Amyloidosis and Amyloid Arthropathy

Introduction to amyloidosis and amyloid arthropathy Amyloidosis is a group of clinical syndromes caused by a variety of causes, not a clinically independent disease, but a group of protein deposition diseases promoted by tissue structure. The disease was first discovered by Wirchow in 1854. In the past 20 years, as the amyloid material was extracted from the tissues of patients with various diseases, the corresponding chemical components were further analyzed and understood, and the diagnostic rate was also significantly improved. In fact, amyloidosis The disease is not uncommon in clinical practice. It is characterized by the deposition of amyloid substances in the blood vessel wall and tissues and causes a variety of lesions, mainly involving the heart, kidney, liver, spleen, gastrointestinal, joint muscles and skin and other organs and tissues. Deposition can occur locally or systemically, and the course of the disease can be benign or malignant. The deposition of amyloid is often a partial manifestation of underlying conditions, and the state of the condition associated with it may be inflammation, autoimmune diseases, genetic diseases and tumors, the symptoms of which depend on the location and deposition of the original disease and amyloid deposits. basic knowledge The proportion of sickness: 0.0001% - 0.0003% Susceptible people: no special people Mode of infection: non-infectious Complications: congestive heart failure, arrhythmia

Amyloidosis and etiology of amyloid joint disease

The cause of deposition of amyloid in the blood vessel wall and tissues is still unclear. Various cytokines, growth factors and related inflammatory mediators may play a certain role. Protein deposition mainly occurs outside the cell, causing tissue damage and function. obstacle.

AL amyloidosis: This amyloid fibrin is derived from the immunoglobulin light chain, called AL, with a molecular weight of 500 to 2500 D, usually containing the amino terminus and part of the immunoglobulin variable region (V). Area (C) can also be a complete light chain. The light chain is mainly composed of type and type. It is characterized by primary or amyloidosis with multiple myeloma and macroglobulinemia. Plasma cell proliferation is very obvious, it has been reported in macrophage mononuclear cells, this week protein can form amyloid fibrin after lysosome in vivo protein lyase.

AA amyloidosis: This amyloidosis is caused by the deposition of amyloids, named AA proteins, in tissues. The AA protein is degraded by a large precursor, which is called serum starch. Protein A-related protein, abbreviated as SAA, is produced independently of immunoglobulin. In the chronic course, SAA is produced too much, exceeding the body's ability to degrade, forming too much AA protein and depositing in tissues. SAA may be Macrophages, monocytes and leukocytes are synthesized and stimulated by interleukin-6, interleukin-1 and tumor necrosis factor, and AA protein deposition forms secondary amyloidosis.

Senile amyloidosis: The cause is unclear. Recent data suggest that these fibrin may be transformed from various tissue-specific proteins, and their structure and antigenicity are also different from other amyloid proteins.

Chronic infection (30%)

Including tuberculosis, osteomyelitis, chronic pyelonephritis, chronic acne, bronchiectasis, lepromatous leprosy, schistosomiasis, etc.

Rheumatism (20%)

Rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, sarcoidosis, dermatomyositis, segmental enteritis, ulcerative colitis, Stell disease, immunoblastic lymphadenopathy, Behcet's disease, etc.

Malignant tumor (15%)

Hodgkin's disease, lymphosarcoma, lung cancer, esophageal cancer, rectal cancer, gastric cancer, reticulum sarcoma, lymphocytic sarcoma, cervical cancer, etc.

Other (10%)

Narcotic addiction, cystic fibrosis and periodic neutropenia.

Pathogenesis

1. Primary amyloidosis: AL amyloid protein is the first biochemical identification, which is the same as the immunoglobulin light chain (Bence-Jones protein) variable region. AL amyloidosis is the most common in the United States. Systemic amyloidosis, associated lesions are plasma cell myeloma (20%) and plasma cell dyscrasia (80%), involving skin and subcutaneous tissue, nerves, liver, spleen, heart , kidney, lung, etc. According to a retrospective analysis of a large series of cases with AL protein, about half of them are caused by fatigue and weight loss. The most common symptoms are peripheral edema, difficulty breathing, paresthesia, dizziness, hoarseness. , purpura and bone pain (usually related to bone damage in plasma cell myeloma), early physical examination, about 1 / 3 cases can touch the liver, and there is peripheral edema, followed by straight hypotension, purpura, giant tongue (macroglossia ), spleen accessible, skin papules, ecchymoses and lymphadenopathy, clinical signs and symptoms, due to the infiltration of amyloids into organs and tissues and the resulting functional changes, such as with the nerves Affected carpal bone Carpal tunnel syndrome, peripheral neuropathy and finger/toe dysfunction, and sympathetic dysfunction such as gastrointestinal disorder caused by orthostatic hypotension, impotence, abnormal sweating and autonomic nerve involvement; another example is congestive heart Symptoms related to exhaustion, mainly right heart failure and restrictive cardiomyopathy, due to ventricular stiffness and loss of flexibility, ventricular septal hypertrophy (multiple discrete 3 ~ 5mm high echo, spots appear on two-dimensional echocardiography Type change), a small number of dilated cardiomyopathy and left and right ventricular failure, both with conduction disorders, renal involvement such as proteinuria, typical nephrotic syndrome and progressive renal failure, in addition, due to small blood vessels The infiltrating texture of the amyloid is fragile, and the skin is slightly traumatic, ie, ecchymosis and "pinch purpura".

