home Drugs Cerebral amyloidosis leads to early cognitive impairment. Treatment of amyloidosis Secondary systemic amyloidosis develops when

Cerebral amyloidosis leads to early cognitive impairment. Treatment of amyloidosis Secondary systemic amyloidosis develops when

Amyloidosis is a systemic disease in which amyloid (a protein-polysaccharide substance (glycoprotein)) is deposited in organs and tissues, which leads to disruption of their functions.

Amyloid consists of globular and fibrillar proteins that are closely intertwined with polysaccharides. Minor amyloid deposition in glandular tissues, stroma of parenchymal organs, and walls of blood vessels does not cause any clinical symptoms. But with significant amyloid deposits in organs, pronounced macroscopic changes occur. The volume of the affected organ increases, its tissues acquire a waxy or greasy sheen. Subsequently, organ atrophy develops with the formation of functional failure.

The incidence of amyloidosis is 1 case per 50,000 people. The disease is more common in older people.

Amyloid deposition is a sign of amyloidosis

Causes and risk factors

Amyloidosis usually develops against the background of long-term purulent-inflammatory (bacterial endocarditis, bronchiectasis, osteomyelitis) or chronic infectious (malaria, actinomycosis, tuberculosis) diseases. Amyloidosis develops somewhat less frequently in patients with cancer:

lung cancer;
kidney cancer;
leukemia;
lymphogranulomatosis.

Amyloidosis can affect various organs, and the clinical picture of the disease is varied.

The following diseases can also lead to amyloidosis:

There are not only acquired, but also hereditary forms of amyloidosis. These include:

Mediterranean fever;
Portuguese neuropathic amyloidosis;
Finnish amyloidosis;
Danish amyloidosis.

Factors causing amyloidosis:

genetic predisposition;
disorders of cellular immunity;
hyperglobulinemia.

Forms of the disease

Depending on the reasons that caused it, amyloidosis is divided into several clinical forms:

senile (senile);
hereditary (genetic, family);
secondary (acquired, reactive);
idiopathic (primary).

Depending on which organ amyloid deposits are predominantly deposited, the following are distinguished:

amyloidosis of the kidneys (nephrotic form);
cardiac amyloidosis (cardiopathic form);
amyloidosis of the nervous system (neuropathic form);
liver amyloidosis (hepapathic form);
adrenal amyloidosis (epinephropathic form);
ARUD-amyloidosis (amyloidosis of organs of the neuroendocrine system);
mixed amyloidosis.

Amyloidosis can also be local or systemic. With local amyloidosis, there is a predominant lesion of one organ, with systemic amyloidosis - two or more.

Symptoms

The clinical picture of amyloidosis is varied: the symptoms are determined by the duration of the disease, the localization of amyloid deposits and their intensity, the degree of organ dysfunction, and the peculiarities of the biochemical structure of amyloid.

In the initial (latent) stage of amyloidosis, there are no symptoms. The presence of amyloid deposits can only be detected by microscopy. Subsequently, as deposits of the pathological glycoprotein increase, functional failure of the affected organ occurs and progresses, which determines the characteristics of the clinical picture of the disease.

Factors causing amyloidosis: genetic predisposition, impaired cellular immunity, hyperglobulinemia.

With renal amyloidosis, moderate proteinuria is observed for a long time. Then nephrotic syndrome develops. The main symptoms of renal amyloidosis are:

the presence of protein in the urine;
arterial hypertension;
swelling;
chronic renal failure.

Cardiac amyloidosis is characterized by a triad of symptoms:

heart rhythm disturbance;
cardiomegaly;
progressive chronic heart failure.

In the later stages of the disease, even minor physical exertion leads to severe weakness and shortness of breath. Polyserositis may develop against the background of heart failure:

effusion pericarditis;
effusion pleurisy;
ascites.

With amyloidosis of the gastrointestinal tract, attention is drawn to an enlargement of the tongue (macroglossia), which is associated with the deposition of amyloid in the thickness of its tissue. Other manifestations:

nausea;
heartburn;
constipation followed by diarrhea;
impaired absorption of nutrients from the small intestine (malabsorption syndrome);
gastrointestinal bleeding.

Amyloid lesions of the pancreas usually occur under the guise of chronic pancreatitis. Amyloid deposition in the liver causes portal hypertension, cholestasis and hepatomegaly.

With amyloidosis of the skin, waxy nodules appear in the neck, face and natural folds. Often, skin amyloidosis in its course resembles lichen planus, neurodermatitis or scleroderma.

With amyloidosis of the musculoskeletal system, the patient develops:

myopathies;
glenohumeral periarthritis;
carpal tunnel syndrome;
polyarthritis affecting symmetrical joints.

Amyloidosis of the nervous system is severe and is characterized by:

persistent headaches;
dizziness;
dementia;
increased sweating;
orthostatic collapse;
paralysis or paresis of the lower extremities;
polyneuropathy.

Diagnostics

Taking into account the fact that amyloidosis can affect various organs, and the clinical picture of the disease is diverse, its diagnosis presents certain difficulties. The functional state of internal organs can be assessed by:

EchoCG;
radiography;
gastroscopy (EGD);
sigmoidoscopy.

The incidence of amyloidosis is 1 case per 50,000 people. The disease is more common in older people.

Amyloidosis can be suspected if the following changes are detected in laboratory test results:

For final diagnosis, it is necessary to perform a puncture biopsy of the affected tissues (mucosa of the rectum, stomach, lymph nodes; gums; kidneys) followed by histological examination of the obtained material. The detection of amyloid fibrils in the test sample will confirm the diagnosis.

Treatment

In the treatment of primary amyloidosis, glucocorticoid hormones and cytostatic drugs are used.

In secondary amyloidosis, treatment is aimed primarily at the underlying disease. Medicines of the 4-aminoquinoline series are also prescribed. A low-protein diet with limited salt is recommended.

The development of end-stage chronic renal failure is an indication for hemodialysis.

Possible complications and consequences

Amyloidosis can be complicated by the following pathologies:

diabetes;
liver failure;
gastrointestinal bleeding;
renal failure;
amyloid ulcers of the stomach and esophagus;
heart failure.

Forecast

Amyloidosis is a chronic, progressive disease. In secondary amyloidosis, the prognosis is largely determined by the possibility of treating the underlying disease.

As complications develop, the prognosis worsens. Once symptoms of heart failure appear, the average life expectancy is usually less than a few months. The life expectancy of patients with chronic renal failure is on average 12 months. This period increases slightly in the case of hemodialysis.

Prevention

There is no prevention for primary (idiopathic) amyloidosis, since the cause is unknown.

To prevent secondary amyloidosis, it is important to promptly identify and treat infectious, oncological and purulent-inflammatory diseases.

Prevention of genetic forms of amyloidosis consists of medical and genetic counseling of married couples at the stage of pregnancy planning.

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The term amyloidosis is retained out of respect for Rudolf Virchow, who pioneered the use of histochemical staining techniques to characterize amyloid deposits in pathological brain specimens in 1854. While all other structures in his brain sections turned yellow after applying iodine and sulfuric acid, the amyloid bodies turned light blue with iodine and brilliant violet with the subsequent addition of acid. Since this type of staining was characteristic of plant cellulose, Virchow concluded that amyloid bodies consisted of a substance similar to cellulose, which he called amyloid. The term "amyloid" means "containing" or "starch-like." However, this is a misnomer because amyloid deposits are now known to contain primarily protein, even though some carbohydrate-containing substances may bind to proteins. Research on amyloid has primarily 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 wild-type protein, deposition of a mutated variant of the protein, or deposition of protein fragments that are formed 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 varies between patients, even among those who have similar types of amyloid proteins, the body's total amyloid load directly correlates with disease severity. Thus, reducing the total amount of amyloid may 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 systemic forms of the disease. In the United States, AL is the most common form of systemic amyloidosis. Reliable data on the prevalence of the disease between 1950 and 1989 have been obtained from residents of Olmsted County, Minnesota. 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 the majority of cases of AA amyloidosis in developing countries.

Amyloidosis can present 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 is, as previously described, caused by 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 varied. The kidneys, heart, and liver are the most commonly and most prominently affected organs; however, any organs other than the central nervous system may be affected. In the kidneys, AL amyloid deposits are observed primarily in the glomeruli, causing nephrotic syndrome, which usually manifests itself with an initial daily urinary protein excretion of more than 2 g. Often in more advanced forms of the disease, daily urinary protein excretion can reach 5-15 g.

