1 Composition and pathogenesis of amyloid
Amyloid is pink or grayish-white waxy to the naked eye, and under ordinary light microscopy, it is a thin, unbranched, and rigid fibril. Different types of amyloid fibrils have different biochemical compositions, peptide subunits, and their origins, but they all share a nearly identical core structure, the β-sheet. Amyloid is composed of three main components: ① amyloid fibrils: amyloid fibrils for its corresponding precursor protein partially hydrolyzed fragments, different types of amyloidosis have their own different precursor proteins, known to be several 10 precursor proteins associated with amyloidosis, amyloidosis, is the basis of the biochemical classification of the structure of precursor proteins, amyloidosis is an important factor in the occurrence of precursor proteins. ② Glucosamine (glycosam-inoglycan GAG): GAG binds to amyloid fibrils in a non-***valence bonding manner, and has the effect of promoting the formation of protein fibrils. Substance P: Serum amyloid Pcomponent SAP is a highly stable, protease-resistant glycoprotein that binds to amyloid in a calcium-dependent manner, contributing to the stabilization of amyloid in the body. Some immune cells and cytokines are involved in the development of acquired amyloidosis. Monoclonal subpopulations of plasma cells that consistently produce λ or κ light chains have been shown to be involved in the development of light-chain amyloidosis; macrophages cleave certain types of immunoglobulins in an abnormal manner, contributing to the development of light-chain amyloidosis; and interleukin-1 (IL-1) contributes to the formation of hepatic SAA (serum amyloid A serum amyloid d-aminoprotein SAA), a protein that is a major contributor to the development of amyloidosis in the body. Interleukin-1 (IL-1) contributes to hepatic SAA (serum amyloid A protein serum amyloid d protein SAA) synthesis, which is involved in reactive amyloidosis, and amyl oid enhancing factor (AEF) is involved in hydrolytic cleavage of precursor proteins and their fragment deposition, which determines to a certain extent the susceptibility of patients to amyloidosis. To date, the pathogenesis of amyloid fibrils is not fully understood, but studies have shown that amyloid fibrils can damage tissues and organs in three ways: (1) physically by causing damage to normal tissue structures; (2) cytotoxically by destroying tissues. ② Destroying the structure and function of tissues and organs through cytotoxicity. The amyloid fibers can damage tissues and organs in three ways: (1) physically causing damage to normal tissue structure; (2) destroying the structure and function of tissues and organs through cytotoxicity; and (3) inducing apoptosis.
2 Clinical manifestations of amyloidosis
The clinical manifestations of amyloidosis are diversified, depending on the scope, degree, and location of amyloid deposition. Common nonspecific symptoms in patients with systemic amyloidosis are: fatigue and weakness (54%), weight loss (45%), swelling (41%), and dyspepsia (33%), and amyloidosis can occur in all tissues and organs of the body, and the corresponding manifestations can occur. Kidneys: the damage to kidneys is often irreversible, which can be manifested as proteinuria and hematuria of different degrees, until uremia. ② Liver: the involvement is very common, often manifested as liver enlargement, liver function abnormalities, bile sludge is rare. Heart: amyloidosis mainly affects the heart, manifesting as restrictive cardiomyopathy, congestive heart failure and arrhythmia. Gastrointestinal tract: the manifestations are caused by the direct deposition of amyloid or the involvement of the corresponding plant nerves, which may manifest as dysfunction, ulceration, hemorrhage, diarrhea, or obstruction, and megaloblastic tongue is characteristic but rare. ⑤Nervous system: peripheral nerve (e.g. carpal tunnel syndrome) and vegetative nerve dysfunction are the main manifestations. (6) Skin and mucous membranes: Skin and mucous membranes are often involved, but there is no clinical manifestation. Waxy papules or plaques that are mildly elevated above the skin surface are more characteristic. (7) Respiratory system: clinical symptoms are often absent, and a few can be manifested as upper respiratory tract obstructive lesions and interstitial lung changes.
3 Classification of amyloidosis
The classification of amyloidosis is complex. Classifying amyloidosis according to the biochemical properties of the protein fibril precursors may partially reflect the nature of the disease, but is not very operational. A working classification that integrates the mode of acquisition, biochemical properties, and clinical features of the disease is of greater value. Acquired amyloidosis accounts for more than 90% of all amyloidosis in the working classification. See the accompanying table for details.