2. Secondary (AA) amyloidosis: AA amyloidosis is the second systemic amyloidosis, the cause is also protein deposition, but its precursor protein is a serum component synthesized in the liver (serum starch Protein A), after inflammatory stimulation, may increase by 100 to 200 times. Some monocyte/macrophage cytokines such as interleukin-1 (IL-1), tumor necrosis factor and IL-6 upregulate liver gene. Protein expression, secondary amyloidosis often affects the liver, spleen, kidney; cardiac involvement is not as common as primary amyloidosis, neurological involvement is extremely rare, related infectious diseases such as osteomyelitis, tuberculosis, bronchiectasis Etc.; non-infectious inflammatory lesions such as rheumatoid arthritis, juvenile rheumatoid arthritis, joint tough spondylitis, Crohn's disease, familial Mediterranean fever, etc., it is necessary to mention that renal lesions may progress slowly Silent, but due to the increasing proteinuria, eventually trapped in the nephrotic syndrome, which lasted 5 to 10 years, entered the terminal renal failure. In Europe, kidney involvement is the leading cause of death in juvenile rheumatoid arthritis patients, but US has not yet Another complication related to this complication is that AA may be absorbed in the body, which is characterized by a reduction in liver/splenomegaly or a reduction in proteinuria, but no definitive treatment for its underlying basal lesions. Because of the familial Mediterranean fever, colchicine treatment has achieved results, which can reduce the onset and development of amyloidosis, decrease proteinuria, and improve renal function in some patients. Therefore, all patients with amyloidosis should be solemn. Consider and exclude the possibility of AA.

3. Familial (ATTR) amyloidosis: ATTR amyloidosis is the third systemic amyloidosis that has been elucidated and has been shown to be associated with the presence of an abnormal prealbumin in plasma, which acts normally to carry Thyroxine and retinol-binding protein, later named transthyretin, transthyretin, originally defined as autosomal dominant peripheral neuropathy, found in middle-aged and late-aged After several decades of development, there are autonomic nerves and different organ involvement, mainly in Portuguese patients. Many clinical syndromes found in different races in Europe and the United States are caused by transthyretin gene mutations (>50). As a result, the substitution of the amino acid in this transport molecule is related to the deposition of different amyloids in the heart, intestine and kidney. Recently, one report pointed out that the variant sequence transthyretin (isoleucine 122) In elderly blacks, delayed cardiac amyloidosis increases.

4. Dialysis-related (2-microglobulin) amyloidosis (A2 M): Most patients with long-term hemodialysis or peritoneal dialysis for more than 8 years will develop this type of localized amyloidosis, joints and joints. Surrounding, bone and carpal tunnel tissue have -microglobulin amyloid deposits, patients may have rheumatic syndrome, such as chronic shoulder pain and subacromial sac tenderness, swelling of wrist and knuckles, tendon sheath hyperplasia of wrist extensor tendon As well as X-ray signs of cartilage erosion in the carpal bone, femur and tibia, pathological fractures of the tibia and femur have also been reported.

2-2-microglobulin is a non-covalent linker of class I histocompatibility main complex molecules. It is found in all human nucleated cells. The catabolism depends on the filtration and discharge of normal kidneys, dialysis patients and end stage renal disease. In patients, plasma 2-microglobulin levels were elevated, and conventional dialysis membranes made of cellulose acetate or cuprophane failed to effectively remove this substance due to poor protein clearance efficiency, and these membranes also induced complement activity.

And IL-1 production can also promote 2-microglobulin aggregation, protein (Alzheimer's disease) amyloidosis.

Alzheimer's disease is the most common cause of senile dementia. It is found in the elderly with 5% to 10 years old. The neuropathological study of the brain of Alzheimer's disease patients shows: amygdala, hippocampus and frontal, temporal, parietal and other common nerve fibers. Tangle and senile plaques, not only in the elderly, Alzheimer's disease patients, the meningeal and cerebral cortex, small diameter artery, and cell-free thickening, conventional histological examination techniques show: meningeal blood vessels The amorphous material in the central region of the wall and senescence is the typical staining property of amyloid. The biochemical properties of the two amyloid deposits have been identified as a new protein of 40 amino acids (-protein), which is a kind A much larger transmembrane glycoprotein called "-amyloid precursor protein" is produced by hydrolysis of precursor proteins in certain types of familial Alzheimer's disease. The single mutations have been replaced by point mutations. Recent studies have found that most of the delayed, apolipoprotein E4 (ApoE4) alleles in patients with sporadic Alzheimer's disease are strongly associated with A deposition in brain and cerebrovascular vessels. Sexuality, there is evidence that the deposition of beta protein amyloid in the cerebral vascular wall is an important cause of non-traumatic-hypertensive cerebral hemorrhage in the elderly. It usually occurs in the form of cerebral hemorrhage, affecting the cortex and subcortical white matter. A familial syndrome found in a Dutch clan, which caused some family members to die of cerebral hemorrhage (Dutch-type hereditary cerebral hemorrhage and amyloidosis) from the fourth to the fifth, which has been shown to be due to the presence of alanine in the protein. Replaced by.

5. Pathology: Amyloid is mainly a polysaccharide protein complex, and its tissue section is amorphous and uniform eosinophilic substance under light microscope. Observed by Congo red staining polarizer, specific apple green fluorescence is observed under electron microscope. Two different structures can be seen, the main component is a fibril with a size of about 10 nm, and the other is a rod-shaped substance (P component) with a pentagonal hollow shape. The chemical and physical properties of the latter are consistent in all amyloid diseases. The fibrils are composed of polypeptide chains, which are generally resistant to proteolytic digestion and thus form amyloid deposits that destroy or replace normal tissues, as shown in Figures 1A, B, and C.

