joints, muscles The respiratory tract and endocrine glands may also be invaded and have corresponding clinical manifestations. If the bone marrow is involved or the coagulation factor binds to amyloid, bloody abnormalities and bleeding tendency may occur. Pericardial and pleural involvement may cause pericardial effusion and pleural effusion. .

2. Clinical classification : There are many classification methods for amyloidosis. In the early years, there are some accompanying diseases, which are classified according to the chemical properties of amyloid, and also according to the distribution of amyloid organs and the staining characteristics of amyloid. However, in recent years, it has been mainly clinically combined with the main components of amyloids for classification.

Amyloidosis examination

Laboratory tests for amyloidosis are almost non-specific.

1. Peripheral blood: hemoglobin, white blood cell count and classification, platelets are generally normal, only 11% of patients with hemoglobin <100g / L, which is related to myeloma involving bone marrow, renal insufficiency or gastrointestinal blood loss, about 9% of patients The platelet count was >500×109/L, which was caused by the decrease of spleen function due to the precipitation of amyloid.

2. Biochemical examination: about 25% of patients have an increase in alkaline phosphatase. In addition to considering liver involvement, it is more considered to be caused by congestive heart failure. Transaminase bilirubin is in the normal range, and only about 3% of patients are seen to have increased. If there is a significant increase, it often indicates that the disease has reached the late stage. Half of the patients with nephrotic syndrome have elevated cholesterol, 29% have elevated triglyceride, and 5% have X-factor deficiency, but rarely cause bleeding. % of patients had serum creatinine 180 mol/L, while half of the patients were completely normal.

3. Serum protein: About half of patients with primary amyloidosis can see monoclonal protein in protein electrophoresis. If further electrophoresis or immunofixation is used, the positive rate can reach 72%, and the median M protein is 14g/L. M protein) a few > 30g / L, about one in four patients with aggreglobinemia, / is 1:2.3.

4. Urine protein: In a group of 429 patients with primary amyloidosis, 73% had urinary protein at the time of presentation, about 9% of patients had concentrated urinary electrophoresis showing albumin peak, and 70% of patients were tested by immunoelectrophoresis or immunofixation. There are M proteins in the urine, 50% are type, 23% are type, 27% are negative, 24 h urinary light chain discharge is 0.01-6.6 g, with an average of 0.4 g, about 36% of patients >3g/24h In summary, about 89% of patients diagnosed with primary amyloidosis found M protein in their serum or urine.

5. ESR increases.

6. Congo red test: Congo red test can be done when the disease is suspected: 1% Congo red solution 0.22ml/kg, intravenously, 10ml of venous blood after 4min and 1h, using double serum samples for colorimetry Check, the percentage of the dye remaining in the serum, in the normal human body, the dye is slowly excreted by the liver, the maximum excretion is 40% in 1h, because the patient's amyloid rapidly absorbs Congo red, serum after 1h or even 4min Specimens have lost most of the dyes, which is helpful for diagnosis. At the same time, urine should be collected after 1 hour, and there should be no dyes. If no dyes are used, the diagnosis can be confirmed. If the dyes should be considered for lipid-induced nephropathy.

7 bone marrow smear: 60% of patients with primary amyloidosis have cytoplasmic cells in the bone marrow 10%, 18% of patients with bone marrow plasma cells 20%, an average of 7% (1% to 95%), and in these About 30% of patients have bone disease of myeloma, and 60% have exact multiple myeloma.

8. Heart color echocardiography: showing cardiac hypertrophy and granular glare.

9 Tissue biopsy: Under the optical microscope, amorphous substances are precipitated between cells, and green refraction under polarized light after Congo red staining is characteristic of amyloid.

10. Immunohistochemical detection: Immunohistochemical examination using an enzyme label or a fluorescently labeled anti- or anti-kappa antibody can confirm that the amyloid is a chain or a chain.

Diagnosis and differentiation of amyloidosis

Diagnostic criteria

(1) Unexplained organ enlargement and/or organ dysfunction.

(2) The presence of a monoclonal immunoglobulin light chain in blood and/or urine.

(3) Histopathological examination and Congo red staining confirmed amyloidosis and confirmed by immunohistochemistry as chain or chain.

Among the above three items, the third biopsy is necessary for the diagnosis of this disease.

Diagnostic evaluation

(1) Because the clinical manifestations of this disease are diverse and non-specific, it is not possible to diagnose the disease based solely on clinical manifestations. For example, hepatic enlargement can be caused by the disease or by hepatitis virus, parasite, bacterial infection, metabolism. Diseases, tumors and other causes, but the clinical manifestations will give us clinical diagnosis thinking to enlighten, when encountering patients with unexplained organ enlargement and organ dysfunction, can think of the possibility of amyloidosis, carry out related inspections In order to confirm the diagnosis and avoid missed diagnosis or misdiagnosis, although the disease is more common in middle-aged and elderly people, it also occurs in children, so the age of onset cannot be absolute.

