What is amyloidosis

"Amyloid" called R. Virchow in 1854 a special identical substance found in the tissues of the internal organs of patients who died from syphilis, tuberculosis, and actinomycosis. It was described as starch, stained with iodine. A century later, Cohen proved the protein nature of amyloid.

The term "amyloidosis" combines a group of diseases associated with the deposition in the parenchyma of a glycoprotein, represented by fibrillar and globular type proteins. Polysaccharide is included in the structure. Diseases are caused by amyloid disorder of the structure and function of the internal organs. Treatment of amyloidosis to date is an unsolvable task for scientists.

Prevalence of the disease

The frequency of amyloid damage increases with age. Since the diagnosis presents significant difficulties, the most accurate data are obtained from the statistical reports of pathologists.

It turns out that in different countries the detection is significantly different:

• in Japan, 0.1% of all autopsies are found;
• in Israel - 0.55%;
• in Spain - 1,9%.

The most acceptable explanation of the fact of different distribution of amyloidosis is the peculiarities of nutrition of the population

The most frequent lesion localization are kidneys (according to data of different authors, from 1.4 to 1.9% of all autopsies).

Theories of development

The causes of amyloidosis remain unclear. All studies of etiology are reduced to three theories.

The theory of local cellular changes in Tailum

Gives explanations for the occurrence of amyloid at the cellular level. Considers that the process passes through 2 phases:

• predamyloid - the cells of the reticuloendothelial system grow intensively (proliferation), turn into a special species enriched with ribonucleic acid;
• amyloid - cell proliferation is depleted, special polysaccharide-containing structures appear, they synthesize the fibrillar precursor protein of amyloid, and the amyloid itself is formed outside the cell by connective tissue fibers.

A number of clinical facts support this view:

• special selective localization of lesions in the reticuloendothelial system of the liver, spleen;
• the possibility of growing a specific protein in tissue culture.

But the theory is not recognized by specialists as universal.

The Immunological Theory of Leszek-Letterer

He believes that the amyloid is obtained as a result of the antigen-antibody reaction. Antigen is a foreign protein, amyloid occurs when there is insufficient production of qualitative antibodies, an excess of antigens. Now indicate the probability of autoantibodies to the body's own structures. For this theory they say:

• the presence of hypergammaglobulinemia in the blood in patients in the presamyloid stage, the fall of globulins upon the appearance of amyloid;
• characteristic changes in internal organs, where antibodies are deposited.

But how then to explain the development of amyloidosis in persons with a very low level of gamma globulins?

Theory of Capsley disproteinosis

He sees in the amyloid the product of the impaired metabolism of proteins, the anomaly of synthesis, the accumulation of coarse fractions. This direction of development is indicated by the appearance of a high level of fibrinogen.

All theories need further study and refinement. Modern scientists are increasingly convinced that it is impossible to find a single theoretical basis for explaining the disease. This is probably due to the absence of one disease, the presence of several types of amyloidosis.

Pathological anatomy and histological signs

Amyloid deposits are localized:

• in the walls of lymphatic and blood vessels;
• in the inner shell of the vessels;
• organs along the reticular and collagen fibers;
• capsule of glandular formations.

Morphogenesis of amyloid deposits is distinguished:

• on loss among the cells (fibroblasts, reticular) - peri-reticular - is located mainly in the stroma of the spleen, kidneys, liver, adrenals, in the vessels, intestines (also called parenchymal amyloidosis);
• connection with collagen fibers - pericollagenic - typical damage to the inner shell of vessels, myocardium, smooth and striated muscles, skin, nerve trunks (systemic or mesenchymal amyloidosis).

The macro preparation of the affected organ has enlarged dimensions, the density of the tree, greasy or waxy cover. Pathologists have characteristic terms: for example, "sebaceous kidney", the organ on the cut does not have clear boundaries of the cortical and cerebral layer, is increased in volume and by weight.

Amyloid is painted in a red shade, for the sake of persuasiveness, it is recommended to look at the sections in polarized light

Small sections of deposits do not change the appearance of the organs, are detected only with biopsy, do not disrupt the function. Progressive process leads to atrophy of parenchymal tissues and replacement of them with sclerotic tissues followed by wrinkling of organs.

Common signs for all forms of amyloidosis are:

• disproteinemia, a violation of the protein composition of the blood, as a consequence of altered metabolism;
• the same microscopic initial changes in the pre-amyloid phase;
• transformation of cells of the reticuloendothelial species into fibrillar (thread) structures;
• a single biochemical structure and microscopic form of amyloid.

Classification of amyloidosis

There are several classifications of amyloidosis. In 1935 it was proposed to allocate:

• primary disease (idiopathic variant);
• secondary amyloidosis, which arose against a background of various diseases.

In 1961, Briggs clarified the types of amyloidosis. Primary subdivided:

• on the generalized;
• family;
• respiratory (tumor-like and diffuse).

To the secondary are added:

• cardiac or senile;
• amyloidosis on the background of myeloma;
• local tumor-like form.