Heart damage develops gradually. By the time most patients with AL amyloidosis develop clinically apparent cardiac pathology associated with amyloidosis, significant myocardial damage has already occurred. As a result of atrium enlargement, 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 deposition in the gastrointestinal tract. A common symptom is also early satiety caused by delayed gastric emptying. 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 often affected. AL amyloid deposits are often observed in the liver, although this rarely causes any symptoms

Involvement of the peripheral nervous system, which may develop months or years before damage to internal organs, is observed in 20% of patients with AL amyloidosis. It may manifest as sensorimotor or autonomic neuropathy, or a combination of both. Paresthesias develop initially in the lower extremities and may spread proximally over time. Motor nerve damage is rare but can be severe and lead to foot drop and gait disturbances. Autonomic neuropathy is often observed in patients with AL amyloidosis and leads to impaired gastrointestinal motility, impotence, and orthostatic hypotension.

There are two predominant pulmonary manifestations of AL amyloidosis. Sometimes in the lung parenchyma, AL amyloid can be present in the form of a mass resembling a tumor, often with concomitant expansion of the hilar and peritracheal lymph nodes. Although these masses may become progressively larger, they are usually not life-threatening.

Alternatively, diffuse interstitial infiltration of the lung parenchyma may occur, causing stiffness and restrictive pulmonary injury. Rarely, AL amyloid can be deposited locally in the larynx and trachea, leading to hoarseness and sometimes significant airway obstruction. Hematological abnormalities in AL amyloidosis include purpura and thrombosis. Amyloid infiltration of blood vessels causes their fragility. Ruptures of 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 an extended period, resulting in the characteristic sign of bruising under the eyes. In this disorder, there is a deficiency of factor X, which is believed to arise from the absorption of this factor into 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 increased incidence 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, can be caused by amyloid deposits in the wrist, resulting in compression of the median nerve, and may occur for several years before full-blown systemic disease appears. Amyloid infiltration of skeletal muscle, usually involving the tendons and capsules of the shoulder joints, can lead to pseudohypergrophy (“shoulder pad sign”) in a patient who is cachexic. Amyloid deposits in bones, such as the femoral neck, appear as cystic lesions 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 to palpation can cause problems with speech and swallowing and a feeling of suffocation.

AL amyloidosis occurs due to 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 appears to be unimportant, since 10–20% of patients with AL amyloidosis have no detectable monoclonal protein in serum or urine. The primary structure of the light chains is likely to be particularly important in the development of this disease because the normal ratios of serum light chains are completely altered, and β chains are much more frequently detected in AL amyloid deposits than κ chains. Certain subtypes of L-chains have a greater tendency to form fibrillar deposits than others. In addition, AL amyloid fibrillar proteins almost always contain a light chain variable segment (either consisting entirely of it or containing it as a segment). However, the reasons for selective organ damage and different rates of disease progression in different patients remain unclear.

AL amyloidosis is the most severe disease among amyloidoses, and 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 development of cardiac involvement at the onset. 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 to patients with neuropathy or cardiomyopathy. For some patients, high-dose melphalan with stem cell transplantation is the treatment of choice. In patients with more advanced disease, intermediate-dose melphalan with stem cell transplantation may be an alternative due to better tolerability. Among patients who are eligible for and undergo a bone marrow transplant, the average life expectancy is 40 months, while for patients who are not suitable for transplantation, it is 18 months.

Amyloidosis AA

AA amyloidosis 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, preceding any signs of systemic amyloidosis by many years.

The most important manifestation of AA amyloidosis is kidney damage, usually presenting as nephrotic syndrome. It can develop 10 to 20 years after the onset of arthritis and can occur even after the underlying primary inflammatory disease has subsided. Thus, AA amyloidosis can be confused with other pathological processes involving the kidney, such as gold-induced nephropathy. In addition, acute inflammatory triggering mechanisms may precipitate 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, perhaps because pre-existing patches of localized amyloid deposits can accelerate the progression of systemic AA amyloidosis.

Gastrointestinal bleeding may occur in patients with AA amyloidosis. Deposition of AA protein in the blood vessel wall results in decreased distensibility and increased fragility, with occasional vessel rupture and bleeding. Although described in the literature, significant damage to the heart, nerves, skeletal muscles or tongue in AA amyloidosis is very rare. 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 observed in patients with familial Mediterranean fever who have subclinical elevations of SAA and other acute phase proteins but no other symptoms. Ultimately, the disease in such patients can progress to systemic amyloidosis. Because many of these patients lived in developing countries, it is conceivable that environmental factors, such as endemic infections, that cause chronic inflammation, thereby increasing the risk of developing AA amyloidosis, may contribute to this disease pattern.

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 more severe forms of the disease in patients with AA amyloidosis, renal function is effectively restored by kidney transplantation. However, if the underlying inflammatory process is not suppressed, AA amyloid can 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 manner. The gene mutation is present at birth, but clinical symptoms of the disease usually do not appear until after 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 should 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 more than a hundred mutations have been identified. TTR is also known as pre-albumin because it moves faster than albumin during gel electrophoresis. Transthyretin is a plasma protein that carries about 20% of plasma thyroxine, 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 the 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 formation of fibrils.

Not all TTR-related amyloidosis is due to mutations in TTR. Wild-type TTR fragments can form amyloid fibrils that deposit in the heart, causing senile cardiac amyloidosis. This non-hereditary disease affects approximately 25% of people over 80 years of age.

Most TTR-related amyloidoses initially present as peripheral neuropathy. It is often a sensorimotor neuropathy involving the distal lower extremities and 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 ATTR amyloid deposits. Autonomic neuropathy may 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 renal pathology. The majority (60%) of deaths are due to cardiomyopathy, while renal involvement accounts for only 5-7% of deaths. Vitreous amyloid deposits are observed in 20% of patients with ATTR amyloidosis. They are thought 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 using genetic methods to identify TTR mutations; most mutations in ATTR are observed in exons 2-4. 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 family members.

ATTR amyloidosis is treated by transplanting the liver or other affected organs. Liver transplantation results in the synthesis of wild-type (normal) TTR, with the 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 the development of severe malnutrition or cardiomyopathy because graft survival is rapidly reduced when such changes occur. Amyloid deposition may continue even after organ transplantation, possibly due to the presence of large deposits of abnormal protein that serve as a nucleus for subsequent deposition of normal proteins. Because of this, patients with earlier manifestations of ATTR amyloidosis may require a second organ transplant.

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 allows one to suspect AP2M amyloidosis or dialysis-related). Signs and symptoms of Ap2M amyloidosis sometimes occurs in patients with chronic renal failure who have not yet undergone dialysis.

Damage to the axial skeleton, which occurs in 10% of patients undergoing long-term hemodialysis, manifests itself as a destructive spondyloarthropathy, the radiographic signs of which include a decrease in the height of the intervertebral discs and erosion of the vertebral endplates without significant osteophyte formation. The lower cervical spine is most often affected; however, similar changes can also be observed in the thoracic and lumbar spine. Cystic deposits of Ap2M amyloid were detected in the odontoid process and the bodies of the upper cervical vertebrae, as well as masses of Ap2M amyloid in periodontoid soft tissues, which are called pseudotumors. Although neurological impairment is rare, significant myelopathy occurs due to deposits of Ap2M amyloid in the cervical and lumbar spine, especially in patients who have been on hemodialysis for 20 years or more.

Cystic bone lesions can develop in the peripheral skeletal bones of patients undergoing long-term hemodialysis. Subchondral amyloid cysts are usually found in the carpal bones and can also occur in the acetabulum and long bones such as the head or neck of the femur, head of the humerus, distal radius, and upper tibia. Unlike brown tumors in hyperparathyroidism, these bone cysts usually arise in tissues adjacent to the joints and increase in size and number over time. Pathological fractures, especially of the femoral neck, can occur in bone weakened by amyloid deposits.

In patients who have been on dialysis for more than 10 years, visceral deposits of Ap2M amyloid have been identified. Although gastrointestinal and cardiovascular complications have been described, visceral Ap2M amyloid deposits usually do not cause symptoms.

Modern theories of the pathogenesis of Ap2M amyloidosis include the participation of the advanced glycosylation end product (AGE) in the modification of proteins, which contributes to their resistance to proteolysis, increases affinity for collagen and the ability to stimulate the secretion of proinflammatory cytokines, such as TNF-a, IL-6 by activated mononuclear leukocytes. AGE-modified proteins are poorly cleared by dialysis. Thus, patients undergoing dialysis have increased concentrations of these modified proteins compared with individuals with normal renal function or functioning renal allografts. Patients with symptoms and massive Ap2M amyloid deposits 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 has also reduced the incidence of AP2M amyloidosis. Ap2M amyloid deposits do not progress and may regress in patients who have had a successful kidney transplant. Patients with Ap2M amyloidosis who undergo successful kidney transplantation report a marked reduction in joint pain and stiffness. Thus, early kidney transplantation in appropriate candidates before the development of significant AP2M amyloid deposits 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 disease manifestation in localized forms are similar to those observed in systemic forms. The most common forms of localized amyloidosis affect the genitourinary and respiratory tracts.

