Treatment of secondary amyloidosis. Amyloidosis. Causes, symptoms, signs, diagnosis and treatment of pathology. Causes and risk factors
The term "amyloidosis" is retained out of respect for Rudolf Virchow, who pioneered the use of histochemical staining techniques in 1854 to characterize amyloid deposits in pathological brain specimens. Whereas all other structures in his brain sections stained yellow after the addition of iodine and sulfuric acid, the amyloid bodies stained light blue with iodine and brilliant violet with the subsequent addition of acid. Because this type of staining was characteristic of plant cellulose, Virchow concluded that amyloid bodies were composed of a substance similar to cellulose, which he called amyloid. The term "amyloid" means "containing" or "resembling starch". However, this is an incorrect term, since it is now known that amyloid deposits contain mainly protein, even though some carbohydrate-containing substances can bind to proteins. Research on amyloid has mainly focused on its protein composition.
The onset and progression of amyloidogenesis is entirely dependent on the causative protein, but usually follows one of three pathogenic processes: overproduction and deposition of a wild-type protein, deposition of a mutated protein variant, or deposition of protein fragments that have been generated by aberrant endoproteolytic cleavage.
The presence of detectable amyloid is a prerequisite for the manifestation of the disease in patients. Although the extent and rate of organ damage and disease severity vary between patients, even in those with similar types of amyloid proteins, the body's total amyloid load is directly correlated with disease severity. Thus, reducing the total amount of amyloid can stabilize or improve the clinical manifestations of the disease.
Prevalence
The prevalence of amyloidosis varies in different regions. Although Alzheimer's disease is the most common form of amyloidosis in the United States and worldwide, we primarily focused on the systemic forms of the disease. In the US, AL is the most common form of systemic amyloidosis. Among residents of Olmsted County, Minnesota, reliable data were obtained regarding the prevalence of the disease between 1950 and 1989. According to this information, approximately 1 in 100,000 people will develop AL amyloidosis.
Worldwide, AA is the most common form of amyloidosis. In industrialized countries, inflammatory diseases are the leading cause of AA amyloidosis, while systemic or chronic infections are responsible for most cases of AA amyloidosis in developing countries.
Amyloidosis can be presented as a systemic or localized disease. There are four classes of systemic amyloidosis: AL, AA, ATTR, and Ap2M. Numerous forms of localized amyloidosis have been identified. Alzheimer's disease and localized amyloid deposits in the larynx and urinary tract are the most common forms of localized amyloidosis.
With the exception of Alzheimer's disease, in which there is a cytotoxic effect on brain cells, the clinical picture of other amyloidoses, as previously described, is caused by a mechanical disruption of normal physiological function. The clinical manifestations of amyloidosis depend on the type of amyloid protein.
Amyloidosis-AL
Clinical manifestations of AL-amyloidosis are different. The kidneys, heart, and liver are the most frequently and most noticeably affected organs; however, any organs other than the central nervous system may be affected. In the kidneys, AL-amyloid deposits are seen primarily in the glomeruli, which causes nephrotic syndrome, which usually manifests as an initial daily urinary protein excretion of more than 2 g. Often, in more advanced disease, daily urinary protein excretion can reach 5-15 g.
Heart failure develops gradually. By the time most patients with AL amyloidosis present with clinically apparent amyloidosis-related cardiac pathology, significant myocardial damage has already been observed. As a result of atrial expansion, supraventricular tachyarrhythmias may occur. Restrictive cardiomyopathy can lead to significant orthostatic hypotension due to limited ventricular filling, which is accompanied by autonomic dysfunction caused by damage to the peripheral nervous system.
Bleeding and impaired peristalsis are the most common manifestations of amyloid deposits in the gastrointestinal tract. Early satiety, caused by delayed gastric emptying, is also a common symptom. Excessive bacterial growth with significant malabsorption can cause diarrhea and lead to vitamin B12, folic acid, and carotene deficiencies. Hemorrhage can occur in any part of the gastrointestinal tract. although the stomach and small intestine are more commonly affected. AL-amyloid deposits are often seen in the liver, although this rarely causes any symptoms.
Involvement of the peripheral nervous system, which may develop months or years before visceral involvement, occurs in up to 20% of patients with AL amyloidosis. It may manifest as sensorimotor or autonomic neuropathy, or as a combination. Paresthesias develop first in the lower extremities and may spread proximally over time. Involvement of the motor nerves is rare, but can cause severe impairment and lead to foot drop syndrome and gait disturbances. Autonomic neuropathy is often seen in patients with AL amyloidosis and results in GI dysmotility, impotence, and orthostatic hypotension.
There are two predominant pulmonary manifestations of AL amyloidosis. Sometimes in the lung parenchyma, AL-amyloid can be presented as a mass resembling a tumor, often with concomitant expansion of the hilar and peritracheal lymph nodes. Although these masses may progressively increase, they are usually not life-threatening.
Alternatively, diffuse interstitial infiltration of the lung parenchyma may occur, which causes stiffness and restrictive lung injury. Rarely, AL-amyloid can be deposited locally in the larynx, trachea, leading to hoarseness and sometimes significant airway obstruction. Hematologic abnormalities in AL amyloidosis include purpura and thrombosis. Amyloid infiltration of blood vessels causes their fragility. Breaks in the skin capillaries lead to extravasation of red blood cells and purpura. In a patient with AL amyloidosis, periorbital purpura can be caused by relatively harmless activities, such as rubbing the eyes or tilting the head down for a long period, resulting in the characteristic bruising under the eyes. In this disorder, there is a deficiency of factor X, which is believed to be due to the absorption of this factor by large deposits of amyloid in the spleen, due to protein loss in nephrotic syndrome. This, along with disturbances in the plasminogen system, leads to an increase in the frequency of venous thrombosis.
Although AL amyloidosis is the most common form of amyloidosis, affecting the skin, skeletal muscle, and tongue, soft tissue and joint changes are rare. Carpal valve syndrome, often bilateral, may be caused by amyloid deposits in the wrist resulting in compression of the median nerve, and may be present years before the onset of a systemic lesion. Amyloid infiltration of skeletal muscle, usually involving the tendons and capsules of the shoulder joints, can lead to pseudohypergrophia ("shoulder pad sign") in a patient who is in a state of cachexia. Amyloid deposits in bones, such as the femoral neck, show up as cystic lumen on radiographs and can reduce bone strength, leading to pathological fractures. Rare cases of macroglossia have been reported in patients with AL amyloidosis. An enlarged tongue that is hard on palpation can cause problems with speech and swallowing and cause a feeling of choking.
