Pediatric amyloidosis

Introduction to infantile amyloidosis Pediatric amyloidosis (pediatric amyloidoidosis) is a systemic disease in which amyloid deposits in various tissues and organs cause multiple organ dysfunction. Especially in the liver, spleen, kidney, heart, adrenal gland, pancreas, gastrointestinal tissue, tracheal wall and blood vessel wall, the amyloid protein reacts with iodine when it reacts brown, like starch, hence the name. Very rare in children. basic knowledge The proportion of illness: 0.005% Susceptible people: children Mode of infection: non-infectious Complications: diabetes insipidus congestive heart failure arrhythmia atelectasis pleural effusion

Causes of childhood amyloidosis

(1) Causes of the disease

The etiology of amyloidosis has not been elucidated so far, but may be related to the following factors:

Physical and chemical factors

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.

2. Immunity factors

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.

3. Genetic factors

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.

4. Plasma cell disease

Amyloidosis occurs in several plasma cell diseases, such as multiple myeloma, macroglobulinemia, and heavy chain disease. Osserman et al. emphasize the relationship between Bence-Jones protein and amyloidosis, and consider Bene in patients with amyloidosis. -Jones protein has a greater tendency to bind to certain normal tissues, called the amyloid Bence-Jones protein, and Glenner et al. confirmed certain amyloid fibrils and Bence-Jones proteins by amino acid sequence studies. The variable region is the same, so the amino acid sequence of the light chain variable region is closely related to amyloidosis. Glenner et al. also digested the Bene-Jones protein with pepsin (pH 3.5, 37 ° C) to produce amyloid fibers. The typical electron microscopy of amyloid and the characteristic staining reaction, in the AL protein, the relationship between the lambda light chain and amyloidosis is more closely related to the kappa light chain, and the lambda light chain also has a -sheet structure.

5. Neoplastic diseases

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.

6. Other

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

(two) 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.

Prevention of childhood amyloidosis

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, and second, do a good job in genetic counseling.

Complications of childhood amyloidosis Complications diabetes insipidus congestive heart failure arrhythmia atelectasis pleural effusion

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 childhood amyloidosis common symptoms weight loss chest pain joint pain ophthalmoplegia growth slow pupil deformation edema abdominal pain liver enlargement renal failure

Secondary

Multiple secondary to chronic infectious diseases with tissue atrophy and cell necrosis, such as chronic osteomyelitis, bronchiectasis, may also be complicated by the long-term process of tuberculosis, rheumatoid arthritis, ulcerative colitis or Crohn's disease In the liver, amyloid deposits in the liver, often with hepatomegaly, but no jaundice, to the late spleen, the kidneys also increase, occasionally ascites and edema, weight loss is abnormal, facial color such as marble, refers to the toe sometimes Symptoms, normal blood pressure.

Renal amyloidosis, mainly manifested as proteinuria, especially urinary albumin increased, while globulin is often a peri-protein, edema of nephrotic syndrome, severe renal impairment or renal failure.

Amyloid deposition in the autonomic and adrenal glands may occur in orthostatic hypotension; deposition in the renal tubules of renal tubular acidosis symptoms, slow growth, polydipsia, such as lesions in the proximal tubules can cause Fanconi syndrome.

Localized amyloidosis, amyloid deposits in the nasopharynx, lower respiratory tract and skin, etc., may have corresponding symptoms.

2. Primary

Primary patients are rare, often with recurrent irregular wavy fever, more common in the Mediterranean coast, also known as familous Mediterranean fever, still have abdominal pain, chest pain and joint pain and other symptoms, or have liver Splenomegaly, urticaria, deafness and multiple neuropathic symptoms, some familial cases may also have chronic gastrointestinal symptoms, hoarseness and autonomic dysfunction, but also may have exophthalmos, ocular paralysis, vitreous opacity, pupil deformation or even Blindness, if the lesion involves the trachea, the airway can be narrowed due to the continued deposition of amyloid, cough, shortness of breath and wheezing, and even infection and hemoptysis.

Examination of infantile amyloidosis

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 have 20% bone marrow plasma cells, an average of 7% (1% to 95%), but About 30% of these patients have bone lesions of myeloma, and 60% have definite 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 differential diagnosis of childhood amyloidosis

diagnosis

Amyloid deposition is not obvious in childhood, such as clinically unexplained proteinuria, peripheral nerve disorders, cardiac insufficiency, hepatosplenomegaly and visual impairment, and a family-positive history should be considered The possibility of diagnosis can be confirmed by a corresponding laboratory examination.

Differential diagnosis

It is differentiated from diseases such as hepatitis, nephrotic syndrome, and chronic bronchitis.

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