Genitourinary amyloidosis

Localized genitourinary amyloidosis can affect the entire tract, but more often the bladder and urethra are involved, causing hematuria or signs of obstruction. Amyloid protein is often represented by light or heavy chains of immunoglobulins. Identification of local amyloid deposits can induce a grueling search for systemic disease, often with negative results. However, localized amyloidosis usually resolves spontaneously and does not portend a dire prognosis. Treatment involves excision of localized amyloid deposits.

Pulmonary amyloidosis

In the respiratory tract, AL amyloid deposition often causes localized forms of the disease. Three forms of localized amyloidosis affect the airways: tracheobronchial amyloidosis. which accounts for half 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 amyloid deposition. Computed tomography (CT) reveals amyloid nodules or plaques, 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 located peripherally and subpleurally. The nodules vary in size from a micronodule to 15 cm in diameter; In half of the cases, calcification is observed. In diffuse parenchymal or alveolar septal amyloidosis, widespread amyloid deposits involving small vessels and parenchymal interstitial tissue are noted; Multifocal small amyloid nodules may also be present. High-resolution CT reveals pathological opacities of the retina, thickening of the interlobular septa, small (2-4 mm in diameter) nodules and confluent united opacities mainly in the 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 limited amyloidosis. Other types of amyloid can also be deposited in the airways, but this is rare and generally does not cause significant pathology.

Methods for diagnosing amyloidosis

Scintigraphy with serum amyloid P is used to identify the systemic distribution of amyloid deposits. Serial films demonstrate the progression and reversal of amyloid deposits. However, this technique is limited because patients are exposed to radioactive allogeneic protein and is only available in specialized centers.

The only widely available imaging technique that provides information specific to the diagnosis of systemic amyloidosis is echocardiography. Specific echocardiographic signs of amyloidosis include atrial enlargement, left ventricular reduction, thickening of the interventricular and interatrial septum, and increased myocardial echogenicity. At 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 the reverse development of amyloidosis even after successful treatment

Cardiac magnetic resonance imaging (MRI) is a rapidly advancing area of research that complements echocardiography in the diagnosis of cardiac amyloidosis. Gadolinium-enhanced cardiac MRI has high resolution (approximately 2 mm) and provides tissue contrast to differentiate the affected area from normal myocardium. In patients with cardiac amyloid disease, cardiac MRI demonstrates qualitative global and subendocardial contrast uptake after intravenous gadolinium administration. Although there is no typical MRI finding of cardiac amyloidosis, future studies may identify a combination of noninvasive techniques that could be used in selecting patients for certain more invasive biopsies. endomyocardium, as well as to monitor the natural progression of cardiac amyloidosis.

Because there are no features 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 affected in systemic amyloidosis, radiographic evidence of gastrointestinal amyloidosis is rarely seen. Ischemia and, resulting from the deposition of amyloid in the vessels, can cause symmetrical thickening of the folds of the mucous membrane, which are detected on CT.

Or CT scans can help detect kidney enlargement in the early stages of amyloidosis. Ultrasonography typically demonstrates diffusely increased echogenicity of the renal parenchyma with preserved corticomedullary enhancement because cortical architecture remains macroscopically normal early in the disease. The progression of the disease may be accompanied by a decrease in the kidney and significant thinning of the cortex.

If amyloidosis is suspected, the diagnosis is confirmed using a biopsy: microscopy of the material in polarized light reveals a characteristic light green birefringence and, using immunohistochemical research, the type of amyloid protein. A biopsy can be taken from either the affected or unaffected organ. The latter approach is usually preferred due to the high risk of complications and discomfort associated with internal organ biopsy. To diagnose amyloidosis, one of three methods is usually used: gastrointestinal biopsy (rectal or gastroduodenal), subcutaneous abdominal fat aspiration, and minor salivary gland biopsy.

Rectal biopsy performed by sigmoidoscopy or sigmoidoscopy is the preferred biopsy of the gastrointestinal tract due to the accessibility of this site. The biopsy specimen should include submucosal blood vessels, which are more likely to contain amyloid deposits than those of the mucosal or muscular 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 specimens from patients with amyloidosis often contained amyloid deposits around adipocytes; The highest density of amyloid deposits was observed in the adipose tissues of the scalp and abdominal wall. The sensitivity of abdominal fat aspiration varies between 55 and 75%, but is similar to that of 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.

During a biopsy of the minor salivary gland, the accessory salivary glands of the lip mucosa are taken. Previously, gingival biopsy was used to detect amyloid deposits, but the sensitivity of this method was found to be low. For AA, ATTR, and AL amyloidosis, the sensitivity of minor salivary gland biopsy is comparable to that of rectal biopsy or abdominal fat aspiration.

If the suspicion of amyloidosis is significant and none of the above methods gives positive results, a biopsy of the affected organ should be performed. For kidney disease, a kidney biopsy usually provides diagnostic information. ATTR and AL amyloidosis affects the heart and bone marrow, so a biopsy of these organs is required to confirm the diagnosis. Although the sural nerve may be involved, biopsy of the sural nerve is less desirable because the procedure is usually painful, the biopsy wound is slow to heal, and it may result in residual sensory loss. In addition, the patchy distribution of amyloid deposits makes sural nerve biopsy a less sensitive procedure than biopsy of other affected organs.

When diagnosing amyloidosis, three points are of particular importance::

The pretest probability of detecting amyloid on biopsy is determined by the clinical manifestations of the disease. To determine pretest probability, it is important to consider 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.
Immunohistochemical examination of tissue samples being evaluated for amyloid deposits should always be performed to identify the specific amyloid protein. Occasionally, a patient with an inflammatory disease may develop AL amyloidosis, or a patient with serum monoclonal protein may develop AA amyloidosis. Since the treatment of these diseases differs dramatically, it is necessary 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 do not show evidence of organ dysfunction. Thus, not all people with AA amyloid deposits have AA amyloidosis; Biopsy results must be interpreted with caution.

The article was prepared and edited by: surgeon

23.01.2017

Amyloidosis is a systemic disease; when protein metabolism is disrupted, the immune system stops working. In this regard, amyloid is formed - a protein-saccharide complex that is deposited in all tissues of human organs.

Over time, amyloid increasingly affects organs, displacing normal cells. As a result, the organ loses functionality and irreversible changes are observed. If the disease is left untreated for a long time, the functions of several organs are impaired, which leads to death.

According to WHO research, amyloidosis is diagnosed in approximately 1% of the world's inhabitants. Secondary amyloidosis is the most common. Genetic amyloidosis is more often diagnosed in people belonging to Jewish, Armenian nationality, as well as in residents of Mediterranean countries.

The incidence rate among men is twice as high as among women. Among all forms of amyloidosis, nephropathic (kidney damage) and generalized (damage to all tissues and organs) amyloidosis are diagnosed.

Types of amyloidosis, causes of development

Depending on the cause of amyloidosis, there are different types of disease, which can develop independently or due to pathologies in other systems and organs. The following types of amyloidosis occur: senile, tumor-associated, primary or idiopathic amyloidosis, hereditary, secondary or reactive, as well as in patients undergoing hemodialysis. Depending on the type, the development of amyloidosis occurs differently, symptoms and prognosis vary. Below we will discuss the types and stages of amyloidosis in detail.

Primary (idiopathic)

Primary amyloidosis in most cases begins without cause. In this form of the disease, amyloid is deposited in tissues and organs, and a mutation of immune system cells is observed. AL-amyloid formed in the process accumulates in muscles, skin, cardiovascular system, and nerves. Also, AL amyloid is formed against the background of tumor myeloma, when plasma cells begin to secrete globulins in large volumes. After binding to plasma nucleoproteins, abnormal globulins are converted into amyloid.

Secondary (reactive)

Secondary amyloidosis develops against the background of progressive inflammatory processes over time. In this case, AA amyloid is formed as a complication of other diseases. The reasons why secondary amyloidosis occurs are:

Chronic infections - leprosy, malaria, tuberculosis, syphilis, pyelonephritis, bronchiectasis.
Purulent chronic diseases - suppuration of wounds over a long time, osteomyelitis.
Tumors – leukemia, lymphogranulomatosis, etc.
The presence of nonspecific ulcerative colitis (inflammation of the large intestine).
Rheumatological disease – ankylosing spondylitis, rheumatoid arthritis, etc.

Secondary amyloidosis can affect any organ or tissue in the body. The manifestation of the disease is not immediately noticeable. Years after the onset of the underlying disease, one can notice dysfunction of the organ where amyloid is most deposited. The liver, kidneys, spleen and lymph nodes are most often affected by this disorder. Over time, other organs are affected, leading to multiple organ failure and death.