AL amyloidosis results from the abnormal and clonal expansion of B-cell lymphocytes. However, monoclonal cell expansion and synthesis of light or heavy chains are necessary but not sufficient conditions for the development of the disease. AL amyloidosis can develop with Waldenstrom's macroglobulinemia, multiple myeloma, monoclonal gammopathy of unknown etiology, or benign B cell expansion. The amount of protein produced by these clones does not seem to matter, since 10-20% of patients with AL amyloidosis do not have a monoclonal protein in serum and urine. The primary structure of the light chains is probably of particular importance in the development of this disease because the normal ratios of serum light chains are completely altered, and α.-chains in AL-amyloid deposits are detected much more frequently than k-chains. Certain subtypes of l.-chains are more prone to the formation of fibrillar deposits than others. In addition, AL-amyloid fibrillar proteins almost always contain a variable light chain segment (either entirely composed of it or containing it as a segment). However, the causes of selective organ damage and different rates of disease progression in different patients remain unclear.
AL-amyloidosis is the most severe disease among amyloidoses, while the survival time after diagnosis does not exceed 18-24 months. The onset of the disease with carpal tunnel syndrome or peripheral neuropathy often means a better prognosis than the onset of cardiac involvement. A small proportion of patients may develop multiple myeloma after diagnosis of AL amyloidosis, highlighting the importance of long-term follow-up and appropriate testing.
Treatment of AL amyloidosis is aimed at suppressing aberrant plasma cell clones using drugs such as melphalan and prednisone. Sometimes chemotherapy drugs such as cyclophosphamide or chlorambucil are also used. Vinca alkaloids and adriomycin should be used with great caution as they may be particularly toxic in patients with neuropathy or cardiomyopathy. For some patients, the treatment of choice is high-dose melphalan with stem cell transplantation. In patients with advanced disease, an intermediate dose of melphalan with stem cell transplantation may be an alternative due to better tolerability. Among patients who are indicated for and undergoing bone marrow transplantation, the average life expectancy reaches 40 months, and in patients who are not suitable for transplantation, it is 18 months.
Amyloidosis AA
Amyloidosis AA is the most common form of systemic amyloidosis in the world. Any inflammatory stimulus can cause AA amyloidosis. The most common cause is tuberculosis; but in industrialized countries, the main causes of AA amyloidosis are rheumatic diseases - rheumatoid arthritis, spondyloarthritis and autoinflammatory syndromes. AA-amyloid fibrils can be detected in biopsies from asymptomatic patients, predating any signs of systemic amyloidosis by many years.
The most important manifestation of AA amyloidosis is kidney damage, usually presented as nephrotic syndrome. It may develop 10 to 20 years after the onset of arthritis and may occur even after the underlying primary inflammatory disease subsides. Thus, AA amyloidosis can be mistaken for other pathological processes involving the kidney, such as gold-induced nephropathy. In addition, acute inflammatory triggers may accelerate the onset of systemic AA amyloidosis in patients who have previously had an inflammatory disease such as tuberculosis or other chronic infections. This is why patients with new active tuberculosis may develop nephrotic syndrome within weeks, possibly because preexisting foci of localized amyloid deposits may accelerate the progression of systemic AA amyloidosis.
Patients with AA amyloidosis may experience gastrointestinal bleeding. The deposition of the AA protein in the wall of the blood vessel leads to a decrease in extensibility and an increase in fragility, with occasional vessel ruptures and bleeding. Although described in the literature, significant damage to the heart, nerves, skeletal muscles, or tongue is very rare in AA amyloidosis. It is important to exclude the presence of AA amyloidosis in patients with severe nephrotic syndrome, even in those who do not have a history of inflammatory or infectious disease. This pattern is seen in patients with familial Mediterranean fever who have subclinical elevations in SAA and other acute phase proteins but no other symptoms. Ultimately, the disease in these patients may progress to systemic amyloidosis. Because many of these patients lived in developing countries, it is possible that environmental factors, such as endemic infections that cause chronic inflammation, may contribute to this pattern of illness, thereby increasing the risk of developing AA amyloidosis.
Treatment is aimed at controlling the underlying inflammatory process. The clinical outcome of AA amyloidosis is more favorable when the SAA concentration remains below 10 mg/L. In a more severe form of the disease in patients with AA amyloidosis, kidney function is effectively restored by kidney transplantation. However, if the underlying inflammatory process is not suppressed, AA-amyloid may also be deposited in the transplanted kidney.
ATTR amyloidosis
Hereditary amyloidoses are caused by various unrelated proteins. These syndromes are inherited in an autosomal dominant fashion. The gene mutation is present at birth, but the clinical symptoms of the disease usually do not appear until the end of the third decade of life. These syndromes have similar clinical manifestations and are accompanied by the development of cardiomyopathy, nephropathy and polyneuropathy. However, each amyloidogenic protein must be considered to cause an independent disease with unique clinical features. The vast majority of hereditary amyloidoses are caused by the deposition of transthyretin (TTR) variants, for which over a hundred mutations have been identified. TTR is also known as pre-albumin because it moves faster in gel electrophoresis than albumin. Transthyretin is a plasma protein that carries about 20% of thyroxine in plasma, as well as vitamin A associated with retinol-binding protein. TTR is synthesized in the liver as a single polypeptide and forms a tetramer in plasma, which consists of four identical monomers. The wild-type protein has a pronounced folded structure; replacement of a single amino acid causes its aggregation and the formation of fibrils.
Not all TTR-associated amyloidosis is due to mutations in the TTR. Wild-type TTR fragments can form amyloid fibrils that are deposited in the heart, causing senile cardiac amyloidosis. This non-hereditary disease affects approximately 25% of people over the age of 80.
Most TTR-associated amyloidoses initially present as peripheral neuropathy. It is often a sensorimotor neuropathy involving the distal lower extremities that progresses to affect the proximal extremities. In 20% of cases, the initial manifestation may be carpal tunnel syndrome as a result of compression of the median nerve by amyloid deposits of ATTR. Autonomic neuropathy can cause gastrointestinal symptoms such as alternating constipation and diarrhea, or genitourinary symptoms such as incontinence or impotence.