The Heller classification of 1966 is more clearly formulated. All species are divided into 3 groups:

• genetic or hereditary;
• acquired forms (analogue of the secondary);
• idiopathic.

Each group is divided into different clinical variants, depending on the primary lesion of target organs. To the hereditary are:

• enzymatic deficiency of protein synthesis in familial Mediterranean fever, the disease is more common in people of Armenian nationality, Arabs and Jews, leads to kidney failure;
• Cardiopathic form with heart damage and fatal outcome from heart failure.

A later classification of Gafni suggests three clinical and morphological groups:

• Nephropathic - accompanied by proteinuria (protein in the urine), nephrotic syndrome with edema and uremia;
• neuropathic - is associated with signs of progressive polyneuritis, muscle atrophy, weight loss, digestive disorders due to damage to the stomach and intestines;
• Cardiopathic - differs changes in the myocardium and increasing heart failure.

The causes of secondary (acquired) amyloidosis are:

• specific chronic infections (tuberculosis, syphilis);
• prolonged suppuration (osteomyelitis, bronchiectasis);
• psoriatic and rheumatoid arthritis;
• nonspecific ulcerative colitis;
• Bechterew's disease;
• cancerous tumors;
• lymphogranulomatosis.

The specialist is able to find out the mechanism of development of pathology

Local or local amyloidosis refers to primary forms. The peculiarity of pathogenesis is the primary lesion:

• mucous membrane of the nasopharynx;
• vocal cords;
• tracheobronchial tree;
• the walls of the ureter and bladder;
• fatty tissue of the eyelids;
• language;
• skin.

Amyloid forms tumor structures on these sites. When senile form is more common triad lesions:

• amyloidosis of the brain;
• islets of Langerhans, producing insulin in the pancreas;
• heart.

Modern approach to the definition of type and clinical characteristics of forms

Modern studies of the composition of amyloid made it possible to distinguish differences in the protein part of the substance. The World Health Organization, in its clinical recommendations, uses the 1993 classification, taking these properties into account. In the formulation of the diagnosis, A (from "amyloid") is first indicated, followed by an abbreviation of several initial letters of the English name of protein molecules and a specific form of the disease.

The relationship between the nature of amyloid and the forms of pathology listed above has been established. For example:

• AA-amyloidosis is a secondary process caused by increased synthesis in the liver of a particular protein from the alpha-globulin group as a response to any chronic inflammatory disease;
• ASC-amyloidosis is a cardiovascular form of a disease that affects elderly people;
• AL-amyloidosis - refers to the primary pathology, in which in any organ are deposited light chains of immunoglobulins;
• AF-amyloidosis - means hereditary Mediterranean fever;
• AH-amyloidosis - is detected only in people who have been treated with hemodialysis, the device is not able to fully utilize the accumulation of a certain microglobulin;
• Aβ-amyloidosis - found in Alzheimer's disease, rarely inherited.

This classification is very cumbersome. Each form includes subspecies. The AA- and AL-forms have the greatest practical significance in the frequency of injury. Therefore, we will consider the symptoms of the disease for these types of protein mutations.

Renal damage

Kidneys are the most frequently affected organ in both primary and secondary amyloidosis. Nephrotic syndrome is formed in 60% of patients.

At the initial stage, the amyloid is deposited in the stroma around the basal membrane, then penetrates through it into the Shumlyansky-Bowman chamber

Expanding, the pathological protein squeezes capillary glomeruli, settles in a capsule of the kidney, vascular walls.

1. In the latent stage, the patient has unstable protein in the urine (proteinuria), erythrocytes and leukocytes.
2. Proteinuricheskaya phase - is characterized by the constant release of protein in the urine, its loss in the blood, the growth of aldosterone synthesis.
3. The development of persistent nephrotic edema indicates a nephrotic stage.
4. Azotemia is an irreversible end of kidney damage, nitrogenous substances (creatinine, urea) that act like poisons, poison organs and tissues accumulate in the blood.

The time of formation of a nephrotic syndrome is individual. In this case, not all patients have symptomatic hypertension (revealed in 10-20%). This is due to reduced production of renin. An important sign in diagnosis is the detection of enlarged or unchanged kidney size on ultrasound, despite the gradual replacement with scar tissue and impaired function.

Symptoms that indicate kidney damage:

• increasing weakness;
• loss of appetite;
• swelling first on the legs and feet, then all over the body;
• pain in the lower back;
• dyspnea;
• bloating and stool disorders (diarrhea);
• decrease in urination (oliguria), is replaced in the final stage by polyuria (a significant amount of excreted urine).

In addition to the massive loss of protein in the urine, in the patient's analyzes,

• increase in cholesterol;
• increased blood coagulability (provokes thrombosis of the kidney vessels);
• anemia and leukocytosis;
• violation of electrolyte composition, causing acidification of tissues (acidosis).

Disorders of the digestive system

Liver involvement is the third most common target organ in amyloidosis (after kidney and spleen). Signs are found in 50% of patients with AA-amyloidosis, in 80% with AL-amyloidosis. In patients, a significant increase in the liver is detected, palpation is determined by a painless, dense, pointed edge.

