Amyloidosis is a disease that exerts its detrimental effect on the body on the cellular sublevel. During certain reactions, the pathological protein is collected in the tissue cells and gradually, the cell behind the cell, destroys the entire organ structure.
Amyloidosis is dangerous not so much for its general manifestations, as for local lesions. To be more precise, amyloidosis affects important functional structures of the body: liver, heart and kidneys. And since any manifestation of amyloidosis sooner or later will end with the destruction of the normal structure of the body, then, accordingly, serious violations of internal homeostasis will appear in the body.
Amyloidosis in the classification is divided into its smaller subspecies. They are usually allocated to organs that are affected by amyloidosis, and because of its occurrence. For etiology, there is primary amyloidosis and secondary. Primary amyloidosis is exclusively a disease associated with gene disorders. It is this type of amyloidosis that is inherited. Secondary amyloidosis is the result of some disease ("primary cause"), which will lead to its appearance.
Also, amyloidosis can be divided into forms according to the prevalence of protein deposition in tissues: systemic amyloidosis (generalized) and local.
By localization in the affected organs, the following subspecies are distinguished: amyloidosis of the kidneys, amyloidosis of the liver, amyloidosis of the heart, amyloidosis of the intestine, amyloidosis of the skin. The most frequent and dangerous are amyloidosis of the kidneys, liver and heart.
Amyloidosis of the kidneys
Amyloidosis of the kidneys is most often a secondary amyloidosis. Also in the kidneys, only one subspecies of amyloid protein is deposited - AA amyloid. In kidney amyloidosis, the distinctive feature is that cells that synthesize this amyloid become mesangium cells in the glomeruli. In addition, the amount of protein - the progenitor AA of amyloid in the blood plasma sharply increases. In turn, this progenitor of amyloid, along with blood, enters the glomeruli of the kidneys for blood filtration. There, it is captured by special cells and is used by mesangium cells to construct new amyloid structures.
Thus, with kidney amyloidosis, there are two mechanisms for creating a pathological protein directly in the kidney structures: a change in the function of mesangium cells and the production of amyloid cells, an increase in the level of the amyloid precursor in plasma, and the maintenance of additional protein synthesis in mesangiocytes. As a result, the amount of amyloid AA will be enormous.
Of course, this level of amyloid does not affect the body in a positive way, let alone the normal function of the kidneys. This amyloid will be deposited in cells, gradually leading to their death and subsequently the death of the whole organ. From the mesangium cells, the amyloid will spread, and will affect the cells of the basal membrane, through which the blood tends to filter through the capillaries, as well as the same basal membrane of the tubules.
In addition to basal membranes, another favorite site for deposition of amyloid is the arterioles. As a result of all these actions, nephrons (structural units of the kidney) will atrophy and die one after another. On the site of the dead structures, the connective tissue will be synthesized and the kidney itself will diminish in size (an amyloid wrinkled kidney).
In the amyloidosis of the kidney, stages are identified which simultaneously coincide with changes in the kidneys and external clinical processes. These stages are classified from a smaller to a larger development process.
The first stage of amyloidosis of the kidneys is the stage of latent changes. With it, the amyloid protein gradually fills the pyramids (microstructure of the kidneys), the proximal canals and the collecting tubes. There may still not be a pronounced lack of renal function, but in urine analysis it is already possible to find excess protein (proteinuria). Its main feature will be that it will increase with physical exertion and due to the appearance of colds. Plus, an analysis of the protein component of urine will reveal a sharp imbalance between individual protein fractions.
The stage of proteinuric phenomena will follow further in the above-described stage of amyloidosis of the kidneys. With it, the amyloid will gradually capture the glomerular structures of the kidneys. He will fill himself with mesangium, capillary loops and arterioles. It is at this stage of amyloidosis that the sclerosis of their individual structures begins to develop (basically these are the pyramids already described). As a consequence, neurons will be disconnected and the blood and lymph drainage will be disturbed. This will lead to the onset of dystrophic changes in the kidneys.