Hereditary amyloidosis

The hereditary form of amyloidosis is caused by the presence of mutated genes in the cells of the immune system. These genetic mutations are passed down through generations, resulting in the formation of amyloidoblasts. The hereditary form affects people in a certain area or belonging to a certain ethnic group. Hereditary amyloidosis is divided into types:

Cardiopathic. It is mainly diagnosed in residents of Denmark. The clinical picture of the disease resembles primary amyloidosis of the generalized type.
Neuropathic. Characterized by damage to nervous tissue. Depending on the location of the lesion, there are Portuguese (nerves of the legs), American (nerves of the arms), Finnish (nervous system, corneas, kidneys) amyloidosis.
Familial nephropathic. Another name is English amyloidosis (Muckle and Wells disease). The clinical picture is urticaria, attacks of fever, hearing impairment.
Periodic (familial Mediterranean fever). The disease is more common among Jews, Arabs, and Armenians. Manifestations – temperature above 39ºС, pain in the head and muscles, profuse sweating. Inflammation of the membranes of the lungs, peritoneal organs, and synovial organs is observed. Mental abnormalities are common.

Senile amyloidosis

In people over 80 years of age, amyloid is deposited locally in various tissues and organs. The disease is associated with other age-related diseases. There are two types of senile amyloidosis:

Cerebral or cerebral. Develops against the background of Alzheimer's disease. Amyloid Ab is deposited in brain tissue.
Cordial. It can affect the ventricles of the heart (when amyloid is formed from a mutated blood protein transthyretin) and the atria (when amyloid is formed from natriuretic peptide secreted by heart cells). In both cases, amyloids are found in the tissues of the lungs, pancreas, and spleen.

For tumors

Some types of tumors affect the malignant transformation of cells of the diseased organ, which as a result produce fibrillar protein. In this case, amyloidosis develops locally in the tissue of the organ affected by the tumor. Reasons that provoke amyloidosis in tumors:

Medullary tumor of the thyroid gland. Cancer develops from the C cells of the thyroid gland, which are normally responsible for the production of calcitocin. When calcitocin synthesis is disrupted, its fragments become part of amyloid AE.
Thyroid islet cancer. Islets are clusters of cells responsible for the production of hormones - glucagon, insulin, somatostatin, etc. Malignant degeneration of cells causes the release of fibrillar protein, which subsequently degenerates into amyloid.

Amyloidosis during hemodialysis

Hemodialysis is a life-saving procedure for patients whose kidneys are unable to cleanse the blood of toxins and metabolic byproducts. Hemodialysis is prescribed for those diagnosed with renal failure (acute, chronic).

The essence of the procedure is passing the blood through a machine that removes harmful substances from it, returning the purified blood to the patient’s body.

During dialysis, B2-microglobulin cannot be removed from the body, and if the patient is forced to undergo hemodialysis for a long time, the protein accumulates in the body in excessive quantities. It binds to plasma nucleoproteins, settles in various organs, and becomes the basis of amyloid.

Symptoms of amyloidosis

Considering that the disease can spread to any organ or tissue, the symptoms will vary. Various forms of the disease at the beginning of its course are characterized by damage and dysfunction of one organ in the human body.

Over time, the disease (if it is not local amyloidosis) progresses, affecting other organs and tissues. Manifestations of amyloidosis can be observed in the kidneys, liver, heart and adrenal glands, spleen, gastrointestinal tract and nervous system, joints, muscles, and skin. The types of the disease are described in detail below.

Kidney damage

Kidney amyloidosis is considered the most dangerous disease when compared with damage to other organs. The clinical picture of renal amyloidosis depends on the stage. In total there are 4 of them - latent, nephrotic, azotemic, proteinuric.

In the latent stage, renal amyloidosis shows virtually no symptoms. If this is a secondary form, the patient feels the symptoms of the underlying disease. Only years later will kidney damage become symptomatic.

In the proteinuric stage, renal amyloidosis lasts 10 years or more. At this time, amyloidosis is gradually deposited in the vessels, intercellular space and glomeruli of the kidneys. Because of this, the nephrons that produce urine are compressed, atrophy and die. The integrity of the kidney filter, which normally does not allow large molecular proteins and blood cells to pass through, is compromised. Subsequently, proteins are excreted in the urine. At this stage, it is difficult to suspect renal amyloidosis, since the excretory function is not impaired. The problem can be detected in the results of laboratory tests.

Renal amyloidosis in the nephrotic stage is manifested by further destruction of the renal filter. Because of this, a large amount of protein is lost in the urine, and its concentration in the blood decreases. Proteins are a component of the process of holding blood in blood vessels. When the concentration of proteins decreases, fluid enters the tissues, swelling occurs at any time of the day, regardless of body position. Further, renal amyloidosis progresses, edema is severe. Fluid accumulates in the peritoneum, pleural cavity, and cardiac sac. This stage lasts 4-6 years.

At the azotemic stage, only 25% of the total volume of renal tissue functions. This is not enough to remove harmful toxins, urea, and therefore their concentration increases. The clinical picture of renal failure is as follows:

urination is impaired. Instead of the prescribed 800 ml per day, the patient excretes less than 50 ml of urine;
your health worsens, weakness and fatigue appear;
digestion is impaired, appetite disappears, nausea and vomiting occurs, dry mouth is accompanied by an unpleasant odor;
the skin becomes pale, dry, and constantly itches;
the cardiovascular system suffers, causing arrhythmia, increased blood pressure, and possible enlargement of the heart muscle;
the brain is damaged under the influence of high concentrations of uric acid, insomnia and memory impairment, irritability, and decreased mental abilities appear;
a decrease in hemoglobin and red blood cells leads to anemia.

Liver damage

Systemic amyloidosis often manifests itself as liver damage. Amyloid deposits put pressure on the bile ducts, blood vessels and liver cells, resulting in impaired organ function. When distinguishing amyloidosis syndromes, they indicate an enlarged liver, felt upon palpation.

The surface of the liver remains smooth, there is no pain. In the case of a long course of the disease, liver failure rarely develops, which is associated with the regenerative abilities of the organ.

Liver amyloidosis manifests itself with symptoms:

Increased liver size.
Portal hypertension. Normally, blood from the internal organs enters the liver, where it is purified and then returned to the bloodstream. When the liver vessels are compressed by amyloid, the pressure in the veins of the internal organs increases. As a result, swelling in the legs, diarrhea with blood, and bleeding in the gastrointestinal tract occur.
Jaundice rarely occurs, only when the bile ducts are compressed by amyloid deposits. If this is the reason, jaundice will be accompanied by itchy skin.

Heart damage

Cardiac amyloidosis develops in primary and other hereditary forms. As a result of amyloid deposits in the myocardium and membranes of the heart, blood circulation is disrupted and muscle cells die.

Symptoms of the disease:

arrhythmia;
restrictive cardiomyopathy;
heart failure.

Arrhythmia occurs against the background of amyloid deposits in the heart muscle, which disrupts the conduction of nerve impulses. As a result, the chambers of the heart contract unevenly, and arrhythmia appears. The patient feels dizzy and faints. Due to impaired blood supply to the brain, death is possible.

Restrictive cardiomyopathy occurs against the background of amyloid deposits in the myocardium. As a result, the heart muscle thickens and becomes less extensible, which leads to poor functioning of the heart chambers. The clinical picture of the disease is fatigue, shortness of breath, a sharp decrease in blood pressure when changing from a horizontal position to a vertical position.

In heart failure, blood circulation in the body is disrupted. This is manifested by swelling and shortness of breath. Heart failure due to amyloidosis does not respond to standard treatment for cardiovascular diseases. The disease progresses rapidly and leads to death within a few months.

Damage to the adrenal glands and spleen

The adrenal glands are glands located on each kidney and are responsible for secreting hormones. Amyloidosis disrupts organ function by stopping the synthesis of hormones. If amyloid is deposited in the spleen, the organ increases in size, which is noticeable upon palpation.

Normally, the spleen removes misshapen cells from the bloodstream that become stuck in its structure. Amyloid deposits cause healthy red blood cells, platelets, and white blood cells to become stuck in the spleen.

As a result, anemia develops (general weakness, pale skin, shortness of breath), thrombocytopenia (nosebleeds, skin hemorrhages), leukopenia (susceptibility to infections).

Gastrointestinal lesions

Intestinal amyloidosis can be generalized, when the absorption of nutrients is impaired, and local, when amyloid accumulations mimic a tumor. In the first case, symptoms such as diarrhea, weight loss, weakness, mental disorders, and anemia occur. In the second case, the disease is characterized by constipation, abdominal pain, and bloating.

Damage to joints and muscles

Amyloid initially affects small joints on the feet and hands, and as the disease progresses, it settles in the elbows and knees. The disease is characterized by pain when moving, swelling of the tissue and redness of the skin, increased temperature in the affected area, and dysfunction of the joint.

Amyloid is deposited unnoticed for a long time in the connective tissue, without disturbing the structure of the muscles and without appearing. Over time, muscle cells are compressed, their blood supply is disrupted, and they die. The disease is characterized by muscle weakness, pain, tightness and muscle hypertrophy.