4 Diagnosis of amyloidosis
The clinical manifestations of amyloidosis are varied and mostly non-characteristic, and sometimes they are part of the manifestations of the underlying disease, so we should be vigilant, and if we suspect this disease, we should be examined as soon as possible.
4.1 Histologic diagnosis Biopsy and specific tissue staining are the most important indicators for the diagnosis of amyloidosis. Tissue sections stained with Congo red show characteristic green birefringence (polarized light microscopy) or red-green birefringence (cross-polarized light microscopy). The most widely used histologic tests are abdominal subcutaneous fat aspiration and rectal mucosal biopsy, while skin and gum biopsy are also commonly used, with a positive diagnostic rate of 80%. Biopsy of vital organs (e.g., heart, liver, kidney) should be used with caution. After the diagnosis of amyloidosis has been established, immunohistochemical examination is required to clarify the biochemical type of amyloidosis. Potassium permanganate and Congo red staining are valuable for AA and AH types of amyloidosis.
Schedule Working classification of amyloidosis
Acquired amyloidosis
1. Light-chain amyloidosis (AL)
2. Reactive amyloidosis (AA)
3. Amyloidosis senile (AS)
4. Dialysis-associated amyloidosis (AH)
5. >5. Restricted amyloidosis (AE type)
6. Others
Hereditary amyloidosis
1. Familial polyneuropathic amyloidosis (FAP type)
2. Visceral amyloidosis (Ostertag type)
3. Hereditary cerebral hemorrhage with amyloidosis (Lcelandic type)
4. Familial Mediterranean fever (Dutch type)
(FMF type)
5. Others
are chromosomally recessive, and the rest of the hereditary amyloidosis
are autosomal dominant
4.2 The SAP scintigraphy is the only systematic systematic method of monitoring amyloidosis. When a certain amount of amyloid is present in the body, radiolabeled SAP can be rapidly and specifically localized at the site of amyloid deposition, allowing qualitative and quantitative diagnosis of amyloidosis, with a sensitivity of 100% for type AA and 90% for type AL. With the help of SAP scintigraphy, it is possible to understand the different distribution patterns of different types of amyloidosis, the relationship between the amount of deposits and organ function, the natural progression of amyloidosis, and the judgment of its efficacy. It is of diagnostic value in amyloidosis where histology is not certain. Histology and SAP scintigraphy are complementary techniques, with SAP providing a noninvasive, macroscopic diagnosis and histology being more sensitive and accurate in confirming the diagnosis of amyloidosis and determining the biochemical type.
4.3 Other Tests Cardiac amyloidosis is difficult to determine by histology and SAP scintigraphy, but the combination of electrocardiography and bidirectional echocardiography is highly sensitive, with the electrocardiogram often presenting with low voltage in the thoracic leads and pathologic Q waves, and the bidirectional echocardiogram presenting with diffuse, highly refractive granular highlights. After the diagnosis of amyloidosis is established, the primary cause of the disease should be actively investigated; in 15% of AL patients, the primary cause of the disease cannot be diagnosed by cytologic and immunologic examination of bone marrow, blood, and urine, and the immunoglobulin gene rearrangement can be examined by DNA blotting or PCR. When hereditary amyloidosis is suspected, gene deletions or mutations should be detected, and family lineage studies should be performed after confirmation. A very small number of patients can only be diagnosed clearly by analyzing the amino acid sequence of the protein in the lesion.
5 Principles of treatment of amyloidosis
There is no specific method to abate amyloid deposition foci, and the focus of clinical management is to reduce the supply of amyloid precursor protein, and a reasonable treatment plan should include the following four aspects: ① control of the primary disease. A rational treatment plan should include the following four aspects: (1) control of the primary disease; (2) reduction of the production of amyloid fibrillar precursors, such as the use of immunosuppressive drugs to control the acute inflammatory response in patients with AA amyloidosis, and the use of combined chemotherapy to inhibit the production of light chains of antibodies in AL amyloidosis. In situ liver transplantation can reduce the production of protein fiber precursors of hereditary amyloidosis, and patients with end-stage renal failure can undergo renal transplantation as early as possible to facilitate the clearance of β2 microglobulin. ③Promote the regression of amyloid deposition foci, and there is no specific method at present. Symptomatic supportive therapy: Symptomatic supportive therapy can delay the failure of target organs, improve the quality of life, and prolong the survival period; the organ failure that has already appeared, such as renal failure, intractable heart failure, and renal and cardiac transplantation have certain value. Some amyloidosis can be prevented, such as colchicine to prevent FMF-type amyloidosis, early kidney transplantation to prevent H A-type amyloidosis.