In the clinic, the patient will have proteinuria, which, unlike the proteinuria of the latent stage, will already be constant and will not depend on any external conditions. In addition to proteinuria, it is still easy to find an imbalance of proteins. New manifestations will be the appearance of cylinders (protein impressions, which are formed in the tubules) and a small number of erythrocytes in the urine (hematuria).
At the stage of nephrotic lesions, the amount of amyloid in the kidney structures continues to increase. It captures most of the glomeruli of the kidney. Continue to appear a lesion of the brain of the kidney. The clinic will begin to develop swelling. The peculiarity of these edemas is that they do not disappear after the administration of diuretics. All the same will be the above described changes in the urine, only proteinuria will become massive. To edema in patients will be added and a significant decrease in the level of blood pressure.
And the last stage of amyloidosis of the kidneys is the stage of azotemia or uremia (similar to that of renal failure). Amyloid sclerosis affects all layers of the kidney. Most nephrons die and are replaced by connective tissue. The clinic will have all the syndromes associated with kidney failure. By the way, kidney failure is the main cause of death of patients with amyloidosis of the kidneys. She threatens them at almost every stage of the disease. In fact, such patients literally every day sit on a "powder keg".
Amyloidosis of the heart
With amyloidosis of the heart, a pathological protein is deposited in its structures. Most often it is deposited in the myocardium, cells of the endocardium. Also, this protein does not bypass the attention and vessels: it can be deposited in the aorta or coronary cardiovascular system of the heart. Most often, amyloidosis of the heart develops with amyloidosis types containing AL-protein.
The main mechanisms for amyloidosis of the heart are the links at which the synthesis of amyloid AL structures occurs. Their detailed pathogenesis is written below, but speaking in general, this protein is synthesized due to disturbances in the synthesis of the right immune cells. This amyloid accumulates in the blood and, apparently, is carried with the blood flow through the organs. Once in the heart, it is deposited mainly in its myocardium and accumulates between the muscle cells. By the way, the constant accumulation of amyloid in the myocardium leads to the fact that its increased mass compresses the intramural arteries and arterioles and causes a lack of nutrition of the heart muscle.
The myocardium filled with amyloid becomes very dense, and most importantly, it loses its ability to stretch. As a result, the cardiac output decreases, the function of the heart is disrupted, and heart failure gradually develops.
And if the amyloid is mostly deposited next to the valve apparatus, then it will cause a bright clinic of valvular defects. That is, the clinical symptomatology of amyloidosis of the heart depends on the place where the amyloid was deposited: for example, if amyloid structures appeared alongside the conducting pathways, there will be signs of conduction disturbance, especially blockade.
Amyloidosis of the heart is characterized by a slow, long course, its symptoms can develop for quite a long time. The disease is sharply manifested after the transferred respiratory infections, stress, overstrain. There may appear a sharp drop in pressure, severe pain, like angina pectoris, or syncope will develop. A selective sign will also be a selective reduction in pressure in the vertical position.
If the disease develops slowly, then gradually develop signs of classical heart failure: shortness of breath, swelling, enlargement of the liver. Such cardiac insufficiency practically does not respond to treatment with cardiac glycosides.
Amyloidosis of the heart also very often accompanies effusions in the pericardial sac, as well as the rapid development of ascites. As already described above, there are violations in the cardiac conduction system: blockade, and especially a specific syndrome of sinus node weakness . This syndrome in patients with amyloidosis can lead to sudden cardiac death.
Amyloidosis of the liver
Amyloidosis of the liver practically never arises by itself. Most often it occurs together with the same amyloid lesions of other organs: the spleen, kidneys, adrenals or intestines.
Most likely, it is caused by immunological disorders or severe purulent infectious and inflammatory diseases. The brightest sign in the manifestation of this disease will be increases in the liver and spleen. Very rarely it is accompanied by any pain symptoms or jaundice. This disease is characterized by an erased clinic and slow progression. At the last stages of the disease, numerous manifestations of hemorrhagic syndrome can develop. In such patients, the protective function of immunity will very quickly decrease, and they will become defenseless before any kinds of infections.