Although damage to the peripheral nervous system is associated with significant impairment, the predominant causes of death among patients with ATTR amyloidosis are cardiomyopathy and kidney disease. Most (60%) deaths are due to cardiomyopathy, while kidney damage causes only 5-7% of deaths and vitreous amyloid deposits are observed in 20% of patients with ATTR amyloidosis. They are believed to result from the accumulation of TTR, which is secreted by the choroid plexus and forms amyloid fibrils that accumulate in the vitreous.
ATTR amyloidosis is diagnosed by using genetic methods to detect TTR mutations, with most mutations in ATTR occurring in exons 2-4. Conducting a polymerase chain reaction to detect restriction fragment polymorphisms has become a common method for diagnosing the disease and identifying carriers of the mutant gene among members of his family.
ATTR amyloidosis is treated by transplantation of the liver or other diseased organs. Liver transplantation results in wild-type (normal) TTR synthesis, with rapid disappearance of the transthyretin variant from the circulation. Patients with ATTR amyloidosis with significant kidney damage undergo combined liver/kidney transplantation. It is important for patients with ATTR amyloidosis to be treated before severe malnutrition or cardiomyopathy develops, as graft survival rapidly declines when such changes develop. Amyloid deposition may continue even after organ transplantation, possibly due to the presence of the largest abnormal protein deposits, which serve as a nucleus for the subsequent deposition of normal proteins. Because of this, patients with earlier manifestations of ATTR amyloidosis may require repeat organ transplantation.
Ap2M amyloidosis
Ap2M-amyloid deposits are mainly located in the tissues of the musculoskeletal system. The presence of pain in the shoulder joint, carpal tunnel syndrome, and persistent flexion contractures of the fingers in a patient undergoing long-term hemodialysis suggests Ap2M amyloidosis or dialysis-related). Signs and symptoms of Ap2M amyloidosis are sometimes seen in chronic renal failure who have not yet had dialysis.
Axial skeletal damage, which occurs in 10% of patients undergoing long-term hemodialysis, manifests as destructive spondyloarthropathy, the radiographic features of which include a decrease in the height of the intervertebral discs and erosion of the vertebral endplates without pronounced osteophyte formation. Most often, the lower part of the cervical spine is affected; however, similar changes can also be observed in the thoracic, lumbar spine. Cystic deposits of Ap2M-amyloid were found in the odontoid process and bodies of the upper cervical vertebrae, as well as masses of Ap2M-amyloid in periodontoid soft tissues, which are called pseudotumors. Although neurological disorders are rare, severe myelopathy occurs due to deposits of Ap2M amyloid in the cervical, lumbar spine, especially in patients who have undergone hemodialysis for 20 years or more.
Cystic bone lesions can develop in the bones of the peripheral skeleton of patients who have undergone long-term hemodialysis. Subchondral amyloid cysts are usually found in the bones of the wrist, but may also occur in the acetabulum and long bones such as the head or neck of the femur, head of the humerus, distal radius, and superior tibia. Unlike brown tumors in hyperparathyroidism, these bone cysts usually occur in tissues adjacent to the joints and increase in size and number over time. Pathological fractures, especially of the femoral neck, may occur in bone weakened by amyloid deposits.
Patients who have been on dialysis for more than 10 years have visceral deposits of Ap2M amyloid. Although complications in the gastrointestinal tract and the cardiovascular system have been described, usually visceral deposits of Ap2M amyloid do not cause symptoms.
Modern theories of the pathogenesis of Ap2M amyloidosis involve the participation of the enhanced glycosylation end product (AGE) in the modification of proteins, which contributes to their resistance to proteolysis, increases their affinity for collagen and the ability to stimulate the secretion of pro-inflammatory cytokines such as TNF-α, IL-6 by activated mononuclear leukocytes. AGE-modified proteins are poorly excreted by dialysis. Thus, patients undergoing dialysis have elevated concentrations of these modified proteins compared to individuals with normal renal function or functioning renal allografts. Patients with symptoms and massive deposits of Ap2M amyloid may require surgery. Over the past decade, the use of new, more permeable membranes in hemodialysis has likely delayed the onset of carpal tunnel syndrome and bone cysts, and reduced the incidence of Ap2M amyloidosis. Ap2M amyloid deposits are non-progressive and may regress in patients who have had a successful kidney transplant. Patients with Ap2M amyloidosis who have had a successful kidney transplant experience a marked reduction in joint pain and stiffness. Thus, early kidney transplantation in eligible candidates before significant AP2M amyloid deposits develop may be the most effective preventive measure available for this disease.
Amyloidosis of internal organs
Localized forms of amyloidosis can affect various organs and systems, including the eyes, genitourinary tract, endocrine system, and respiratory tract. With the exception of Alzheimer's disease, these types of amyloidosis are rare and difficult to diagnose. The pathophysiological principles governing the manifestation of the disease in localized forms are similar to those observed for systemic forms. The most common forms of localized amyloidosis involve the genitourinary and respiratory tracts.
Genitourinary amyloidosis
Localized urogenital amyloidosis may involve the entire tract, but more commonly the bladder and urethra are involved, causing hematuria or signs of obstruction. Amyloid protein is often represented by light or heavy chains of immunoglobulins. The detection of local amyloid deposits can induce a debilitating search for systemic disease, often with negative results. However, localized amyloidosis usually resolves spontaneously and does not portend a poor prognosis. Treatment consists of excision of localized amyloid deposits.