(1) Heart: Under the microscope, amyloid deposits are deposited between the myocardial fibers. Usually, the papillary muscles are extensively diseased. The conduction system can also have the same lesions and fibrosis. In the coronary arteries and veins, the outer membrane is usually deposited with amyloid. Causes a narrow lumen.

(2) Skin: Under the light microscope, the epidermis was thinned, the nipple was flattened, the collagen fiber bundle was edematous, and amyloid deposits were observed in the subcutaneous fat, sweat glands and sebaceous glands.

(3) Kidney: Early histological changes have nodular or diffuse thickening of the glomerular basement membrane, massive deposition on the basement membrane during the course of the disease, obvious occlusion of the glomerular space, and occasional amyloid in the medulla Calming, there may be glomerular atrophy in the later stage.

(4) Nerve: In patients with peripheral neuropathy, under the light microscope, amyloid deposits are diffusely deposited in the diseased nerve sheath. Sometimes the nerve fiber sheath is also massive, accompanied by granule-like degeneration of the nerve sheath, and the nerve fibers disappear in the later stage.

(5) Others: Amyloid deposits can be seen in other tissues. The lesions are usually located around small blood vessels, and gradually expand outward as the lesion progresses.

Amyloidosis and prevention of amyloid joint disease

1. Pay attention to exercise, increase the body's ability to resist disease, do not fatigue, excessive consumption, quit smoking and alcohol.

2. Early detection and early diagnosis and early treatment, establish confidence in the fight against disease, adhere to treatment.

Amyloidosis and complications of amyloid joint disease Complications congestive heart failure arrhythmia

1. Amyloid deposits mainly in the myocardium and conduction system, leading to diastolic dysfunction, congestive heart failure and arrhythmia, including conduction block, atrial and ventricular tachyarrhythmia, amyloid deposition in the ventricular myocardium causes cardiac enlargement , constrictive pericarditis, amyloid cardiomyopathy.

2. The main complications of renal amyloidosis are nephrotic syndrome and renal failure.

3. Simple tracheobronchial nodular amyloidosis: may have respiratory bleeding and (or) obstruction, diffuse pulmonary parenchymal amyloidosis: often caused by severe alveolar capillary blockage.

4. Intestinal and colonic amyloidosis can cause diarrhea, constipation, alternating diarrhea and constipation, intestinal bleeding, intestinal obstruction, intestinal perforation and ischemic intestinal necrosis.

5. When autonomic nerve involvement, it is often associated with peripheral neuropathy, which can be complicated by abnormal gastrointestinal motility, sphincter dysfunction, impotence, sweating disorder, or orthostatic hypotension.

Symptoms of amyloidosis and amyloid arthritis common symptoms leukopenia plaque valvular thickening intestinal bleeding intestinal perforation constipation alopecia areata

The clinical manifestations of amyloidosis vary widely, depending on the distribution of amyloid tissue infiltration and the degree of dysfunction of the affected organs.

1. The damage of various systems of amyloidosis. Whether AL, AA or other types of amyloidosis, the infiltration of amyloid in tissue can cause substantial cell damage and organ dysfunction. According to reports in the literature, amyloidosis can be Involved in cardiovascular, kidney, lung, gastrointestinal tract, liver, pancreas, spleen, nerves, endocrine glands, skin and joints and other organs or systems.

(1) amyloid cardiomyopathy: cardiac involvement is seen in most AL, a small number of AA and some ATTR amyloidosis patients, amyloid deposits mainly in the myocardium and conduction system, leading to diastolic dysfunction, congestive heart failure and arrhythmia Including conduction block, atrial and ventricular tachyarrhythmia, amyloid deposition in the ventricular myocardium causes cardiac enlargement, ventricular wall thickening and ventricular diminution (or normal), mainly as a restrictive cardiomyopathy with diastolic dysfunction Dilated cardiomyopathy with abnormal systolic function is rare; refractory congestive heart failure can be the first manifestation of AL amyloidosis, which is one of the important causes of death. Endocardial, pericardial or heart valve involvement is rare, part Patients may have pericardial tamponade, abnormal valve function or myocardial rupture, amyloid may also deposit in the coronary arteries, usually involving the myocardial small arteries, manifested as ischemic heart disease, for elderly patients with unexplained heart disease (especially angina symptoms) Not obvious), or young patients with restrictive cardiomyopathy, should pay attention to the exclusion of amyloid cardiomyopathy.

Electrocardiogram examination can be found that limb lead low voltage, various arrhythmia, Q wave and ST-T changes (like acute myocardial infarction), etc., echocardiography is the most valuable non-invasive examination for the diagnosis of cardiac amyloidosis, can be displayed Ventricular wall thickening, thickening of the interventricular septum and enhanced granular sparkling echo, the latter highly suggesting amyloid cardiomyopathy, Doppler ultrasound can be used to evaluate diastolic function, initial ventricular relaxation disorder, later The deceleration time is shortened (<150ms), and finally the constrictive pericarditis-like changes are present. The left ventricular ejection fraction is mostly normal, and the late stage can be reduced. Other abnormalities include heart valve thickening and regurgitation, atrial enlargement and atrial wall thrombus (rare), the combined use of electrocardiogram and echocardiography is the most diagnostic value. Intracardiac biopsy through intravenous catheter for histopathological examination is of great significance for the diagnosis of amyloid cardiomyopathy.