Diagnosis of amyloidosis

Doctors of different specializations - rheumatologists, cardiologists and urologists, neurologists, dermatologists, etc. - can suspect a diagnosis such as amyloidosis. Therefore, the diagnosis of amyloidosis should be based on a comprehensive assessment of the medical history, clinical signs, laboratory and instrumental examination. To examine the condition of the organs, an ECG, x-ray of the esophagus, endoscopy, and sigmoidoscopy are prescribed. If renal amyloidosis is suspected, diagnosis necessarily includes an ultrasound of the abdominal cavity.

Treatment of amyloidosis

Although there are various serious diseases, amyloidosis carries a poor prognosis. The fact is that the disease cannot be detected in the early stages, and its clinical manifestations are noticeable many years after the onset of the disease. With a diagnosis such as renal amyloidosis, treatment is only supportive in nature, since therapeutic measures are not effective.

At the first suspicion of the presence of the disease, hospitalization in nephrology is necessary for examination of the genitourinary system, since kidney damage is considered the most dangerous manifestation. Other specialists are also involved to examine the presence of damage to other organs.

If the diagnosis does not reveal serious disturbances in the functioning of vital organs, treatment of amyloidosis can be carried out at home, where the patient must strictly follow all the doctor’s instructions. Treatment may include medication, diet, dialysis, and organ transplantation.

“Amyloidosis” is a term that unites a group of diseases that are distinguished by a wide variety of clinical manifestations and are characterized by extracellular deposition of insoluble pathological fibrillar proteins in organs and tissues. This pathology was first described in the 17th century. Bone - sago spleen in a patient with liver abscess. In the middle of the 19th century. Virchow used the botanical term "amyloid" (from the Greek amylon - starch) to describe the extracellular material found in the liver at autopsy, since he believed that it was similar in structure to starch. Subsequently, the protein nature of the deposits was established, but the term “amyloid” has been preserved to this day.

In the 20s In the 20th century, Benhold proposed staining amyloid with Congo red, then the effect of birefringence in polarized light was discovered - a change in brick-red color to apple-green. In 1959, Cohen and Calkins used electron microscopy to establish the fibrillar structure of amyloid.

Clinical ideas about amyloidosis also underwent evolution: Rokitansky in 1842 established a connection between “sebaceous disease” and tuberculosis, syphilis, and rickettsiosis; Wilkes in 1856 described “fat organs” in a patient who had no concomitant diseases; Atkinson discovered amyloidosis in patients with multiple myeloma in 1937. Senile (Soyka, 1876) and hereditary (Andrade, 1952) forms of the disease were identified, amyloidosis was divided into genetic, primary and secondary, and finally, in 1993, the WHO classification was adopted, based on the specificity of the main fibrillar protein of amyloid.

In our country, E. M. Tareev, I. E. Tareeva, V. V. Serov made a great contribution to the development of ideas about amyloidosis. A huge role in the study of primary and genetic variants of amyloidosis and periodic disease belongs to O. M. Vinogradova, whose monographs, published in 1973 and 1980, have not lost their relevance today.

Currently, amyloidosis is clinically divided into systemic and local forms. Among the systemic forms, depending on the composition of fibrillar deposits, four types are distinguished ( ).

Local forms of amyloidosis currently include Alzheimer's disease (A-beta, fibrils consist of β-protein deposited in the brain), amyloidosis of the pancreatic islets, possibly having a pathogenetic connection with type 2 diabetes, amyloidosis arising in endocrine tumors, amyloid tumors of the skin, nasopharyngeal region, bladder and other rare types.

AL amyloidosis

The development of AL amyloidosis is possible in myeloma, Waldenström's disease, B-cell lymphomas, and it can be idiopathic in primary amyloidosis. All these options are united by a common pathogenesis; primary amyloidosis is the most difficult to recognize due to the absence of obvious signs of a hematological disease, so it is this form that is worth dwelling on in detail.

In primary amyloidosis, a benign plasma cell dyscrasia related to multiple myeloma, abnormal clones of bone marrow plasma cells produce amyloidogenic immunoglobulins. Some amino acids in the variable regions of the light chains of these immunoglobulins occupy an unusual position, which leads to their instability and causes a tendency to fibrillogenesis. In patients with primary amyloidosis, the content of plasma cells in the bone marrow is increased to 5-10% (normally less than 4%, in myeloma - more than 12%), and they produce a certain isotype of immunoglobulin light chains, which predominates in immunohistochemical staining. Free monoclonal light chains of the predominant lambda or (less commonly) kappa isotype are detected in the blood and urine, but their content is lower than in multiple myeloma.

The clinical picture of primary amyloidosis is diverse and is determined by the predominant involvement of certain organs in the pathological process - the heart, kidneys, nervous system, gastrointestinal tract, liver, etc. The first symptoms are weakness and weight loss, but at this stage, before the appearance of organ symptoms , the diagnosis is made extremely rarely.

The target organs for AL amyloidosis most often are the kidneys and heart. Kidney damage is manifested by nephrotic syndrome, which persists even with the onset of chronic renal failure; hematuria and arterial hypertension are not typical.

When amyloid is deposited in the myocardium, various rhythm disturbances and progressive heart failure develop, which may be preceded by asymptomatic changes on the ECG in the form of a decrease in wave voltage. Echocardiographic examination reveals concentric thickening of the walls of the left and right ventricles, a decrease in the volume of the heart cavities, a moderate decrease in ejection fraction, and diastolic dysfunction of the left ventricular myocardium.

Symptoms of nervous system involvement are often observed - autonomic, in the form of orthostatic hypotension, and peripheral, in the form of sensitivity disorders. In recent years, lesions of the central nervous system have also begun to be described, although previously it was believed that they were not characteristic of primary amyloidosis.

Dyspeptic symptoms (feeling of fullness, constipation, diarrhea) and malabsorption syndrome can be caused by both damage to the autonomic nervous system and amyloidosis of the gastrointestinal tract. Hepatomegaly is very characteristic, the nature of which should be differentiated between congestion due to heart failure and amyloid liver damage. The latter is confirmed by an increase in serum alkaline phosphatase levels. The spleen is often affected, but splenomegaly is not always detected and is not of great clinical significance.

Macroglossia, a classic sign of primary amyloidosis, is observed in 20% of patients; infiltration of soft tissues can lead to atrophy of muscles, skin, nail dystrophy, alopecia and the appearance of tumor-like formations - amyloid.

Less common is vascular lesions, the symptoms of which are periorbital purpura - “raccoon eyes” and ecchymoses. Bleeding may occur, including bladder bleeding, caused by both changes in the vascular wall and a violation of the coagulation system, primarily a deficiency of the X factor, which binds to amyloid. The thrombocytosis characteristic of amyloidosis is also commonly explained by a deficiency of coagulation factors.

Pulmonary amyloidosis is often discovered only at autopsy. However, in some cases, shortness of breath, hemoptysis and hydrothorax may be caused not only by congestive heart failure and nephrotic syndrome, but also by amyloid lung disease. Deposition of amyloid in the alveoli and the development of pulmonary amyloid are possible. X-rays can reveal reticular and nodular changes in the lung tissue.

Damage to the adrenal glands can lead to adrenal insufficiency, which often remains unrecognized, since hypotension and hyponatremia are considered symptoms of heart failure and damage to the autonomic nervous system. In 10-20% of patients, hypothyroidism may occur as a manifestation of damage to the thyroid gland; enlargement of the submandibular salivary glands is often encountered.

The diagnosis of primary amyloidosis, in addition to the indicated clinical features, which may be similar in secondary amyloidosis, is based on a number of laboratory data. In 85% of patients, immunoelectrophoresis of serum and urine proteins reveals monoclonal immunoglobulins. In routine studies, the same monoclonal immunoglobulins are detected in the urine in the form of Bence Jones protein. Bone marrow biopsy allows for a differential diagnosis of multiple myeloma and also reveals a moderate increase in the number of plasma cells and their monoclonality with immunohistochemical staining.

However, even the combination of a characteristic clinical picture and the presence of monoclonal plasma cells and proteins is not yet sufficient to confirm the diagnosis of primary amyloidosis. Biopsy data play a decisive role here. The least invasive is aspiration of the subcutaneous fatty tissue of the anterior abdominal wall, which gives 80-90% positive results in AL amyloidosis (this method has not yet found application in our country). A biopsy of the gums and rectal mucosa has a certain diagnostic value, but the percentage of positive results varies widely, depending on the stage of the process, so it is advisable to perform a biopsy of one of the affected organs - the kidney, liver, heart, which gives almost 100% positive results for amyloidosis AL-type.

First of all, the biopsy material is stained with Congo red. If congophilia of the material under study is detected, it must be examined in polarized light; the effect of birefringence is characteristic only of amyloid; other congophilic substances do not acquire an apple-green color. After this, amyloid typing is desirable. The most accurate is the immunohistochemical method using monoclonal antibodies to amyloid precursor proteins. However, at present it is practically unavailable in our country. Therefore, for diagnosis, staining with solutions of alkaline guanidine or potassium permanganate is used, which allows, although indirectly, to determine the type of fibrillar deposits.