Amyloidosis of the lungs
In the respiratory tract, deposition of amyloid AL often causes localized forms of the disease. The airways are affected by three forms of localized amyloidosis: tracheobronchial amyloidosis. which accounts for half of the cases; nodular parenchymal amyloidosis, which occurs in approximately 45% of cases; and diffuse parenchymal amyloidosis, which accounts for approximately 5% of cases. In tracheobronchial amyloidosis, there is either localized or diffuse involvement of the tracheobronchial tree with submucosal deposition of amyloid. Computed tomography (CT) reveals nodules or plaques of amyloid, sometimes with calcification or annular thickening of the trachea, main bronchus, lobar or segmental bronchi with narrowing of the lumen. In nodular parenchymal amyloidosis, CT demonstrates nodules with sharp and lobular edges, localized peripherally and subpleurally. Nodules vary in size from a micronodule to 15 cm in diameter; in half of the cases, calcification is observed. Diffuse parenchymal or alveolar septal amyloidosis has widespread amyloid deposits involving small vessels and parenchymal interstitial tissue; multifocal small amyloid nodules may also be present. High-resolution CT shows abnormal retinal opacities, interlobular septal thickening, small (2–4 mm in diameter) nodules, and confluent pooled opacities mainly in subpleural areas. This pattern of localized amyloidosis is sometimes indistinguishable from systemic amyloidosis. Patients with this form of diffuse parenchymal pulmonary amyloidosis are more likely to die from respiratory failure than patients with tracheobronchial or nodular parenchymal amyloidosis.
Localized amyloid deposition limited to the airways can be resected to treat this form of localized amyloidosis. Other types of amyloid can also be deposited in the airways, but this is rare and generally does not result in significant pathology.
Methods for diagnosing amyloidosis
Serum amyloid P scintigraphy is used to identify the systemic distribution of amyloid deposits. Serial images demonstrate the progression and regression of amyloid deposits. However, this technique is limited because patients are exposed to the radioactive allogeneic protein and is only available in specialized centers.
The only imaging technique that is widely available that provides information specific to the diagnosis of systemic amyloidosis is echocardiography. Specific echocardiographic features of amyloidosis include atrial dilatation, left ventricular contraction, thickening of the interventricular and interatrial septum, and increased myocardial echogenicity. In a later stage, more pronounced restrictive changes are noted. Unfortunately, the average life expectancy after the appearance of echocardiographic signs of amyloidosis is only 6 months. Also, echocardiography does not reveal regression of amyloidosis even after successful treatment.
Magnetic resonance imaging (MRI) of the heart is a rapidly advancing field of research that complements echocardiography in the diagnosis of cardiac amyloidosis. Cardiac MRI with gadolinium contrast has a high resolution (approximately 2 mm) and provides tissue contrast, allowing differentiation of the affected area from normal myocardium. In patients with amyloid cardiac disease, cardiac MRI demonstrates qualitative total and subendocardial contrast enhancement following intravenous gadolinium administration. Although there is no typical MRI evidence of cardiac amyloidosis, future studies may determine a combination of non-invasive techniques that could be used in selecting patients for certain more invasive biopsies. endomyocardium, as well as to monitor the natural development of cardiac amyloidosis.
Since there are no signs specific to systemic amyloidosis, imaging should be used as an adjunct to clinical examination and appropriate laboratory tests to evaluate patients with characteristic symptoms. Although the gastrointestinal tract is almost always involved in systemic amyloidosis, radiographic evidence of gastrointestinal amyloidosis is rare. Ischemia and due to the deposition of amyloid in the vessels can cause symmetrical thickening of the mucosal folds, which are detected on CT.
Or CT scans help detect kidney enlargement in the early stages of amyloidosis. Ultrasonography usually demonstrates diffusely increased echogenicity of the renal parenchyma with preservation of cortical-medulla contrast because the architecture of the cortical layer in the early stages of the disease remains macroscopically normal. The progression of the disease may be accompanied by a decrease in the kidney and a significant thinning of the cortical layer.
If amyloidosis is suspected, the diagnosis is confirmed by biopsy: microscopy of the material in polarized light reveals a characteristic light green birefringence and, using immunohistochemical studies, the type of amyloid protein. A biopsy can be taken from either an affected or unaffected organ. The latter approach is usually preferred due to the high risk of complications and discomfort associated with visceral biopsy. One of three methods is commonly used to diagnose amyloidosis: biopsy of the gastrointestinal tract (rectal or gastroduodenal), aspiration of subcutaneous abdominal fat, and biopsy of the minor salivary gland.
Rectal biopsy performed by sigmoidoscopy or sigmoidoscopy is the preferred biopsy of the gastrointestinal tract due to the accessibility of this site. The biopsy should include submucosal blood vessels, which are more likely to contain amyloid deposits than those of the mucosa or muscle layers. Although the most reliable results can be obtained from a rectal biopsy, a biopsy of the stomach or duodenum can also diagnose amyloidosis if the tissue sample contains blood vessels of the appropriate size.
Abdominal fat aspiration was first performed after it was observed that autopsy samples from patients with amyloidosis often contain amyloid deposits around adipocytes; the highest density of amyloid deposits was observed in the fatty tissues of the scalp and abdominal wall. The sensitivity of abdominal fat aspiration varies between 55 and 75%, but is similar to that of a rectal biopsy. This technique is useful for diagnosing AA, AL, and ATTR amyloidosis; however, due to the limited distribution of Ap2M amyloid deposits in organs, abdominal fat aspiration may not be a reliable method for diagnosing Ap2M amyloidosis.
With a biopsy of the minor salivary gland, additional salivary glands of the mucous membrane of the lip are taken. Previously, gingival biopsy was used to detect amyloid deposits, but the sensitivity of this method was found to be low. In AA, ATTR, and AL amyloidosis, the sensitivity of a minor salivary gland biopsy is comparable to that of a rectal biopsy or abdominal fat aspiration.
If the suspicion of amyloidosis is significant and none of the above methods gives positive results, it is necessary to perform a biopsy of the affected organ. When kidneys are involved, a kidney biopsy usually provides diagnostic information. In ATTR and AL amyloidosis, the heart and bone marrow are affected, so a biopsy of these organs is required to confirm the diagnosis. Although the sural nerve may be involved, it is less desirable to biopsy it because the procedure is usually painful, the biopsy wound heals slowly, and there may be residual sensory impairment. In addition, the patchy distribution of amyloid deposits makes sural nerve biopsy a less sensitive procedure than biopsy of other affected organs.
When making a diagnosis of amyloidosis, three points are of particular importance::
- The pre-test probability of detecting amyloid in a biopsy is determined by the clinical manifestations of the disease. To determine pretest probability, it is important to take into account the history (including a complete family history), a complete clinical examination and laboratory evaluation, which includes serum and urine protein electrophoresis, and a urinalysis to assess the degree of proteinuria.