The amyloid is deposited between the hepatic lobules

Dysfunctions are rare (jaundice and signs of portal hypertension). In biochemical blood tests, no deviations in the content of transferases are detected. The liver is characterized by the ability to contract to normal size with the reverse development of the process.

Signs of the pathology of other organs of the digestive system are difficult to relate to amyloidosis against the background of already existing chronic diseases. Patient's complaints are not typical. People are concerned:

• bloating (flatulence);
• decreased appetite;
• propensity to diarrhea.

Malabsorption syndrome - a violation of absorption from the intestine, arises from the deposition of amyloid in the wall of the intestine. Diarrheas are caused by:

• swelling of the mucous membrane;
• intestinal dysbiosis;
• consequences of uremic changes.

Aetonic constipation contributes to the deposition of amyloid and thickening of the intestinal wall with a loss of ability to contract. Less frequent manifestations include:

• a sharp increase in the tongue (macroglossia), is detected in 22% of patients, makes it difficult to talk, swallow food, at night, possible sinking and asphyxiation from blocking the airways;
• amyloid damage to the esophagus and stomach with intense pain in the epigastrium, nausea, vomiting, detecting tumor-like formation;
• violation of blood supply to the stomach or intestine with a local infarction, necrosis, ulceration, a picture of intestinal bleeding due to deposition of amyloid in feeding vessels;
• involvement of the pancreas with a slight increase in glucose in the blood, transient disorders in the synthesis of enzymes.

Chicken liver contains substances that activate the synthesis of normal protein

Heart Attack

The most common signs are revealed in the AL-type of amyloidosis. The deposition of protein in the myocardium is accompanied by an increase in tissue density and a decrease in elasticity, disrupting, in the first place, diastolic relaxation.

The growth of the heart (cadio-megalemia) and heart failure become the most frequent cause of death (in 40% of cases). With the defeat of coronary vessels, a clinic of myocardial infarction is developing. The violation of the valve reduction in the clinic resembles heart defects. Possible the development of constrictive pericarditis. According to the ECG, focal changes, wall thickening, rhythm disturbances, blockades are established.

How does the pathology of other organs manifest itself?

Breathing organs suffer in half of patients with AL-amyloidosis, in every tenth case of AA-type. Symptoms are detected early:

• hoarseness of voice (amyloid is in the vocal cords);
• tracheobronchitis with cough;
• alveolitis in the lung tissue with the formation of infiltrates (pneumonia), atelectasis (air does not pass through the overlapped small bronchioles and part of the respiratory surface subsides).

The defeat of the nervous system along the peripheral trunks manifests itself:

• symmetrical violation of sensitivity, movements;
• disorder of the sphincter of internal organs;
• orthostatic hypotension;
• impotence in men.

From the side of the brain, pathology is rarely detected. Joint lesions are associated with a dialysis form of amyloidosis. The combination with the deposits in the muscles leads to immobility of the patient. On the skin, the changes look like:

• nodules;
• papules;
• infiltrates with violation of trophism;
• sites of albinism.

Nodules can be located on the skin of the eyelids, causing hemorrhages

How is diagnostics performed?

An accurate diagnosis should confirm the presence of an altered amyloid protein. Laboratory tests indicate a violation of the function of organs, but are not specific. Samples are used with the introduction into the blood of dyes absorbed by amyloid, and then monitor its excretion in the urine or concentration in the blood.

The most reliable method is biopsy. Begin with sampling from the gums, epithelium of the rectum. To detect AL-amyloidosis, examine the puncture of the bone marrow or fatty tissue from the abdomen. Puncture of the liver, kidneys. The spleen is performed when differential diagnosis is required with other diseases. The method of scintigraphy with labeled iodine allows to reveal the distribution of amyloid throughout the body.

How is amyloidosis treated?

For therapy, it is necessary to inhibit the formation of a pathological protein. The method of adherence to the diet with the intake of liver meat remains in force (raw is better than after treatment). It is believed that it contains natural components that restore proper protein synthesis. The alternation of liver administration and the administration of Sirepas is common.

Secondary amyloidosis requires treatment of the underlying disease by any available methods. Preparations from the group of aminoquinoline derivatives are able to inhibit the production of myofibrils. Apply:

• Delagil;
• Plaquenil;
• Rezokhin;
• Khingamin.

For the destruction of sulfhydryl groups of myofibrils, an intravenous solution of Unithiol

Patients are treated with Dimexide, Colchicine, immunomodulators. Patients have to take many medications for life. To more "aggressive" methods include chemotherapy regimens with combinations of cytostatics and steroid hormones. The primary task in a particular situation may be to fight with bleeding, eliminate edema. Amyloidosis of the liver and kidneys requires an organ transplant operation.

Difficulties in diagnosing a disease often make it difficult to prescribe a timely treatment. The disease is recognized only at a late stage, when many organs are involved in the pathological process. Doctors need attention to unusual symptoms of other diseases, and from patients - a patient attitude towards the survey.