Also characteristic changes in amyloidosis of the liver are exposed to the skin - it becomes pale and dry. Possible manifestations of portal hypertension and subsequent cirrhosis of the liver : amyloidosis gradually kills hepatocytes, and those are replaced by a connective tissue.
The most dangerous complication for such patients will be the development of hepatic insufficiency and hepatic encephalopathy.
The causes of amyloidosis directly depend on its subspecies. If amyloidosis is primary, the cause of its occurrence is solely due to errors in its own genetic code. This kind of amyloidosis is transmitted hereditarily, there are even entire families, where all members are ill with primary amyloidosis.
Secondary amyloidosis, as already mentioned above, is a consequence of primary diseases. Most often, rheumatoid arthritis and Bekhterev's disease lead to its appearance. There is also a high risk for amyloidosis to end with NUK (ulcerative colitis) and Crohn's disease . High ability to stimulate the development of amyloidosis have lymphomas and lymphogranulomatosis . In addition, such pathological conditions as chronic purulent-inflammatory diseases and osteomyelitis also easily lead to the appearance of the first signs of secondary amyloidosis.
The greatest risk for amyloidosis is also affected by those patients who, for certain reasons, are on systemic dialysis. Most often, of course, these are patients with chronic forms of kidney failure. This is because a certain protein during dialysis does not pass through the membrane of the device, accumulates in the body and gradually settles in the cells of the tissue. Over time, this protein will become the basis for amyloidosis.
Some tumors can lead to amyloidosis. This is pancreatic cancer , thyroid cancer , pituitary adenoma and parathyroid glands. The peculiarity of this amyloidosis is that in the cancer of these organs the cells of a special system (APUD) are affected. As a result of the aggression of cancer cells, these apudic cells are destroyed, and their residues become the basis for the formation of the amyloid protein.
But in addition to the main causes (etiology) of amyloidosis, it is also important to know the basic patterns and mechanisms that occur with this disease. You should know that each type of amyloidosis proceeds in its own way. In pathogenesis, it is customary to isolate the types of amyloidosis from its basic protein. The most important are amyloidosis, which contains a protein type AA (it is he that causes amyloidosis of the kidneys described above) and amyloidosis with the protein AL.
Despite different proteins, in amyloidosis it is possible to distinguish the main stages of the process:
- Stage preparation. At this stage a mutation of the cells of the reticuloendothelial structure occurs, and amyloid synthesizers (amyloidoblast) cells appear. It is important to say that each type of amyloid has its own parent cells (eg macrophages or renal mesangium cells)
- Production of amyloid protein by the mother cells and subsequent assembly of its structures
- The final formation of a pathological protein structure in which it combines with specific blood proteins or tissue factors
Interestingly, the course of the course of this subtype is slightly similar with the course of myeloma . Here, in the same way, there is a disruption in the production of "correct" B-lymphocytes and pathological B-lymphocytes appear, which begin to develop chains of the future amyloid. Only in myeloma, these chains were called heavy, and here, in amyloidosis, lightweight immunoglobulin chains are synthesized. Then these chains cease to turn into normal immunoglobulins, disintegrate and collect individual amyloid structures.
It is believed that the main reason for this type of amyloidosis is a decrease in T-lymphocytes and, as a consequence, the number of T-suppressor control cells that can inhibit pathological B lymphocytes decreases. Constant synthesis of pathological chains is also facilitated by the fact that the cell - an amyloid clone, completely loses its cell death ability. This kind of amyloidosis is considered immune dependent.
This subtype is characterized by the presence of the parent cell, which synthesizes the precursor protein protein SAA substance. These maternal cells are macrophages of the liver, spleen or mesangium cells in kidney amyloidosis. In the initial stage, cells intensively synthesize this substance. Due to the fact that this substance is abundant, it does not completely turn into amyloid - the mother cells collect amyloid from separate fragments of this substance. Gradually, during the subsequent stages, the entire substance goes to the assembly of the amyloid molecules.