The prognosis for primary amyloidosis is worse than for other forms of the disease, the average life expectancy does not exceed two years, in the presence of heart damage or multisystem damage without treatment, patients die within a few months. The most common causes of death are cardiac and renal failure, sepsis, vascular complications and cachexia. Pathogenetic similarity with multiple myeloma allows one to expect inhibition of disease progression with chemotherapy administered to suppress monoclonal plasma cells. There are several treatment regimens ().

The use of chemotherapy, if treatment is successful, can increase the life expectancy of patients by 10 to 18 months. But the effectiveness of therapy is low, in particular due to the fact that in many cases the progression of the disease leads to the death of patients before completing the course of treatment, as well as due to the development of cytopenia, infectious complications, and fatal rhythm disturbances during treatment with ultra-high doses of dexazone. The use of high doses of melfolan with autologous stem cell transplantation allows achieving remission in more than 50% of cases, however, the use of this method is limited by the severity of the condition, the age of the patients, and functional disorders of the heart and kidneys. In many cases, only symptomatic maintenance therapy is possible.

AA amyloidosis

The development of AA amyloidosis occurs during chronic inflammatory processes; the precursors of AA amyloid are serum acute phase proteins, α-globulins, produced by different types of cells, mainly neutrophils and fibroblasts. Secondary amyloidosis develops with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, various tumors, lymphogranulomatosis, ulcerative colitis and Crohn's disease, with periodic disease (familial Mediterranean fever), as well as with tuberculosis, osteomyelitis, bronchiectasis.

Characteristic clinical features of AA amyloidosis are kidney damage in most patients, as well as relatively rare damage to the liver and/or spleen (about 10%) and the heart (detected only by echocardiography). Macroglossia is not typical for secondary amyloidosis. The diagnosis is based on a combination of renal amyloidosis and chronic inflammatory disease, confirmed by immunohistochemical staining of biopsy material; in our country, the indirect staining methods already mentioned above are used.

The prognosis largely depends on the nature of the underlying disease; during the natural course, a third of patients develop renal failure 5 years from the moment proteinuria is detected. For periodic disease, the five-year survival rate is 25%.

Treatment is based on suppression of the focus - the source of production of serum precursor proteins. Removal of tumors, sequestrectomy, bowel resection, treatment of tuberculosis, reduction of the activity of rheumatoid arthritis (with the use of cytostatics) lead to the cessation of the progression of amyloidosis, and sometimes to the reverse development of clinical manifestations, in particular nephrotic syndrome.

The use of colchicine for periodic illness is the method of choice, its effectiveness has been proven, treatment prevents the development of amyloidosis and inhibits its progression. In other forms of secondary amyloidosis, the effectiveness of colchicine has not been confirmed.

Senile and hereditary forms of systemic amyloidosis, as well as local forms, are rare; dialysis amyloidosis is well known to specialists and is practically never encountered in general practice.

Symptomatic therapy depends not on the type of amyloidosis, but on the affected target organs ( ).

Amyloidosis, especially primary, is considered an uncommon pathology, but in reality it is not so rare as it is difficult to diagnose. Adequate diagnosis requires not only knowledge of the clinical picture and pathogenesis of the disease, but also the availability of certain diagnostic capabilities. To illustrate this point, we present our own data ( ). In the nephrology department of the S.P. Botkin Moscow City Clinical Hospital in 1993-2003. 88 patients were observed who were diagnosed with amyloidosis.

The diagnosis was confirmed morphologically in all patients with AL amyloidosis, senile and unspecified amyloidosis, and in 30 patients with secondary amyloidosis - in a total of 53 cases. In 12 patients a kidney biopsy was performed, in two patients a liver biopsy was performed, in eight patients a bowel biopsy was performed, in 12 cases a gum biopsy was performed, and in another 19 cases the diagnosis was confirmed by morphological examination of sectional material.

In most cases, the diagnosis of amyloidosis was made for the first time as a result of examination in the nephrology department. We made a comparison among patients with AL amyloidosis of referral and clinical diagnoses ( ).

In only two cases out of 20 (10%) the referral diagnosis was “primary amyloidosis”, and one of these patients was diagnosed at the MMA therapy and occupational diseases clinic, and the other at a foreign clinic.

All patients who were diagnosed with myeloma with the development of AL amyloidosis were transferred to hematology departments. Of the 11 patients with primary amyloidosis, seven patients received chemotherapy with a combination of melfolan and oral prednisolone in intermittent courses, four of them in combination with dialysis treatment, and another patient received only dialysis and symptomatic treatment. Of these patients, five people died within a period of two weeks to two years from the start of treatment (all with renal failure and multiple organ damage), one patient is on dialysis, one patient was referred for autologous stem cell transplantation, and one patient is receiving treatment until present time. In one patient, chemotherapy was postponed due to the presence of a long-lasting gastric ulcer, and two other patients refused treatment.

Among patients with secondary amyloidosis in our study, patients with rheumatoid arthritis predominated; chronic osteomyelitis and psoriatic arthritis were in second place among the causes; other diseases were less common ( ).

Treatment of rheumatoid arthritis and psoriatic arthritis was carried out with the use of cytostatics (metatrexate, azathioprine), although in many cases the treatment options were limited due to the presence of chronic renal failure and concomitant pathology. Patients with chronic osteomyelitis were sent to purulent surgery departments. Patients with ankylosing spondylitis and Crohn's disease received specific treatment, patients with COPD and tuberculosis were also sent to specialized hospitals. One of the patients with a stomach tumor was successfully operated on, and over the course of four years of observation, the nephrotic syndrome gradually regressed; in other cases of tumors, the prevalence of the process allowed only symptomatic therapy; the patient with lymphogranulomatosis was admitted in a terminal condition. The mortality rate among patients with secondary amyloidosis was 38% (due to patients with advanced lesions at the time of diagnosis). All patients with periodic illness received colchicine therapy.

Features of the diagnosis and application of modern methods of treatment of primary amyloidosis can be illustrated by the following example: patient K., 46 years old, was first hospitalized at the end of October 2002 with complaints of swelling in the legs, palpitations, and amenorrhea. The history includes colds, an appendectomy, two normal emergency deliveries, no indications of kidney disease, and no chronic diseases. In April 2002, she suffered acute pneumonia in the upper lobe of the right lung, was treated as an outpatient, and received injections of abactal and lincomycin. Due to the localization of pneumonia, she was examined at a tuberculosis clinic, and the diagnosis of tuberculosis was excluded. At the beginning of June, swelling in the legs first appeared, for which she was not examined. The swelling disappeared on its own after a short time and then resumed. The patient was hospitalized in a therapeutic hospital; examination revealed proteinuria up to 1.65%, hypoproteinemia (total serum protein 52 g/l), normal blood pressure (120/80 mm Hg), unchanged urinary sediment, creatinine plasma levels are also within normal limits. A diagnosis of acute glomerulonephritis was made, treatment with ampicillin, chimes, heparin, triampur was performed, and a tonsillectomy was performed. Proteinuria persisted, edema gradually increased, and therefore, for further examination and treatment, the patient with a diagnosis of chronic glomerulonephritis was sent to the hospital named after. S. P. Botkina.

On examination, the skin is clean, of normal color, anasarca, massive, dense edema, ascites is detected, peripheral lymph nodes are not enlarged. Blood pressure 110/70 mm Hg. Art., heart sounds are sonorous, clear, rhythmic, heart rate 90 beats/min, liver and spleen are not enlarged, diuresis is up to 1000 ml/day, stool is regular, without pathological impurities. The examination revealed nephrotic syndrome - proteinuria 3 g/l, scanty urinary sediment, hypodysproteinemia, hyperlipidemia (total serum protein 39 g/l, albumin 12 g/l, globulins 7-30-15-19%, respectively α 1 -α 2 -β-γ cholesterol 17.8 mmol/l, β-lipoproteins 250 IU), when analyzing urine for Bence-Jones protein - the reaction is negative, daily excretion of 17-KS is not reduced. Clinical blood test and other biochemical parameters are within normal limits, coagulogram shows severe hyperfibrinogenemia, increased level of RKFM. Study of blood immunoglobulins: Ig-A - 0.35, Ig-M - 35.7 (two norms), Ig-G - 1.96 g/l. X-ray of the chest organs, skull and pelvic bones, ultrasound of the abdominal cavity, kidneys, thyroid gland, ECHO-CG without pathology, pelvic ultrasound - signs of adenomyosis of the uterine body, endoscopy - reflux esophagitis, chronic gastritis. When examined by a neurologist, no pathology was found; the oncologist diagnosed fibrocystic mastopathy.