- Immunohistochemistry should always be performed on tissue samples that are being evaluated for amyloid deposits to identify the specific amyloid protein. Occasionally, a patient with an inflammatory disease may develop AL amyloidosis, or a patient with a serum monoclonal protein may develop AA amyloidosis. Since the treatment of these diseases differs dramatically, it is imperative to establish an accurate diagnosis.
- Deposits of amyloid AA in abdominal fat are often observed in inflammatory diseases, such as rheumatoid arthritis or ankylosing spondylitis. However, even after long-term follow-up, most of these patients show no evidence of organ dysfunction. Thus, not all people with AA amyloid deposits have AA amyloidosis; biopsy results must be interpreted with caution.
Candidate of Medical Sciences V.N. Kochegurov
AMYLOIDOSIS OF THE INTERNAL ORGANS
In recent years, many ideas about amyloidosis and methods of its treatment have changed. Entitled "amyloidosis" a group of diseases is combined, the hallmark of which is the deposition in the tissues of a special glycoprotein, consisting of fibrillar or globular proteins closely associated with polysaccharides, with a violation of the structure and function of the affected organs.
The term "amyloid" was introduced in 1854 by R. Virchow, who studied in detail the substance deposited in the tissues during the so-called sebaceous disease in persons suffering from tuberculosis, syphilis, actinomycosis, and considered it similar to starch due to its characteristic reaction with iodine. And only 100 years later, Cohen, using electron microscopy, established its protein nature.
Amyloidosis is a fairly common pathology, especially considering the existence of its local forms, the frequency of which increases significantly with age.
The variety of forms and variants of amyloidosis makes it impossible to systematize information about the etiology and pathogenesis.
Modern classification amyloidosis is built on the principle of specificity of the main protein that forms amyloid. According to the WHO classification (1993), the type of amyloid is given first, then the precursor protein is indicated, and only then are the clinical forms of the disease, listing the primary target organs. In all the names of types of amyloid, the first letter is "A", meaning "amyloid", followed by the abbreviation of the specific fibrillar protein from which it was formed:
AA amyloidosis. The second "A" is the designation of an acute phase protein (SSA--globulin) produced in response to inflammation or the presence of a tumor (anacute-phase protein);
AL-amyloidosis."L" is the light chains of immunoglobulins (lightchains);
ATTR-amyloidosis."TTR" is transthyretin, a transport protein for retinol and thyroxine;
A 2 M-amyloidosis." 2 M" is 2 -microglobulin (dialysis amyloidosis).
AA amyloidosis. AA-amyloid is formed from serum acute phase protein, which is α-globulin, which is synthesized by hepatocytes, neutrophils and fibroblasts. Its amount increases many times with inflammation or the presence of tumors. However, only some of its fractions are involved in the formation of amyloid, so amyloidosis develops only in a proportion of patients with inflammatory or neoplastic diseases. The final stage of amyloidogenesis, the polymerization of a soluble precursor into fibrils, has not been fully elucidated. It is believed that this process occurs on the surface of macrophages with the participation of membrane enzymes and tissue factors, which determines the organ damage.
AA amyloidosis combines 3 forms:
Secondary reactive amyloidosis in inflammatory and neoplastic diseases. This is the most common form. In recent years, among the causes of secondary amyloidosis, rheumatoid arthritis, Bechterew's disease, psoriatic arthritis and tumors have come to the fore, incl. blood systems (lymphoma, lymphogranulomatosis), as well as ulcerative colitis and Crohn's disease. At the same time, chronic purulent-obstructive pulmonary diseases recede into the background, as well as tuberculosis and osteomyelitis.
Periodic illness (familial Mediterranean fever) with an autosomal recessive form of inheritance. There is an ethnic predisposition to it among Arabs, Armenians, Jews and Gypsies. There are 4 forms of this disease: febrile, articular, thoracic and abdominal. In the first or second decades of life, patients develop unmotivated fever or manifestations of arthritis. The debut of the disease is possible with the development of a clinic of dry pleurisy or a picture of an "acute" abdomen. Moreover, these episodes are usually short-term, lasting 7-10 days, stereotypical in their manifestations and do not cause complications for a long time (deformations and defigurations of the joints, adhesions or mooring of the pleural sheets, adhesive disease of the abdominal cavity). However, progressive amyloidosis of the kidneys develops in 40% of patients in the second or third decades of life.
Muckle-Wales syndrome or familial nephropathy with urticaria and deafness, inherited in an autosomal dominant manner. In the first years of life, patients periodically experience allergic rashes, often in the form of urticaria or Quincke's edema, accompanied by fever, lymphadenopathy, arthrosis and myalgia, abdominal pain, eosinophilic infiltrates in the lungs. These symptoms spontaneously disappear after 2-7 days, followed by remission. In parallel, hearing loss occurs and progresses, and in the second or third decades of life, amyloidosis of the kidneys joins. This is the most common variant of hereditary amyloidosis.
target organs AA amyloidosis most often affects the kidneys, as well as the liver, spleen, intestines, and adrenal glands.
BUT L -amyloidosis . AL-amyloid is formed from light chains of immunoglobulins in which the amino acid sequence is changed, causing destabilization of these molecules and promoting the formation of amyloid fibrils. This process involves local factors, the characteristics of which determine the defeat of certain organs. Immunoglobulins are synthesized by an abnormal clone of plasma or B cells in the bone marrow, apparently as a result of mutations or T-immunodeficiency and decrease in the controlling function of the latter.
AL-amyloidosis includes 2 forms:
1) Primary idiopathic amyloidosis, in which there is no previous disease;
2) Amyloidosis in multiple myeloma and B-cell tumors(Waldenström's disease, Franklin's disease, etc.). AL-amyloidosis is now considered within the framework of a single B-lymphocytic dyscrasia.
To the main target organs AL-amyloidosis includes the heart, gastrointestinal tract, as well as the kidneys, nervous system, and skin. Coagulation factor X deficiency in AL-amyloidosis is considered the cause of the development of hemorrhagic syndrome with characteristic hemorrhages around the eyes (“raccoon eyes”).
In the differential diagnosis of systemic amyloidosis, it should be taken into account that the AA type is more “young”, the average age of the diseased is less than 40 years, and in AL-amyloidosis - 65 years, and in both types there is a predominance of men (1.8-1 ).