(2) amyloid nephropathy: the kidney is one of the most frequently invaded sites of amyloid, renal amyloidosis may be the most serious manifestation and main cause of death in patients with amyloidosis, renal amyloidosis in AL and AA (including Amyloidosis is common in hairy, familial Mediterranean fever and chronic intravenous drug addiction. The main manifestations of renal amyloidosis are nephrotic syndrome and renal failure. Proteinuria is very common. In severe cases, there may be a large amount of proteinuria (24h urine protein quantitation >3.5g is called "nephropathy proteinuria"), 35% AL And 50 amyloidosis patients with nephrotic syndrome, hematuria is relatively rare, but obvious hematuria can suggest lower urinary amyloid infiltration, pyuria and tubular urine can also occur, but not common, renal vein thrombosis is renal amyloidosis More common complications, hypertension is rare, chronic renal insufficiency is more common, and sometimes acute renal insufficiency can occur (multiple secondary to hypovolemia, hypotension, shock, bleeding and other complications), uremia Symptoms are the late manifestations of renal amyloidosis, but dialysis treatment can stabilize the condition, sometimes renal hypoglycemia, renal diabetes collapse, renal tubular acidosis, Fanconi syndrome and other renal tubular dysfunction, abnormal penile erection and kidney Vascular abnormalities have also been reported. The prognosis of patients with renal amyloidosis is mainly related to serum creatinine and urinary protein levels. A considerable number of patients with renal failure requiring dialysis, combined with adrenal amyloidosis , leading to a decrease in adrenal function.

Amyloid deposits mainly in the glomerular and renal arteriolar wall, can also be deposited along the basement membrane of the renal tubule, or deposited around the small tube, amyloid deposition in the glomerulus, mainly in the mesangial area, subendothelial and upper Subcutaneous and other parts, a large number of amyloid deposition can cause glomerular sclerosis, renal artery stenosis or occlusion, tubular atrophy, interstitial fibrosis and mononuclear cell infiltration, etc., early kidney amyloidosis, the kidneys increase or The size is normal, and in the case of advanced renal failure, there is a double kidney atrophy, and renal biopsy tissue sections for Congo red staining are the main diagnostic basis for renal amyloidosis.

(3) Amyloidosis of the respiratory system: any part of the respiratory tract, including the nasopharynx, larynx, tracheobronchial tree and lung, may have amyloidosis, which can be used as the only system involved, ie the upper respiratory tract and (or The focal amyloidosis of the lower respiratory tract can also be part of systemic amyloidosis, about 20 and most AL amyloidosis affects the respiratory tract, tracheobronchial and lung can be nodular or diffuse lesions, clinical symptoms depend on At the site and extent of amyloid deposition, general focal or nodular amyloidosis is benign, not associated with systemic amyloidosis, and diffuse amyloidosis and primary systemic (AL) starch Related to the change, the long-term prognosis is poor.

At present, there are five types of airway amyloidosis:

1 simple tracheobronchial amyloidosis: may have respiratory bleeding and / or obstruction.

2 diffuse tracheal bronchial amyloid infiltration: extensive submucosal amyloid deposition can cause dyspnea and episodes of wheezing, although the clinical symptoms are heavier, but X-ray examination is generally normal.

3 isolated nodular lung amyloidosis: lung tissue may have single or multiple nodules, nodules contain giant cells, the general symptoms are mild, the prognosis is better, and the nodules can be removed for obvious symptoms.

4 diffuse pulmonary parenchymal amyloidosis: common in primary systemic (AL) amyloidosis, mostly associated with cardiac involvement, a large number of amyloid deposits in the alveolar septum, severe symptoms, poor prognosis, often due to severe alveolar capillaries Blocking causes death.

5Hilar adenopathy: less common, other manifestations include pleural effusion, diaphragmatic weakness, pulmonary hypertension and solitary mediastinal masses.

(4) Digestive system amyloidosis: Gastrointestinal involvement is common in all types of amyloidosis, and amyloidosis can occur in any part of the digestive system, including tongue, gums, esophagus, gastrointestinal and liver.

Giant tongue, gum thickening is quite common in the examination of the body, the giant tongue often prompts primary (AL) amyloidosis, the incidence rate is about 10%, it can be its first performance, the giant tongue can affect swallowing and breathing, even in severe cases can lead to serious Obstructive apnea requires continuous positive nasal pressure ventilation or tracheotomy, and esophageal amyloidosis can cause esophageal swelling and peristaltic stiffness.

Gastric amyloidosis can cause abnormal gastric motility, hemorrhage, nausea, vomiting, pyloric obstruction, gastric acid deficiency and vitamin B12 deficiency. Sometimes it looks like stomach cancer. X examination shows no specificity, and gastroscopy results often have a larger diagnosis. Significance, diagnosis depends on the results of Congo red staining of biopsy tissue sections.

Amyloidosis in the small intestine and colon can cause diarrhea, constipation, alternating diarrhea and constipation, intestinal bleeding, intestinal obstruction, intestinal perforation and ischemic intestinal necrosis, etc., vitamin B12 deficiency, malabsorption syndrome and protein-losing enteropathy can occur. Amyloid deposition is more common in the intestinal mucosa and vascular plexus. Rectal amyloidosis is also common. In addition to the direct deposition of amyloid protein, autonomic neuropathy is also an important factor causing gastrointestinal dyskinesia.

Hepatic amyloidosis is very common. In fact, all patients with AA amyloidosis, as well as most patients with AL amyloidosis, have liver involvement. Liver amyloidosis is mainly characterized by hepatomegaly, portal hypertension, intrahepatic cholestasis and liver function. Incomplete dysplasia, liver enlargement can be abnormally significant, often not parallel with the degree of liver function enzyme abnormalities, serum alkaline phosphatase and transaminase can be slightly increased, and hyperbilirubinemia is not common, once jaundice appears Poor prognosis, spleen amyloidosis can cause splenomegaly, usually asymptomatic; clinical manifestations of hypersplenism (such as leukopenia, thrombocytopenia), in fact, peripheral blood is common, Hao-week corpuscle, suggesting functional spleen deficiency For example, due to a large amount of amyloid deposition caused by significant swelling of the liver and spleen, individual patients may have spontaneous liver rupture or spleen rupture, requiring surgical emergency surgery.