In order to clarify the genesis of nephrotic syndrome, a fine-needle puncture biopsy of the right kidney was performed under local anesthesia and ultrasound guidance; there were no complications. When examining a biopsy specimen, amyloid deposition is noted in the glomerular mesangium and in extraglomerular vessels. Amyloid loads up to 25% of glomerular vascular loops. An immunohistochemical study did not find any specific luminescence. When the preparations are treated with an alkaline guanidine solution for 2 hours, congophilia and their properties in polarized light are preserved, which is characteristic of AL amyloidosis.

To clarify the nature of AL amyloidosis, an immunochemical study of blood and urine was performed in the Immunotest laboratory. M-lambda paraproteinemia with a decrease in the level of polyclonal immunoglobulins and Bence-Jones lambda-type paraproteinuria against the background of massive non-selective proteinuria were detected. The patient was consulted by a hematologist, the presence of Waldenström's disease was suggested, and a bone marrow biopsy was performed. Conclusion: in the existing bone marrow cavities, cells of all three germs of normal hematopoiesis are visible, as well as lymphoid cells that do not form clusters. The diagnosis of Waldenström's disease was rejected due to the absence of lymphoid infiltration of the bone marrow, enlargement of the lymph nodes and spleen, and the absence of tumor substrate.

A diagnosis of primary amyloidosis with kidney damage, nephrotic syndrome, preserved renal function was established; no signs of other organ damage were detected. In January 2003, chemotherapy was started with melfolan 16 mg/day and prednisolone 100 mg/day, courses of four days every six weeks. Symptomatic treatment is also carried out: furosemide, veroshpiron, potassium preparations, famotidine, albumin transfusions. To date, five courses of chemotherapy have been carried out with good tolerance, edema has decreased, proteinuria has decreased to 1.8 g/l, and the severity of hypodysproteinemia has slightly decreased (total protein 46 g/l, albumin 18 g/l, α 2 -globulins 20%). Kidney function remains intact, plasma creatinine is 1.3 mg/dL, and no signs of damage to other organs and systems were detected during dynamic control examinations.

This case clearly illustrates the fact that morphological, immunological and immunochemical examination is necessary to diagnose amyloidosis. Thus, in our patient, the most obvious clinical diagnosis was “chronic glomerulonephritis,” and in the absence of the possibility of performing a kidney biopsy, this diagnosis would most likely have been made. The patient did not have any clinical indications of the systemic nature of the disease, a chronic inflammatory process, or a disease of the blood system, with the exception of an increase in the level of Ig-M. And only the data obtained from the study of the renal biopsy entailed a bone marrow trephine biopsy and an immunochemical study, which together made it possible to make a diagnosis of primary amyloidosis before the appearance of systemic damage. Pathogenetic therapy was started, although against the background of already developed nephrotic syndrome, but before the onset of renal failure and when only 25% of the glomeruli were loaded with amyloid, which has a relatively favorable prognosis.

In conclusion, we note that amyloidosis is a serious disease with a high mortality rate, which is extremely difficult to diagnose, however, timely and high-quality examination of patients makes it possible to make a diagnosis earlier, and the timely prescription of adequate therapy, in turn, makes it possible to improve the prognosis in this case. group of patients.

Literature

E. V. Zakharova
Moscow City Clinical Hospital named after. S. P. Botkina

Table 2. Treatment regimens for primary amyloidosis

Cyclic oral administration of melfolan (0.15-0.25 mg/kg body weight per day) and prednisolone (1.5-2.0 mg/kg per day) for four to seven days every four to six weeks for a year, up to achieving the course dose of 600 mg
Oral administration of melfolan at a dose of 4 mg/day for three weeks, then, after a two-week break - 2-4 mg/day four days a week continuously, until a course dose of 600 mg is reached, in combination with prednisolone
Intravenous administration of high doses of melfolan (100-200 mg/m² body surface for two days) followed by autologous stem cell transplantation
Intravenous dexamethasone 40 mg for four days every three weeks—eight cycles
Intravenous administration of dexamethasone at a dose of 40 mg on the first-fourth, 9-12th and 17-20th days of a 35-day cycle, three to six cycles, followed by the use of a-interferon at a dose of 3-6 million units three times a day a week
Vincristine-doxoribucin-dexamethasone (VAD) regimen

Amyloidosis (amyloid dystrophy, Latin amyloidosis, Greek amylon starch + eidos species + ōsis) is a group of diseases that are distinguished by a wide variety of clinical manifestations and are characterized by extracellular (in the extracellular matrix) deposition (systemic or local) of insoluble pathological fibrillar proteins (protein- polysaccharide complex - amyloid) in organs and tissues that are formed as a result of complex metabolic changes (protein dystrophies). The main target organs are the heart, kidneys, nervous system [central and peripheral], and liver, however, in systemic forms, almost all tissues can be affected (rare localizations include adrenal amyloidosis). They were called amyloids because, in reaction with iodine, they resembled starch. Amyloid persists in the body for a long time and even after death does not rot for a long time (I.V. Davydovsky, 1967). Amyloidosis can occur independently or “secondarily” as a result of another disease.

Currently, amyloidosis is considered as a group of diseases that are characterized by the deposition in tissues and organs of fibrillar amyloid protein (AFA) - a special protein structure with a diameter of 5 - 10 nm and a length of up to 800 nm, consisting of 2 or more parallel multidirectional (antiparallel) filaments that form cross-β-sheet conformation(see picture on the left). It is this that determines the specific optical property of amyloid - the ability to undergo birefringence (detected by Congo red staining [= method for determining amyloid in tissues]). According to modern data, the prevalence of amyloidosis in the population ranges from 0.1 to 6.6%.

The protein name amyloid was proposed by Rudolf Virchow, who borrowed it from botany, where the word meant cellulose or starch. In its structure, amyloid is a complex glycoprotein in which fibrillar and globular proteins are found in a structure with polysaccharides (galactose, glucose, glucosamine, galactosamines, mannose and fructose). Amyloid contains proteins similar in their characteristics to α1-, β- and γ-globulins, albumin, fibrinogen, and it contains neuraminic acid. The bonds between proteins and polysaccharides are very strong, which maintains its stability. The structure of amyloid also contains a P component, which makes up up to 15% of the total amyloid and is identical to the serum protein SAP (serum amyloid P). SAP is a protein produced by liver cells, classified as acute phase (SAP is a constant component of amyloid deposits in all forms of amyloidosis).

Amyloidosis is polyetiological. Of primary importance is the amyloidogenicity of the major amyloid precursor protein (BPA), which is specific for each form of amyloidosis. Amyloidogenicity is determined by changes in the primary structure of APA, fixed in the genetic code or acquired during life due to mutations. To realize the amyloidogenic potential of BPA, exposure to a number of factors is necessary, such as inflammation, age, and physicochemical conditions in situ.

TABLE: Classification of amyloidosis (in all names of types of amyloidosis, the first letter is the capital letter “A”, meaning the word “amyloid”, followed by the designation of the specific APA - A [amyloid A protein; formed from the serum precursor protein SAA - acute phase protein, in normally synthesized by hepatocytes, neutrophils and fibroblasts in trace amounts], L [immunoglobulin light chains], TTR [transthyretin], 2M [β2-micro-globulin], B [B-protein], IAPP [islet amyloid polypeptide], etc. .).

note! The structural and chemical-physical characteristics of amyloid are determined by the main BPA, the content of which in the fibril reaches 80% and is a specific feature for each type of amyloidosis. Each protein (AP) has significantly different mechanisms of synthesis, utilization, and biological functions, which determines differences in clinical manifestations and approaches to the treatment of amyloidosis. For this reason, different forms of amyloidosis are considered different diseases (see table).

Despite the progress achieved in the study of various types of amyloid, the final stage of amyloidogenesis—the formation of amyloid fibrils in the intercellular matrix of BPA—remains largely unclear. Apparently, this is a multifactorial process that has its own special features in different forms of amyloidosis. Let us consider the process of amyloidogenesis using the example of AA amyloidosis. It is believed that in the formation of AA from SAA, the process of incomplete cleavage of SAA by proteases associated with the surface membrane of monocyte-macrophages and the polymerization of soluble AA protein into fibrils, which is believed to also occur with the participation of membrane enzymes, are important. The intensity of AA amyloid formation in tissues depends on the concentration of SAA in the blood. The amount of SAA synthesized by cells of different types (hepatocytes, neutrophils, fibroblasts) increases many times during inflammatory processes and tumors (increased SAA levels in the blood play a major role in the pathogenesis of AA amyloidosis). However, for the development of amyloidosis, only a high concentration of SAA is not enough; the presence of amyloidogenicity in the BPA (i.e., SAA) is also necessary. The development of amyloidosis in humans is associated with SAA1 deposition. Currently, 5 isotypes of SAA1 are known, of which the greatest amyloidogenicity is attributed to isotypes 1.1 and 1.5. The final stage of amyloidogenesis - the formation of amyloid fibrils from BPA - occurs during incomplete cleavage of monocyte-macrophages by proteases. Stabilization of the amyloid fibril and a sharp decrease in the solubility of this macromolecular complex are largely due to interaction with interstitial polysaccharides.