ATTR -amyloidosis includes 2 options:
Familial neuropathy (less often cardio- and nephropathy) with autosomal dominant inheritance. At the same time, ATTR-amyloid is formed from mutant transthyretin synthesized by hepatocytes. Mutant proteins are unstable and, under certain conditions, precipitate into fibrillar structures, forming amyloid.
Systemic senile amyloidosis, developing exclusively in the elderly (over 70 years). It is based on transthyretin, normal in amino acid composition (i.e., not mutant), but with altered physicochemical properties. They are associated with age-related metabolic changes in the body and cause the formation of fibrillar structures.
For this option typical defeat nervous system, rarely kidneys and heart.
A 2 M-amyloidosis is a relatively new form of systemic amyloidosis, which appeared in connection with the introduction of chronic hemodialysis into practice. The precursor protein is 2 -microglobulin, which is not filtered during hemodialysis through most membranes and is retained in the body. Its level rises 20-70 times, which serves as the basis for the development of amyloidosis after an average of 7 years from the start of hemodialysis.
Main target organs are bones and periarticular tissues. Pathological bone fractures may occur. In 20% of cases, carpal tunnel syndrome is observed (numbness and pain in the first three fingers of the hand, spreading to the forearm, followed by the development of thenar muscle atrophy due to compression of the median nerve by amyloid deposits in the area of the carpal ligament).
In addition to systemic forms, there are local amyloidosis , which occurs at any age, but more often in the elderly, and affects any tissue or organ. Of practical importance is pancreatic islet myloidosis in the elderly(AAIAPP-amyloid). Now enough evidence has been accumulated showing that almost all cases of type 2 diabetes in the elderly are pathogenetically associated with amyloidosis of the pancreatic islet apparatus, which is formed from the polypeptide -cells.
Cerebral amyloidosis(AV-amyloid) is considered as the basis of Alzheimer's cerebral dementia. At the same time, whey -protein is deposited in senile plaques, brain neurofibrils, vessels and membranes.
Among all types of amyloidosis, the AA and AL forms of systemic amyloidosis are of the greatest importance.
Amyloidosis of the kidneys. The kidneys are the most commonly affected organ in systemic amyloidosis. . First, amyloid is deposited in the mesangium, then along the basement membrane of the glomeruli, penetrating into it and opening the subepithelial space and the Shumlyansky-Bowman chamber. Then amyloid is deposited in the walls of blood vessels, the stroma of the pyramids, and the capsule of the kidneys.
The first clinical manifestation of renal amyloidosis is proteinuria, which depends not so much on the amount of amyloid deposits, but on the destruction of podocyte cells and their legs. At first, it is transient, sometimes combined with hematuria and/or leukocyturia. it latent stage nephropathic variant of amyloidosis. Since the stabilization of proteinuria, the second - proteinuric stage. With the increase in proteinuria and the formation of hypoproteinemia with the development of secondary aldosteronism and the occurrence of nephrotic edema, the third occurs - nephrotic stage. With a decrease in kidney function and the appearance of azotemia, the fourth occurs - Azotemic stage kidney damage.
In "classic" cases, patients with kidney amyloidosis develop nephrotic syndrome(NS) with its edematous period, and the time of development of NS is individual. It is important to note that arterial hypertension is not a characteristic sign, since JGA is affected with a decrease in renin production, and it can occur only in 10-20% of patients with advanced CRF.
It is noteworthy that in amyloidosis, the size of the kidneys remains unchanged or even increases ( "large sebaceous buds"), despite the increase in their functional inferiority. Identification of this symptom with the help of ultrasound scanning and X-ray method is an important diagnostic criterion for amyloid kidney damage.
Heart in amyloidosis it is often affected, especially in the AL variant. As a result of the deposition of amyloid in the myocardium, the rigidity of the heart wall increases, and the function of diastolic relaxation suffers.
Clinically, this manifests itself cardiomegaly(up to the development of a "bull's heart"), deafness of tones, progressive heart failure refractory to treatment, which is the cause of death in 40% of patients. Some patients develop myocardial infarction due to amyloid deposits in the coronary vessels, stenosing their lumen. Possible involvement of the heart valves with the development of one or another heart disease and pericardial involvement, resembling constrictive pericarditis.
On the ECG, a decrease in the voltage of the teeth is recorded, with echocardiography, a symmetrical thickening of the walls of the ventricles with signs of diastolic dysfunction is noted. Depending on the localization of amyloid deposits in the myocardium, sick sinus syndrome, AV blockade, various arrhythmias, and sometimes focal lesions with an infarct-like picture on the ECG can be observed.
Gastrointestinal tract with amyloidosis, it is affected throughout. macroglossia, found in 22% of patients with amyloidosis, is pathognomonic symptom. At the same time, it develops dysphagia, dysarthria, glossitis, stomatitis, and at night, asphyxia due to retraction of the tongue and overlapping of the airways is not excluded.
amyloid deposition in the esophagus accompanied by violations of its functions, sometimes found tumors in the stomach and intestines. The muscular layer of the intestine and nerve plexuses are often affected, which leads to impaired motility of the gastrointestinal tract, up to the occurrence of ileusa. Amyloid deposition in the small intestine leads to syndromes of malabsorption and maldigestion. As a result of vascular damage, intestinal ulcers with the development of bleeding, which simulates a picture of tumors or ulcerative colitis.
deposition of amyloid in pancreas leads to its external and intrasecretory insufficiency.
Involved in the process with great frequency liver(in 50% of patients with AA amyloidosis and in 80% with AL amyloidosis). Characterized by long-term preservation of liver function with absence of cytolysis and cholestasis syndromes. In the expanded stage appear signs of portal hypertension with bleeding from varicose veins. typical jaundice due to compression of the bile capillaries. Often defined splenomegaly with hypersplenism, as well as enlargement of peripheral lymph nodes.
Respiratory system most often involved in the process in AL-amyloidosis (in 50% of patients), less often in AA-amyloidosis (10-14%).
Early signs include hoarseness associated with the deposition of amyloid in the vocal cords. Then the defeat of the bronchi, alveolar septa, and vessels joins. Arise atelectasis and lung infiltrates, diffuse changes by the type of fibrosing alveolitis with respiratory failure and pulmonary hypertension, contributing to the formation chronic cor pulmonale. Pulmonary bleeding or the development of local pulmonary amyloidosis, which mimics the picture of lung cancer, are possible.