Gingival, tongue or rectal mucosal biopsy is one of the commonly used methods for the diagnosis of amyloidosis, and liver biopsy is relatively rare in the diagnosis of amyloidosis.

(5) Nervous system amyloidosis: After the peripheral nerve is infiltrated by amyloid, there may be sensory disturbances, limb weakness and painless ulcers, usually manifested as extremities, symmetry, progressive sensorimotor neuropathy, sensory nerves Affected, lower limbs are more common and more severe than upper limbs, autonomic nerves can also be affected, often associated with peripheral neuropathy, manifested as abnormal gastrointestinal motility, sphincter dysfunction, impotence, sweating disorder, or posture Sexual hypotension, etc. Clinically, amyloid neuropathy is similar to diabetic neuropathy. Cranial neuropathy is rare. Spinal nerve roots, sympathetic ganglia, brain and other parts can also be infiltrated. Symptoms, signs and cerebrospinal fluids are present. Biochemical visible protein and / or IgG light, moderately elevated, EMG examination, visible neurogenic damage, the diagnosis of peripheral nerve amyloidosis depends on sacral nerve biopsy, in small myelinated fibers and unmyelinated fibers, common To axonal degeneration, peripheral neuropathy is seen in 20% to 35% AL and 2 amyloidosis patients, severe peripheral nerves and autonomic neuropathy are familial amyloid Neuropathy (outstanding performance ATTRA, Gel, AApo-A1's.

Carpal tunnel syndrome is common in AL, A2 M and ATTR amyloidosis, and is not associated with AA amyloidosis. Carpal tunnel syndrome is caused by amyloid deposition in the wrist ligament, resulting in compression of the median nerve and insufficient blood supply to the hand artery. Need surgery.

(6) skin amyloidosis: more than 50% of patients with AL or AA amyloidosis have amyloid deposits in the skin, regardless of whether there is obvious skin lesions in the clinic, skin lesions are mainly found in the face and trunk, mainly showing skin growth Thick, swollen, "wax-like", purpura, plaque, blisters, hyperpigmentation, nodules and hardened papular-like changes, sometimes resembling scleroderma or mucinous edema; hemorrhagic blisters, mossy lesions, Nail atrophy, breast lesions, hair loss and alopecia areata have also been reported. Amyloid deposition under the small blood vessels of the skin and mucous membranes can lead to increased capillary fragility and skin mucosal bleeding. Spontaneous periorbital sputum causes typical "tennis gaze" (racoon eyes) change, often suggesting AL amyloidosis.

Amyloid protein is mainly deposited in the dermis and subcutaneous blood vessel wall, often involving skin appendages. Local skin amyloidosis mainly has two types of mossy and nodular types. Mossy amyloidosis is more common in middle-aged and elderly people. The predilection site is The lower extremities and buttocks are characterized by a continuous papule-like change, which resembles moss. Skin biopsy shows a small amount or scattered amyloid deposits in the dermal papilla, and local hyperkeratosis is also observed. Nodular amyloidosis is more in the limbs, trunk, On the face or glans, single or multiple nodules or masses, brown or golden yellow, sometimes with bleeding tendency, skin biopsy visible dermis, subcutaneous tissue and blood vessel wall have many amyloid deposits.

(7) amyloid joint disease: various types of amyloidosis can affect the joints, especially AL and A2M amyloidosis is easy to appear.

AL amyloidosis mainly affects the shoulder, wrist, knee and interphalangeal joints, etc., may have morning stiffness, soft tissue swelling around the joints, tenderness and limited mobility, sometimes resembles rheumatoid arthritis, and more than half of the patients can see subcutaneous Nodules, some patients may have carpal tunnel syndrome and/or "shoulder pad sign", amyloid may also be deposited in skeletal muscle, developing muscle hypertrophy or myopathy, massive amyloid infiltration of bone Can cause osteolytic lesions, leading to pathological fractures.

The main manifestations of A2M amyloidosis include carpal tunnel syndrome, joint effusion, limited joint activity, spondyloarthropathy and cystic bone destruction.

Osteoarthritis, calcium pyrophosphate deposition and intervertebral disc calcification can also be associated with articular amyloidosis.

(8) Endocrine gland amyloidosis: AL and AA amyloidosis can cause structural damage and dysfunction of endocrine glands. Adrenal amyloid dysfunction is not uncommon in recent years, often accompanied by renal amyloidosis. In mild cases, fatigue, anorexia, hyperpigmentation, and hypotension may occur in the Addison crisis. It is reported that a group of 22 patients with renal amyloidosis (AL12, AA10), 13 patients with clinical examination Adrenal dysfunction was confirmed in the laboratory or pathology, 2 of which died of the Addison crisis. Patients with thyroid amyloidosis may have dry skin, anorexia, fatigue, cold, constipation, bradycardia, etc. Some may be accompanied by edema proteinuria, and testicular amyloidosis may show signs of sexual dysfunction.

2. Clinical features of various types of amyloidosis

(1) AL amyloidosis: AL amyloidosis includes primary and myeloma-associated amyloidosis. Primary amyloidosis is a fairly common clinical syndrome, usually accompanied by abnormal proliferation and immunity of plasma cells. The abnormality of globulin or its related substances, the amyloid deposits are mostly immunoglobulin light chains, and its pathogenesis is generally unrelated to infectious, inflammatory, neoplastic or familial diseases.