In this form of amyloidosis there are certain patterns. The first is that the amount of amyloid directly depends on the amount of production of the precursor substance: the higher its synthesis, the more amyloid will be synthesized. The second law is that in amyloidosis AA, the ratio of functional activity between cells synthesizing amyloid and amyloid absorbing cells is disrupted: the function of the latter is greatly reduced. And this means that the destruction of amyloid protein decreases and it is deposited in tissues.
Symptomatic of amyloidosis depends on its subspecies. So, for example, with local amyloidosis, characteristic signs of a violation of the function of individual organs: cardiac, hepatic or renal failure.
In addition, skeletal muscle is often affected. Muscles increase in volume, due to the deposition of amyloid in them. Develops the so-called false hypotrophy (pseudohypotrophy). In addition, the muscles become more dense.
The gastrointestinal tract is also often affected (for example, the amyloidosis of the liver described above). In addition to the liver, amyloidosis can affect the muscles of the tongue. In this case, its increase - macroglossia or "big language" will develop. This symptom will develop in a quarter of patients with amyloidosis. This is a rather serious symptom, because a significant increase in the tongue in volume can cause breathing difficulties. In addition to language, amyloidosis also likes to affect the esophagus or intestines. With lesion of the esophagus, serious disturbances can develop, up to the complete narrowing of its lumen and the inability to pass further to the food-lump chyme.
When intestinal cells are affected, a symptom appears, as is known to all diarrhea . Most often in amyloidosis, it appears due to the fact that the structures of amyloid are located close to the endings of nerve fibers in the intestine and have a permanent stimulating effect on them. If the cells of the small intestine were affected by amyloidosis, then there will be syndromes of impaired intestinal absorption. By the way, this localization is one of the coronary manifestations of AA-containing amyloidosis.
Another place for amyloidosis in the body will be the respiratory tract. Here amyloidosis can affect any of its structures. If his protein is deposited on the vocal cords, then there will be hoarseness of the voice. When amyloid damage to bronchial cells can occur, chronic bronchitis . In the lungs, amyloidosis can mimic tumor processes. Such manifestations are most often the prerogative of AL-containing amyloidosis.
The nervous system can also be exposed to amyloidosis. It is also a sign of AL-containing amyloidosis. There are "amyloid" polyneuropathies: a violation of sensitivity in the affected areas, a decrease in muscle strength and tendon reflexes. When amyloidosis affects the autonomic nervous system, an extremely rich palette of symptoms can develop: a decrease in pressure when taking a vertical position, enuresis and impotence.
And another system affected by amyloidosis is the hematopoiesis system. It depends on which germ in the bone marrow is affected by amyloid. There are violations of the coagulation function and numerous hemorrhages. Like the two syndromes described above, this is also characteristic of AL-containing amyloidosis.
In addition to secondary amyloidosis, there is a clear symptom in primary hereditary amyloidosis. They exhibit turbidity of the vitreous, there is a vivid picture of damage to the peripheral nervous system with sensory-motor disorders, which usually occur from an early age. To this, kidney lesions and lesions of the gastrointestinal tract are also added.
One of the signs of amyloidosis in the initial diagnosis is, of course, clinical and laboratory signs of damage to certain organs. So, in renal amyloidosis, changes in urine analysis are important: various signs of proteinuria, imbalance between protein fractions in urine (disproteinemia) and various levels of erythrocytes in urine.
It is also necessary to look at the clinical signs: swelling and violation of pressure levels. One of the signs that can make you think about the possible presence of amyloidosis is that the patients with amyloidosis of the kidneys will not be swollen even when taking diuretics.
Also it is necessary to take into account the indicators of the level of creatinine clearance and glomerular filtration rate. Especially these signs will be important for determining the presence of the degree and type of renal failure.