6 Clinical aspects of common amyloidosis syndromes
6.1 Systemic AL amyloidosis Of the primary causes of AL amyloidosis, 80% are "benign" clonal? The clinical manifestations of systemic AL amyloidosis are complex and variable, and all organs except the brain can be involved, with cardiac, renal, and peripheral nerve involvement being the most common, and the "black-eye sign" caused by periorbital vascular purpura, and the giant tongue sign having specificity. The "black eye sign" and giant tongue sign caused by periorbital vascular purpura are specific. This type is the most common amyloidosis and has the worst prognosis, with an average survival period of 12-15 months. Treatment of AL amyloidosis focuses on inhibition of B-cell proliferation, with the optimal regimen being MP (marfan + prednisolone), which is 50% effective, VAD (vincristine + adriamycin + dexamethasone), and high-dose marfan + PBST (autologous peripheral hematopoietic stem (PBS)), which is 50% effective. VAD (vincristine + adriamycin + dexamethasone) and high-dose marfan + PBST (autologous peripheral blood hematopoietic stem cell transplantation) have an efficiency rate of 85%. The new anthracycline antibiotic I-DOX may be better, and interferon is only effective in AL amyloidosis due to myeloma.
6.2 Systemic reactive amyloidosis Any pathologic stimulus that causes a sustained inflammatory response can be combined with AA amyloidosis. The combination of AA-type amyloidosis diseases are: ① rheumatic diseases: including rheumatoid arthritis, juvenile arthritis, psoriasis and psoriatic arthritis, Reiter′s syndrome, adult Still′s disease, leukemia, Crohn's disease. Chronic infections: including leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, Whipple′s disease. Neoplastic diseases: including Hodgkin's lymphoma, renal tumors, tumors of the lungs, intestines and genitourinary tract, basal cell carcinoma, hairy cell leukemia.
There is no linear relationship between the amount of AA amyloidosis deposits and the severity of clinical manifestations. Kidney involvement is the most common, with 30% of patients having enlarged liver, spleen, and adrenal glands. Cardiac and intestinal involvement is also common, but generally asymptomatic.The prognosis of AA amyloidosis is not optimistic, with survival rates of 50% and 25% after 5 and 15 years, respectively, and the majority of deaths are due to renal failure. Treatment emphasizes control of the underlying disease. The use of cytotoxic drugs such as nitrogen mustard phenylbutyrate and cyclophosphamide has significantly improved the prognosis.
6.3 Geriatric systemic amyloidosis Asymptomatic systemic amyloidosis due to wild-type TTR (transthyretin) is present in more than 25% of the elderly and does not usually require treatment.
6.4 Dialysis-associated amyloidosis is seen in patients on hemodialysis and peritoneal dialysis with renal failure, in which amyloid (β2-microglobulin) is deposited mainly in the joints, periarticular tissues, and bone, causing joint pain, carpal tunnel syndrome, and bone cysts. Kidney transplantation is the most important treatment, and nonsteroidal drugs and adrenocorticotropic hormones control most of the symptoms.
6.5 Restricted amyloidosis Restricted amyloidosis occurs in the skin, respiratory tract, and genital tract and can be cured by surgical excision.
6.6 Hereditary generalized amyloidosis Hereditary generalized amyloidosis is very rare, but can exist in many forms. It is caused by mutations in certain genes that regulate protein production, and is often inherited in an autosomal dominant pattern. FAP is characterized by progressive peripheral neuropathy and vegetative neuropathy and various degrees of visceral amyloid deposition. Currently, symptomatic supportive treatment is still the mainstay of FAP, and since 1997, 4 cases have been treated with liver transplantation, and 3 cases had good results. Postal code: Utopia, 442008, Hubei, China.