Primary amyloidosis occurs mostly in middle and old age, and the average age of onset is about 60 years old. The main clinical features are:

1 giant tongue;

2 non-thrombocytopenic purpura;

3 types of rheumatoid arthritis;

4 restrictive cardiomyopathy;

5 nephrotic syndrome;

6 carpal tunnel syndrome;

7 sensation, exercise and autonomic dysfunction;

8 hemorrhagic quality, often associated with acquired factor X defects;

9 monoclonal immunoglobulin or light chain appears in serum or urine, of which light chain is dominant.

6% to 15% of patients with multiple myeloma have amyloidosis. This amyloidosis is associated with excessive deposition of light chain in tissues, and kappa light chain is more common.

(2) AA amyloidosis: AA amyloidosis, also known as secondary systemic amyloidosis or reactive amyloidosis, is the most common systemic amyloidosis, and its cause is mainly long-term infection (such as leprosy, Osteomyelitis, tuberculosis) or non-infectious (such as rheumatoid arthritis, familial Mediterranean fever) inflammation, and a small number of tumors.

In developing countries, AA amyloidosis occurs after untreated long-term infection, with tuberculosis, leprosy (especially leprosy) accompanied by amyloidosis, but the incidence varies greatly from country to country. According to reports, about 3/4 (150/200) of the secondary amyloidosis in India is caused by tuberculosis, while North America is rarely caused by tuberculosis. Tumor-type leprosy with amyloidosis mainly occurs in Africa, India, Southeast Asia. In South America and other places, the incidence rate is 3% to 33%, chronic osteomyelitis, bronchiectasis, cystic fibrosis, chronic pyelonephritis, hemorrhoids, syphilis, diacetal morphine (heroin) addicts, paraplegia with infection, chronic liver disease Chronic bacterial dysentery, subacute infective endocarditis, chronic empyema, schistosomiasis and other chronic infections, may also be associated with secondary amyloidosis.

In many countries, including developed countries in Europe and America, the incidence of chronic infections such as tuberculosis and leprosy has decreased significantly. AA amyloidosis is mostly caused by chronic rheumatic diseases, of which rheumatoid arthritis is the most common, juvenile chronic arthritis. Ankylosing spondylitis and other common, other, such as Wright syndrome, psoriatic arthritis, Behcet's disease, nodular polyarteritis, Sjogren's syndrome, polymyositis, dermatomyositis , scleroderma, systemic lupus erythematosus, inflammatory bowel disease and Wipple syndrome can also be associated with secondary amyloidosis. Foreign autopsy results suggest that nearly 25% of RA patients have amyloid deposits, the degree of lesions and The severity of RA is related to the course of the disease. Studies have suggested that AA amyloidosis is the most common cause of nephrotic syndrome in RA patients. At least 10% of deaths in RA patients are caused by amyloidosis.

AA amyloidosis is clinically involved in multiple systems, with the most prominent renal lesions, nephrotic syndrome, renal failure and renal tubular dysfunction; gastrointestinal involvement, hepatomegaly, splenomegaly and autonomic neuropathy; peripheral neuropathy And cardiomyopathy is rare, AA amyloidosis progresses slowly, and survival usually exceeds 10 years.

AA amyloidosis has been found to be associated with some tumors, mainly in renal cancer and Hodgkin's disease, and atrial myxoma is rare.

AA amyloidosis can also occur in familial Mediterranean fever (FMF) patients, FMF is autosomal recessive, the main affected area is the Mediterranean coast and the Middle East, is a cyclical fever disease with serositis, arthritis And rash, the incidence of amyloidosis in different ethnic FMF patients is also different, an average of 20.3%, the highest incidence of Jews (32.3%), mainly kidney disease, proteinuria, nephrotic syndrome, colchicine Treatment can reduce the frequency and severity of fever episodes.

In addition, AA amyloidosis can also occur in patients with Mlmkle-Wells syndrome, a hereditary periodic fever disease characterized by kidney damage, deafness, urticaria and fever.

(3) ATTR amyloidosis: ATTR amyloidosis includes most familial amyloidosis and senile systemic amyloidosis, and is also a systemic disease that can affect the surrounding and autonomic nervous system, heart and gastrointestinal tract, It is very similar to AL amyloidosis; however, unlike AL amyloidosis, kidney damage is rare as its main feature.

ATTR amyloidosis can occur in both variant (point mutation) TTR and normal TTR molecular structures. The variant TTR is associated with most (more than 50%) familial (hereditary) amyloidosis, autosomal dominant, usually involving The heart and/or peripheral nerves, the majority of patients in the 30 to 70 years old, clinical course often reaches 5 to 15 years, and gradually progress, the normal sequence of TTR-formed amyloid often deposited in the ventricle, gastrointestinal tract, wrist ligament Organs are more common in the elderly. In addition, not all variant TTRs are associated with amyloidosis. As of June 1999, 71 different amyloid variants have been found in 55 of the 127 amino acid TTR molecules. Related amino acid substitutions.

Familial amyloidosis syndrome caused by different TTR mutations often has different affected organs and clinical manifestations. Specific TTR mutations often have their specific clinical phenotypes, which can be divided into neuropathy and myocardial lesions. Primary, mixed neuropathy and myocardial lesions, carpal tunnel syndrome.