Despite the differences in the types of amyloid protein, there is a common pathogenesis of various clinical forms of amyloidosis. The main reason for the development of the disease is the presence of a certain, often increased amount of amyloidogenic APA. The appearance or enhancement of amyloidogenicity may be due to the circulation of protein variants with increased overall hydrophobicity of the molecule, an imbalance in the ratio of surface molecular charges, which leads to instability of the protein molecule and promotes its aggregation into an amyloid fibril. At the last stage of amyloidogenesis, amyloid protein interacts with blood plasma proteins and tissue glycosaminoglycans. In addition to structural features, the physicochemical properties of the intercellular matrix, where the amyloid fibril is assembled, are also important. Many forms of amyloidosis can also be combined based on their occurrence in old and senile age (AL, ATTR, AIAPP, AApoA1, AFib, ALys, AANF, A-beta), which indicates the presence of mechanisms of age-related evolution of the structure of certain proteins towards increasing amyloidogenicity and allows consider amyloidosis as one of the models of aging of the body.

Neurological aspects of amyloidosis :

ATTR amyloidosis. ATTR amyloidosis includes familial amyloid polyneuropathy, which is inherited in an autosomal dominant manner, and systemic senile amyloidosis. The precursor protein in this form of amyloidosis is transthyretin, a component of the prealbumin molecule, synthesized by the liver and performing the functions of the thyroxine transport protein. It has been established that hereditary ATTR amyloidosis is the result of a mutation in the gene encoding transthyretin, which leads to the replacement of amino acids in the TTR molecule. There are several types of hereditary amyloid neuropathy: Portuguese, Swedish, Japanese and several others. In the most common familial variant (Portuguese), in the 30th position from the N-terminus of the transthyretin molecule, methionine is replaced with valine, which increases the amyloidogenicity of the precursor protein and facilitates its polymerization into amyloid fibrils. Several variant transthyretins are known, which accounts for the variety of clinical forms of hereditary neuropathy. Clinically, this disease is characterized by progressive peripheral and autonomic neuropathy, which is combined with damage to the heart, kidneys and other organs of varying degrees. Systemic senile amyloidosis develops after age 70 as a result of age-related conformational changes in normal transthyretin, apparently increasing its amyloidogenicity. The target organs of senile amyloidosis are the heart, cerebral vessels and aorta.

read also the post: Transthyretin amyloid polyneuropathy(to the website)

read also the article “Damage to the peripheral nervous system in systemic amyloidosis” Safiulina E.I., Zinovieva O.E., Rameev V.V., Kozlovskaya-Lysenko L.V.; Federal State Autonomous Educational Institution of Higher Education “First Moscow State Medical University named after. THEM. Sechenov" Ministry of Health of the Russian Federation, Moscow (magazine "Neurology, neuropsychiatry, psychosomatics" No. 3, 2018) [read]

Alzheimer's disease(AD) is a genetically determined progressive neurodegenerative disease, which is based on the death of neurons in the cerebral hemispheres; clinical manifestations of the disease are a decrease in memory and other cognitive functions (intelligence, praxis, gnosis, speech). At the moment, 4 main genes have been identified that are responsible for the development of this disease: the gene encoding the amyloid precursor protein (APP, chromosome 21), genes encoding enzymes [alpha-, beta-, gamma-secretases] that metabolize APP: presenilin-1 (chromosome 14), presenilin-2 (chromosome 1). A special role is played by hetero- or homozygous carriage of the fourth isoform of apolipoprotein E (APOE 4).

Normally, the amyloid precursor protein (APP) is cleaved by alpha-secretase into soluble (equal in size) polypeptides that are not pathogenic, and (APP) is excreted from the body; in the case of pathology of the genes responsible for the metabolism of APP, the latter is cleaved by beta and gamma secretases into fragments of different lengths. In this case, the formation of insoluble long fragments of amyloid protein (alpha-beta-42) occurs, which are subsequently deposited in the substance (parenchyma) of the brain and the walls of cerebral vessels (stage of diffuse cerebral amyloidosis), which leads to the death of nerve cells. Next, in the brain parenchyma, aggregation of insoluble fragments occurs into a pathological protein - amyloid beta ("nest" deposits of this protein in the brain parenchyma are called senile plaques). Deposition of amyloid protein in cerebral vessels leads to the development of cerebral amyloid angiopathy, which is one of the causes of chronic cerebral ischemia.

read the article: Cerebral amyloid angiopathy(to the website)

Beta-amyloid and insoluble fractions of diffuse amyloid protein have neurotoxic properties. The experiment showed that against the background of cerebral amyloidosis, tissue inflammatory mediators are activated, the release of stimulating mediators (glutamate, aspartate, etc.) increases, and the formation of free radicals increases. The result of this entire complex cascade of events is damage to neuronal membranes, which is indicated by the formation of neurofibrillary tangles (NFTs) within the cells. NSF are fragments of a biochemically altered inner membrane of a neuron and contain hyperphosphorylated tau protein. Normally, tau protein is one of the main proteins in the inner membrane of neurons. The presence of intracellular NSFs indicates irreversible damage to the cell and its rapid death, after which NSFs exit into the intercellular space (“NPS-ghosts”). The neurons surrounding the senile plaques are the first and most affected.

It takes 10-15 years from the onset of amyloid protein deposition in the brain to the development of the first symptoms of the disease - mild forgetfulness. To a large extent, the rate of progression of asthma is determined by the severity of concomitant somatic pathology, vascular risk factors, as well as the intellectual development of the patient. In patients with a high level of education and sufficient intellectual activity, the disease progresses more slowly than in patients with secondary or primary education and insufficient intellectual activity. In this regard, the theory of cognitive reserve was developed, according to which, during intellectual activity, the human brain forms new interneuronal synapses and increasingly larger populations of neurons are involved in the cognitive process. This makes it easier to compensate for cognitive defects even with progressive neurodegeneration.

Diagnosis of amyloidosis. Amyloidosis suspected on the basis of clinical and laboratory data must be confirmed morphologically by the detection of amyloid in tissue biopsies. If AL-type amyloidosis is suspected, a bone marrow puncture is recommended. Most often, to diagnose different types of amyloidosis, a biopsy of the mucous membrane of the rectum, kidney, and liver is performed. A biopsy of the mucous and submucosal layers of the rectum can detect amyloid in 70% of patients, and a kidney biopsy - in almost 100% of cases. In patients with carpal tunnel syndrome, tissue removed during carpal tunnel decompression surgery should be tested for amyloid. To detect amyloid, biopsy material must be stained with Congo red, followed by polarized light microscopy to detect birefringence.

Modern morphological diagnosis of amyloidosis includes not only detection, but also typing of amyloid, since the type of amyloid determines therapeutic tactics. For typing, a test with potassium permanganate is often used. When Congo red-stained preparations are treated with a 5% solution of potassium permanganate, the AA-type amyloid loses its color and loses its birefringence properties, while the AL-type amyloid retains them. The use of alkaline guanidine makes it possible to more accurately differentiate between AA and AL amyloidosis. The most effective method for typing amyloid is immunohistochemical research using antisera to the main types of amyloid protein (specific antibodies against AA protein, light chains of immunoglobulins, transthyretin and beta-2-microglobulin).

note! Amyloidosis is a multisystem disease; damage to only one organ is rarely observed. If the history suggests a combination of symptoms such as general weakness, emaciation, easy bruising, early onset of dyspnea, peripheral edema, sensory changes (carpal tunnel syndrome), or orthostatic hypotension, amyloidosis should be suspected. Hereditary amyloidosis is characterized by a burdened family history of “neuromuscular” lesions of unknown etiology or dementia, Aβ2M amyloidosis is characterized by the use of hemodialysis, and AA amyloidosis is characterized by the presence of a chronic inflammatory process. Also, amyloidosis must be excluded in patients with kidney diseases of unknown origin, especially with nephrotic syndrome, incl. in patients with restrictive cardiomyopathy. Amyloidosis is more likely in the presence of both of these syndromes. In AA amyloidosis, the dominant target organ, in addition to the kidneys, is the liver, therefore, in the differential diagnosis of the causes of severe hepatomegaly in combination with kidney damage, amyloidosis should be excluded.

additional literature:

article “Difficulties in diagnosing and treating AL amyloidosis: review of the literature and own observations” by V.V. Ryzhko, A.A. Klodzinsky, E.Yu. Varlamova, O.M. Sorkina, M.S. Sataeva, I.I. Kalinina, M.Zh. Aleksanyan; Hematological Research Center of the Russian Academy of Medical Sciences, Moscow (journal “Clinical Oncohematology” No. 1, 2009) [