When amyloidosis affects the heart, echocardiography and chest X-ray can be performed. And with liver damage, attention should be paid to changes in the protein in the blood plasma (especially alpha2globulin), as well as biochemical indicators: alkaline phosphatase and aminotransferrazy (alanine aminotransferrazy or AlAt). You also need to conduct a liver biopsy and study punctate by staining.
In addition to the diagnostic signs that indicate the inadequacy of the function of a particular organ for the detection of amyloidosis, specific specific reactions are used. The most famous of them is a biopsy of the affected tissue. Subsequently, the biopsy is stained with special dyes and the presence or absence of amyloid protein in it is determined. The most common specific dye for amyloidosis is the Congo-mouth (Congo-red) dye.
In addition, an additional possible index of amyloidosis (most often it is AL-containing amyloidosis) is an increase in the level of plasma cells in the bone marrow biopsy. Most often, the count of plasma cells is combined with their staining with the above-mentioned dye to determine the presence of individual amyloid structures in them. In addition to amyloid in these plasma cells, it is also possible to determine the light chains (using immunohistochemical methods).
It is also important to conduct a series of studies in order to distinguish the two most important types of amyloidosis: AL-containing amyloidosis and AA-containing amyloidosis. Most often for this, the biopsy specimen is stained with Congo red dye, trypsin or potassium permanganate is added to it. Due to exposure to these substances under certain lighting, AA-containing amyloidosis does not refract light rays, and AL-containing amyloidosis does not lose its ability to refract.
Treatment of amyloidosis, like its causes, a clinic or diagnosis depends on the characteristics of each of its subtypes.
In secondary amyloidosis treatment should start with the treatment of primary disease and also try to fill the reduced volume of the function of an organ. So with amyloidosis of the kidneys, a special diet is prescribed. It is distinguished by a small protein content (per 0.8 kg of body weight should account for 0.8 g of protein) and contains a high level of carbohydrates and vitamins (especially much attention is paid to vitamin C). Also it is practically the only diet in which it is allowed to eat sweet: marmalade and pastille. This is necessary in order to increase the caloric intake of food. Extremely restrict the use of protein and salt.
In drug therapy prescribers are prescribed desensitizers (Dimedrol, Suprastin). In order to inhibit the production of amyloid, preparations are prescribed that are part of a series of 4-aminoquinolines. But these drugs have adverse reactions with prolonged use. Therefore, they are prescribed in conjunction with B-vitamins, ascorbic acid and antihistamines.
It is almost impossible to completely stop the development of amyloidosis of the kidneys. But in order to inhibit its progression, experimental schemes using Unithiol or Colchicine are prescribed.
To improve the nitrogen metabolism are prescribed drugs from a number of anabolic steroids. Immunostimulants are also used to increase the strength of the immune system. It is believed that with high activity, the immune system can also slow down the development of amyloidosis of the kidneys.
With a strong nephrotic syndrome, plasma transfusions and the introduction of albumen proteins are made, osmotic diuretics are prescribed (a vivid example of Mannitol).
Cardiac lesions in amyloidosis, as in the case of its kidney variant, are very difficult to cure. The main principle of therapy is the same as with similar kidney lesions - to inhibit the development of the disease and concomitant heart failure as much as possible. Prescribed symptomatic drugs.
With the "dangerous" weakness of the sinus node, surgical therapy can be performed to install an artificial pacemaker.
Therapy for amyloidosis of the liver is similar to that of amyloidosis of the kidneys.
It is believed that AA-containing amyloidosis is practically not treated, and AL-containing amyloidosis, because of its immune dependence, is easier to suppress. For this purpose, cytostatics and glucocorticoids are prescribed. With AA-containing amyloidosis, the main component of all experimental schemes for suppressing its activity is the preparation Colchicine.
In addition to therapeutic methods of treatment, surgical procedures are sometimes used. One of these is the removal of the spleen. It is believed that it is one of the main reservoirs for the content of amyloid protein in the manifestation of amyloidosis and its removal can significantly improve the state of the body.