Neuroamyloidosis syndrome: formerly known as familial amyloidosis polyneuropathy (FAP) type I, characterized by prominent peripheral and autonomic neuropathy, involving the heart, gastrointestinal tract and vitreous, clinically progressive Peripheral neuropathy, more common in the lower extremities, with temperature and pain loss; prominent autonomic and gastrointestinal disorders, orthostatic hypotension, impotence, decreased sweat, diarrhea and constipation; may have varying degrees of heart and kidney damage During disease progression, proteinuria, renal failure, cranial nerve involvement, decreased salivary secretion, giant tongue, goiter, and neurological knee or ankle injury also occur; visual impairment (incomplete pupillary edges, vitreous opacity, and poor light reflex) It has also been reported that the earliest discovered and most common variant TTR is TTRMetl30, that is, the proline at position 30 is replaced by methionine, and the population of northern Portugal, Japan and northern Sweden is 30 to 50 years old.

Mixed neuropathy and cardiomyopathy: These TTR variants are characterized by both neuropathy (autonomic neuropathy) and cardiomyopathy. Patients often die of heart damage, and TTR-alanine (TTR-Ala) is one of the variant TTRs. The Irish descendants who first met in West Virginia, are quite common in Northern Ireland, affecting 1% of the population.

Carpal tunnel syndrome: Some TTR mutations are characterized by carpal tunnel synthesis, vitreous opacity is common, and cardiomyopathy is often the cause of death. First seen in the Indian state of Indiana, TTR is TTR Ser84, ie 84 isoleucine was Alkaline substitution; other mutation types (such as TTR His58) have also been reported.

Myocardial lesions: A special group of TTR mutations are characterized by familial cardiomyopathy without neuropathy. TTR ILE122 (isoleucine replaces 122 proline) is found in 3% to 4% African Americans; TTR Met111 is in The Danes have reported.

The elderly (>70 years old) often have a small amount of amyloid deposits in the brain, heart, aorta and pancreas. The senile systemic amyloidosis is mainly affected by the heart, and can also involve the lungs and blood vessels. The ventricular TTR deposition is seen in 10%. ~25% of the elderly over 80 years old, the amyloid protein is the normal sequence TTR or variant TTR (TTR Ile122), the elderly have myocardial amyloidosis and congestive heart failure, should pay attention to distinguish between ATTR (median survival of 5 years) ) and AL (median survival period of 6 months), the prognosis of the two is different.

(4) A2 M amyloidosis: A2 M amyloidosis, also known as hemodialysis-related amyloidosis, is mainly seen in patients with renal failure who have undergone hemodialysis for a long time. The disease can occur as early as 5 years after dialysis. The incidence rate in 10 years increased to 20%, 30% to 50% in 15 years, and 80% to 100% of patients developed A2 M amyloidosis during dialysis for 20 years; it has been reported that chronic peritoneal dialysis and non-dialysis treatment have been reported. A2 M amyloidosis can also occur in patients with renal failure.

A2M amyloidosis mainly involves the synovium, clinically characterized by bone and joint symptoms, including carpal tunnel syndrome, persistent joint effusion, spondyloarthropathy and cystic changes of the bone. Carpal tunnel syndrome is usually the first episode of this disease. Performance, continuous joint effusion can be seen in 50% of patients receiving dialysis for more than 12 years, bilateral joints (shoulders, knees, wrists and hips) are more common; synovial fluid is non-inflammatory, Congo red staining can be found in 2 microspheres Protein amyloid deposits, spondyloarthropathy can have disc destruction and paravertebral erosion lesions, cystic changes of the femoral head, acetabulum, humerus, humerus, vertebral body and carpal bone can sometimes lead to pathological fractures, visceral 2 microglobulin Less deposition, gastrointestinal tract, heart, liver, lung, prostate, adrenal gland, tongue, tendon and subcutaneous tissue of the buttocks can also be involved, kidney transplantation is an effective prevention and treatment.

(5) Other types of amyloidosis:

1 Other familial (hereditary) amyloidosis: AApo-Al amyloidosis, also known as type III neuroamyloidosis (England/Grange/Irish), was first discovered in England and other areas, mainly as lower extremity peripheral neuropathy (Mental sensory disturbance), obvious renal damage and duodenal ulcer, etc., AGel amyloidosis, also known as type II neuroamyloidosis (Finnish type), first found in Finnish patients, with progressive cranial neuropathy, cornea Characterized by damage and skin changes, AFib and ALys amyloids become familial autosomal genetic amyloidosis, mainly involving the kidneys, without neuropathy.

2 central nervous system amyloidosis: primary central nervous system amyloidosis including: ACys amyloidosis, also known as hereditary cerebral hemorrhage with amyloidosis (Icelandic); A amyloidosis, including hereditary cerebral hemorrhage With amyloidosis (Dutch type), Alzheimer's disease and Down's syndrome; APrp amyloidosis, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker (GSS) disease, fatal familial insomnia (FFI), mad cow disease (bovine spongiform encephalopathy), Creut disease and scrapie.

3 corneal amyloidosis: including AGel, Aker, and ALac amyloidosis, all autosomal dominant inheritance.

4 other focal amyloidosis: 4 peptide hormones have been identified as tissue-specific precursor amyloid precursor proteins: AANF in isolated atrial amyloidosis; ACal in medullary thyroid carcinoma; AIAPP in the elderly The islets may be involved in the pathogenesis of type 2 diabetes; APro comes to pituitary adenomas; and Aker is confined to the skin (Figure 5).

In addition, immunoglobulin light chains ( or ) can also be deposited locally in the organs. Focal AL amyloidosis is common in the respiratory tract and lungs, the lower urinary tract, the skin, the mediastinum and the posterior peritoneum.