Involvement peripheral and autonomic nervous system observed in systemic amyloidosis of various types, but to a greater extent in AL- and ATTR-types. Peripheral sensory, sometimes motor neuropathy (usually symmetrical, beginning in the distal extremities and extending to the proximal) may predominate in the clinical picture, creating diagnostic difficulties. Disorders of the autonomic nervous system can be significantly pronounced and are manifested by symptoms of orthostatic hypotension, impotence, sphincter disorders.
central nervous system rarely affected in amyloidosis.
Among the lesions of other organs, it should be noted the possibility of damage adrenal and thyroid gland with the development of symptoms of their insufficiency.
amyloid deposits in skin may have the appearance of papules, nodes, plaques, its diffuse infiltration with trophic changes, acquired total albinism.
Involvement in the process joints and periarticular tissues, as already mentioned, is associated with dialysis amyloidosis.
Defeat skeletal muscle usually dramatically reduces the quality of life of patients. First, pseudohypertrophy of the muscles is noted, followed by their atrophy, leading to immobilization of the patient.
Change laboratory indicators non-specific in amyloidosis: increased ESR, hyperglobulinemia, thrombocytosis, which, along with small platelets and the appearance of erythrocytes with Jolly bodies, is considered as evidence hypersplenism.
Diagnostics amyloidosis suspected on clinical grounds must be confirmed by finding the substrate of the pathology, namely amyloid.
For this purpose, you can use colorful samples. In one of the modifications, the patient is intravenously injected with a dye ( Evans blue, Congo red), which can be captured by amyloid masses, which leads to a decrease in its concentration in the blood.
In another version of the study, the patient is injected subcutaneously into the subscapular region with 1 cm 3 of a 1% freshly prepared solution methylene blue and then monitor the change in color of the urine. If the amyloid masses have taken up the dye, the color of the urine does not change and the sample is considered positive, confirming the diagnosis of amyloidosis. If the sample is negative (the color of the urine is changed), then this does not exclude the presence of amyloidosis.
Another diagnostic method is biopsy. If a biopsy of the affected organ (kidney, liver, etc.) is performed, then the frequency of positive results reaches 90-100%. The higher the degree of infiltration of target organs by amyloid, the greater the possibility of its detection. Usually, the diagnosis of amyloid begins with biopsies of the oral mucosa with a submucosal layer in the gingival region of about 3-4 molars or in the rectum. In AL-amyloidosis, it is recommended first of all to conduct a bone marrow biopsy or aspiration biopsy of the subcutaneous fat of the anterior abdominal wall (sensitivity is about 50%). In dialysis amyloidosis, a biopsy of the periarticular tissues is reasonable.
In recent years, there has been an increasing use scintigraphy with labeled I 123 serum P-component to assess the in vivo distribution of amyloid in the body. The method is especially useful for monitoring the dynamics of its tissue deposits during treatment. It is important not only to detect amyloid in tissues, but also to carry out its typing using staining methods or, more precisely, using antisera (poly- and monoclonal antibodies) to the main proteins of amyloid fibrils.
Amyloidosis treatment should be aimed at reducing the synthesis and delivery of precursor proteins from which amyloid is built.
During treatment AA amyloidosis , its secondary variant, a necessary condition is the treatment of the disease that led to the development of amyloidosis by all available methods (antibiotics, chemotherapy, surgery).
The drugs of choice are 4-aminoquinoline derivatives(delagil, plaquenil, rezokhin, hingamin, etc.). They inhibit the synthesis of amyloid fibrils in the early stages of amyloidogenesis by inhibiting a number of enzymes. Delagil is prescribed 0.25 g for a long time (for years).
Amyloid-forming protein fibrils contain a large number of free sulfhydryl groups (SH), which are actively involved in the aggregation of proteins into stable structures. In order to block them, they use unithiol 3-5 ml of a 5% solution intramuscularly daily with a gradual increase in dose to 10 ml per day for 30-40 days and repeated courses 2-3 times a year.
Raw or cooked food is still recommended. liver 100-150 g per day for 6-12 months. Liver proteins and antioxidants inhibit the development of amyloidosis. Can also be used liver hydrolysates, in particular sirepar(2 ml of sirepar correspond to 40 g of the liver), and treat it by alternating the intake of raw liver for 1-2 months with 2-3 months of sirepar (5 ml intramuscularly 2 times a week).
Apply immunomodulators: levamisole (decaris) 150 mg 1 time in 3 days (2-3 weeks), thymalin 10-20 mg intramuscularly 1 time per day (5 days), T-activin 100 mcg intramuscularly 1 time per day (5 days) .
Recognized as a positive effect dimexide, which has a direct absorbing effect. It is administered orally as a 10-20% solution in a daily dose of at least 10 g for 6 months.
With periodic illness shown colchicine with antimitotic activity. The drug slows down amyloidogenesis. Its early administration can prevent the occurrence of renal amyloidosis, which is the most dangerous in this pathology. It is prescribed for a long time (for life) at a dose of 1.8-2 mg per day (tab. 2 mg).
Treatment A L -amyloidosis . Since this type of amyloidosis is considered within the framework of monoclonal plasma or B cell proliferation, various regimens are used in the treatment. polychemotherapy in order to reduce the production of precursors - light chains of immunoglobulins. The most commonly used scheme is cytostatic melfolan + prednisolone(melfolan at a dose of 0.15 mg/kg, prednisolone at 0.8 mg/kg for 7 days every 4-6 weeks for 2-3 years). Now more aggressive schemes are also used with the inclusion of vincristine, doxorubicin, cyclophosphamide.
There is an opinion about the advisability of using levamisole or other immunomodulators to increase the function of T-suppressors.
AT treatment of ATT R -amyloidosis most effective liver transplant.
For treatment A 2 M- or dialysis amyloidosis apply high-flow hemodialysis with hemofiltration and immunosorption. Due to this, the level of 2 -microglobulin decreases. If necessary, produce kidney transplant.
It should be noted that adequate treatment is often impossible due to late recognition of the disease with the involvement of many organs in the pathological process. Therefore, early diagnosis based on knowledge of the various manifestations of amyloidosis is of decisive importance.