(2) The presence of monoclonal immunoglobulin light chain in blood and/or urine is found in most patients with this disease, but a small number of patients with this disease have no detectable monoclonal immunoglobulin light chain in urine or urine, and monoclonal immunoglobulin Protein light chain can also be found in other diseases (multiple myeloma, Waldenström macroglobulinemia, MGUS, autoimmune diseases, chronic lymphocytic leukemia, lymphoma, etc.), therefore, monoclonal immunoglobulins appear in blood and urine. The light chain is conducive to the diagnosis of this disease, but it is not a necessary condition for the diagnosis of this disease.

(3) Histopathological examination confirmed that amyloidosis is a necessary condition for the diagnosis of this disease: this examination must include:

1 Under the optical microscope, it can be seen that the amorphous amyloid is widely precipitated between the tissue cells and is green-refractive under polarized light after being stained by Congo red.

2 Immunohistochemical examination of the enzyme-labeled or fluorescently-labeled anti- antibody or anti-kappa antibody confirms that the amyloid deposited between the cells is a lambda light chain or a kappa light chain, and the first point can only confirm whether it is amyloid. Denaturation, all kinds of different types of amyloidosis are positive, the second point is the characteristic of primary systemic amyloidosis and systemic amyloidosis associated with multiple myeloma, therefore, only living The results of histopathological examination meet the above two points in order to serve as a basis for the diagnosis of this disease.

(4) The heart is the organ often involved in this disease: color echocardiography shows that more than half of the patients have cardiac hypertrophy, and the myocardium has a strong light spot image, which has certain specificity, but the positive result of this test can only be used as Contribute to the diagnosis of this disease, but can not be used as the basis for the diagnosis of this disease, the diagnosis of this disease depends on the pathological examination and immunohistochemical detection of the above-mentioned living tissue.

Differential diagnosis

The differential diagnosis of this disease should be divided into two steps: the first step is the identification of amyloidosis and other diseases; the second step is to confirm the identification of amyloidosis type after diagnosis of amyloidosis, because different types of amyloid Denaturation has different treatment and prognosis, so the identification of amyloidosis type has important clinical significance, and this point is easy to be ignored.

The disease is a chronic disease, mostly in the middle-aged and elderly people. For chronic and enlarged organs and/or dysfunction of unexplained organs in middle-aged and elderly people, the possibility of this disease should be considered, especially for multiple organs with unknown causes (heart, kidney, liver). , spleen, tongue, etc.) swelling and dysfunction, this disease should be listed as one of the identified diseases, because the clinical manifestations of this disease are not specific, so the exclusion method is used, that is, the organ enlargement and function can not find a clear cause Incomplete, the disease should be listed as one of the diseases that must be investigated, and the final diagnosis depends on the pathological examination of living tissue.

When the pathological examination of living tissue (light microscopy, detection under polarized light after Congo red staining) is confirmed as amyloidosis, the type of amyloidosis should be identified. The identification of amyloidosis type is based on clinical manifestations and amyloidogenic substances. (Bioprotein) biochemical characteristics, if the clinical manifestations of multiple systems, multiple organ involvement, patients without hemodialysis history, family history, polyneuropathy, can basically rule out hemodialysis-related amyloidosis, familial Mediterranean fever, Familial polyneuropathy, senile amyloidosis, central nervous system amyloidosis and localized amyloidosis, should consider primary systemic amyloidosis, associated with systemic amyloidosis of multiple myeloma and Secondary systemic amyloidosis, the identification of these three systemic amyloidosis is based on both clinical manifestations and amyloid properties. Patients with systemic amyloidosis associated with multiple myeloma should have bone marrow. Clinical manifestations of tumors (bone pain, anemia, infection, hyperviscosity syndrome, hypercalcemia, etc.), bone can be seen in myeloma Cells, X-ray examination can be seen in osteolytic lesions, protein electrophoresis can be seen in M protein, so it is not difficult to distinguish from primary systemic amyloidosis, secondary systemic amyloidosis is secondary to chronic infectious diseases (tuberculosis, Osteomyelitis, bronchiectasis, leprosy, etc.) or chronic inflammation (such as rheumatoid arthritis, Sjogren's syndrome), clinically significant manifestations of primary disease (infection or inflammation), can be identified, and second, primary The systemic amyloidogenic protein is the light chain lambda or of immunoglobulin, and the secondary systemic amyloidogenic protein is the AA protein, which can be distinguished by enzyme labeling or fluorescently labeled monoclonal antibody detection.

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