Peripheral neuropathy occurs in 25% to 31% of patients with AL, but is rare in AA patients. The involvement of musculoskeletal bone may also occur in primary and secondary amyloidosis. Joint deposition of amyloid is often similar to RA. The clinical manifestations, autopsy found that there may be amyloid deposition in all joints, AL amyloidosis caused by joint disease is subacute, progressive, essentially the same, the common affected joint has shoulders, Wrist, knee, MCP and PIP, joints are only slightly tender, with mild morning stiffness. CTS is common in patients with B2M disease, which is directly related to the duration of hemodialysis. Subcutaneous nodules are present in 60% of cases. AL amyloidosis may be associated with soft tissue swelling and synovial deposition. In up to 75% of cases, the "shoulder pad" sign involves amyloid deposition of the ankle joint of the tibia, and the volar fascia may become nodular and painful. Contraction and weakening and thickening, muscles may also produce pseudohypertrophy due to weakness and pain. Peripheral arthritis of the scapula joint occurs in synovial tissue and subacromial mucus, similar to tear or adhesion of the rotator The sac, dialysis for 8 years, patients often develop bilateral exudation, knee and shoulder exudation often occurs, joint capsule damage containing amyloid deposits occurs in DRA disease, usually involving the end of long bones to make it easy to fracture .

The lesion begins to occur symmetrically in front of the calf tibia. After the front arm stretches the back and the thigh, the early rash becomes a needle-shaped papule after the needle-sized brown rash, gradually increasing into a soybean size, hemispherical, conical or more. Angled papules, which can be brown, yellow, reddish or normal skin tone, rash is hard, the surface can be waxy like the ocean, there may be a little scaly, or keratinized rough, early rash is scattered, later densely integrated, but often not Fusion, calf and back rash often arranged in a bead-like shape along the skin, which has diagnostic value. The central lesion can form large plaque-like hyperplasia or mossy patches, which can be seen with pigmentation and scars, no exudation, and violent itching. Itching can also be preceded by skin lesions for 1 to 2 months. There is no systemic symptoms. The disease is mostly in young and middle-aged people. It occurs in middle-aged people. Once the rash appears extremely difficult to disappear, the course of disease can vary from several years to several decades.

Examination of amyloidosis and amyloid arthropathy

1. Blood routine and erythrocyte sedimentation rate: Secondary amyloidosis varies with primary disease, may have mild anemia, increased white blood cell count, increased erythrocyte sedimentation rate, no abnormal changes in primary and familial types, secondary to plasma cell disease It can be seen that there is red blood cell bunching in the surrounding blood.

2. Urine routine: There are proteinuria, white blood cells, red blood cells or casts in patients with kidney disease.

3. Immunological examination: Blood and urine protein electrophoresis and serum immunoglobulin quantitative determination, if the discovery of special immunoglobulin, is of great significance for the diagnosis of AL amyloidosis.

4. Electrocardiogram: Patients with heart disease can be seen with low voltage, myocardial infarction-like changes, atrial fibrillation, atrioventricular block, sick sinus syndrome.

5. X-ray examination: This disease often involves multiple symmetry involving the joint, which is characterized by soft tissue mass at the joint site. The bone near the joint end can show osteolytic changes, and there may be localized necrosis. Due to bone and joint ischemia, the proximal joint end The bone may be localized necrosis, the articular surface is flattened, and the bone is dense. When the hip is involved, the X-ray appearance is like avascular necrosis of the femoral head, the edge is clear, there is no hardened edge, and there is no dead bone formation or periosteum. Response, when the vertebral body is onset, extensive osteoporosis and cystic bone destruction can occur, and the cone compression can be wedge-shaped, similar to myeloma changes.

6. Ultrastructural examination of amyloid: Under the electron microscope, the amyloid is a non-branched hard fiber of diameter (70-90)×10-10 m, and each fiber can be 2~5 fine branches (25-30)×10 -10m is arranged in parallel around the long axis of the fiber, mainly deposited outside the cell, and the deposited fibrils are separated and analyzed by X-ray diffraction to have a characteristic -sheet formation.

Diagnosis and differentiation of amyloidosis and amyloid joint disease

Diagnostic criteria

The clinical manifestations of this disease are complex and variable, and it is difficult to identify early, and often there are multiple systems damaged. To correctly diagnose, it is necessary to understand the clinical manifestations.

1. Clinical manifestations

(1) AL amyloidosis: systemic involvement, including secondary to plasma cell disease and primary subtypes, the former age of onset and plasma cell disease are the same, the latter is more than 40 years old, both onset All of them are male. In addition to the characteristics of plasma cell disease, the most common systemic symptoms are fatigue, weight loss, paresthesia, dizziness and sound changes. It is a common early symptom of this disease. Early signs include ankle edema and purple spot. Hepatosplenomegaly, about 1/5 of the patients have giant tongue, with submandibular structure swelling, gingival hyperplasia and tongue hardening, the affected organ system is as follows:

1 cardiovascular disease has the following performance:

A. Congestive heart failure: It is a common manifestation of this disease. It can be seen in half of patients, showing chronic progressive heart enlargement, but it is rare to be enlarged. It is not responsive to treatment. It can be sensitive to digitalis and is about to die. About 1/3 of patients Have angina.

B. Restrictive cardiomyopathy: myocardial stiffness, poor myocardial relaxation, mainly manifested as right heart failure, and obvious peripheral edema.

C. Arrhythmia and orthostatic hypotension.

2 respiratory system performance: caused by alveolar septum and pulmonary vascular amyloidosis, symptoms of cough, asthma, severe bronchial involvement, respiratory failure can occur, throat lesions resemble laryngeal cancer, can cause hoarseness.

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