Prevention. The main prevention of secondary amyloidosis is the successful treatment of purulent-inflammatory, systemic and neoplastic diseases. In cases of idiopathic amyloidosis, the problem of prevention should be solved by carefully collecting an anamnesis of family and hereditary diseases and medical genetic counseling.
- Which Doctors Should You See If You Have Secondary Renal Amyloidosis
What is secondary amyloidosis of the kidneys
Renal amyloidosis- one of the manifestations of amyloidosis of internal organs - a systemic disease characterized by the deposition in various organs of a pathological protein-like substance - amyloid. The kidneys are affected by amyloidosis most often, less often the liver, intestines, adrenal glands, spleen, heart and other parenchymal organs can be involved in the process.
There are primary, or "idiopathic", amyloidosis, in which it is not possible to identify the etiological factor, and secondary renal amyloidosis. Primary amyloidosis is rare, predominantly in the elderly, and it is characterized by more frequent damage to the skin, muscles, cardiovascular system, and partly the digestive tract than the spleen, kidneys, liver, and adrenal glands.
What Causes Secondary Renal Amyloidosis?
Secondary renal amyloidosis includes cases specifically associated with some chronic communicable or non-communicable disease. Secondary amyloidosis develops as a complication of chronic suppurative processes in the lungs and bones, destructive forms of tuberculosis, chronic pyelonephritis, rheumatoid arthritis, ulcerative colitis, occasionally lymphogranulomatosis and other diseases.
Pathogenesis (what happens?) during Secondary Renal Amyloidosis
Currently, there are three theories of the pathogenesis of amyloidosis. In accordance with the theory of "cellular genesis", amyloid is a product of impaired protein synthesis by cells of the reticuloendothelial system. According to the immunological theory, amyloidosis is the result of an antigen-antibody reaction, where the antigen is a product of tissue breakdown or a foreign protein, and amyloid is a protein precipitate deposited primarily at the sites of antibody formation. The theory of dysproteinosis considers amyloid as a product of perverted protein metabolism. From the standpoint of this theory, the main link in the pathogenesis of amyloidosis is dysproteinemia with the accumulation in the plasma of coarse protein fractions and abnormal proteins - paraproteins.
Since amyloidosis affects unevenly most of the internal organs, the features of the clinical manifestation are associated with the predominant lesion of one or another organ. The most common amyloidosis of the kidneys leads to the gradual spread of amyloid deposits in the glomeruli, involvement in the process of the vascular wall. This is manifested by increasing proteinuria, a gradual decrease in renal blood flow, glomerular filtration, the appearance of renal hypertension and renal failure. The most striking clinical manifestation of renal amyloidosis is nephrotic syndrome.
The pathogenesis of hypertension in amyloidosis is more associated with changes in intrarenal blood flow due to lesions of arterioles than with an increase in the activity of the juxtaglomerular apparatus of the kidneys and increased secretion of renin.
The defeat of adrenal amyloidosis leads to the development of chronic adrenal insufficiency with loss or a sharp decrease in the secretion of hormones of both the cerebral (catecholamins) and cortical (aldosterone, corticosterone, androgens) layer of the adrenal glands. Intestinal damage leads to disruption of the secretory and absorption functions of the intestine, the clinical expression of which is diarrhea and malabsorption syndrome. Involvement in the process of the liver and spleen is expressed by an increase in these organs, and their function is disturbed only in advanced stages. Occasionally, amyloidosis of the heart occurs, leading to the development of heart failure.
pathological anatomy
In terms of chemical structure, amyloid is close to proteins, but its amino acid composition differs significantly from that of serum and tissue proteins. However, protein is only one part of amyloid. Another component of amyloid are polysaccharides, consisting mainly of galactose and glucose. Sialovaya (neuraminic) acid is also a part of polysaccharides.
With amyloidosis in the initial period, there is a slight increase in the size of the kidneys, they are dense, the capsule is removed easily. Microscopically, the glomeruli are enlarged with thickened cleaved capillary membranes, isolated clumps of amyloid are found under the endothelium.
On electron microscopy, amyloid deposits are found on one or both sides of the basement membrane subepithelially. With progression, the structure of the basement membranes is lost and they seem to dissolve in the mass of amyloid.
As the process progresses, the kidneys increase even more, their surface is fine-grained, they become dense, and on the cut they become waxy. The picture corresponds to a "large white amyloid kidney". There is a deposition of amyloid in the walls of the vessels of the kidneys, in the walls of the afferent arterioles. In advanced stages, amyloid fills almost all the glomeruli. In the epithelium of the tubules, significant dystrophic changes are found.
The process ends with amyloid wrinkling of the kidneys with desolation and atrophy of kephrons. Thickening of the walls of the vessels of the kidneys leads to ischemia of the kidneys, the development of hypertension.
Symptoms of secondary amyloidosis of the kidneys
In the early stages of a disease such as secondary renal amyloidosis complaints are absent or are reduced to general weakness, loss of appetite and performance. At later stages, there are complaints of edema, often first occurring in the lower extremities, pain in the lower back. With the development of high hypertension, renal failure, complaints become diverse. Sometimes diarrhea occurs.
In the clinical picture, several main syndromes can be distinguished - urinary, nephrotic and hypertensive. The main symptom of renal amyloidosis is usually significant proteinuria, which develops in all its forms.
Per day, 2-20 g of protein is excreted in the urine, the main part of which is albumin. In smaller amounts and different proportions, other plasma proteins can also be determined. Significant proteinuria persists with the development of chronic renal failure.
In addition to proteinuria, a number of other changes in urine are found that make up the urinary syndrome. According to the degree of proteinuria, hyaline and less often granular casts are found. Relatively often persistent microhematuria is detected, leukocyturia is often found without concomitant pyelonephritis. Finally, in amyloidosis, lipoiduria can be found with the presence of birefringent crystals in the urine sediment.
Significant and prolonged loss of protein by the kidneys leads to the development of hypoproteinemia, primarily hypoalbuminemia. Simultaneously with hypoproteinemia, and sometimes ahead of it, a significant dysproteinemia is detected. Usually there is an increase in the content of a- and y-globulins in serum. Along with severe dysproteinemia, most patients have a significant increase in ESR and altered sediment samples (thymol, sublimate, etc.).
A common symptom of severe amyloidosis is hyperlipidemia. Cholesterol increase, increase
