Symptoms of amyloidosis

The symptoms of amyloidosis are varied and depend on the localization of amyloid deposits and their prevalence. Localized forms of amyloidosis, such as cutaneous amyloidosis, are asymptomatic for a long time, as is senile amyloidosis, in which amyloid deposits in the brain, pancreas, and heart are often detected only at autopsy.

The symptoms of amyloidosis become more pronounced when the kidneys are affected, the most common localization of amyloid. The gradual spread of amyloid deposits and the involvement of the vascular wall in the process cause the development of the leading symptoms of renal amyloidosis. These include increasing proteinuria with the typical occurrence of nephrotic syndrome, a gradual decrease in blood flow, a decrease in glomerular filtration, azotemia, and often nephrogenic arterial hypertension. In cases of secondary amyloidosis, manifestations of the underlying disease in which amyloidosis developed may persist. The clinical picture in this case acquires a peculiar character, in which signs of nephropathy, especially incipient, may be barely noticeable.

Proteinuria, the most important and reliable symptom of renal amyloidosis, develops in all its forms, but is most characteristic and pronounced in secondary amyloidosis, when it occurs in 64-72% of cases. Proteinuria can be detected at different times: both in the first 3 years and after 10 years of the underlying disease. As a rule, proteinuria persists during the development of chronic renal failure, including its terminal stage. Long-term loss of protein by the kidneys, as well as a number of other factors (increased protein breakdown in the body, decreased absorption, and sometimes increased excretion of protein through the gastrointestinal tract) lead to the development of hypoproteinemia with hypoalbuminemia and the associated edema syndrome. The combination of massive proteinuria with severe edema is a characteristic clinical sign of renal amyloidosis. Dysproteinemia develops simultaneously with hypoproteinemia, and sometimes ahead of it. Its nature may depend on the characteristics of the disease in which amyloidosis developed, but amyloidosis itself is often accompanied by a noticeable, although non-specific, change in the ratio between different fractions of plasma proteins. Along with pronounced dysproteinemia, most patients have altered sediment tests, as well as an increase in ESR, which may be a consequence of dysproteinemia.

A very common sign of severe amyloidosis is hyperlipidemia. Increased cholesterol levels with an imbalance in the lipoprotein ratio and an increase in β-lipoproteins and triglycerides in the blood can be quite significant, especially in children, although not to such a high degree as in the nephrotic variant of chronic glomerulonephritis. Hypercholesterolemia usually persists in exhausted patients also in the uremic stage together with high proteinuria and edema. Such a combination of massive proteinuria, hypoproteinemia with hypoalbuminemia, hypercholesterolemia and edema, which make up the classic nephrotic syndrome, is very characteristic of renal amyloidosis. Nephrotic syndrome develops in an average of 60% of patients with renal amyloidosis. Nephrotic syndrome caused by amyloidosis may occur classically or without edema, as well as in combination with arterial hypertension and signs of damage to the liver, spleen, adrenal glands, gastrointestinal tract, and pancreas. The most typical is the gradual development of nephrotic syndrome following a prolonged stage of moderate proteinuria, which can last for a very long time. This distinguishes renal amyloidosis from chronic glomerulonephritis, in which nephrotic syndrome often occurs at the onset of the disease and subsequently recurs. It should be noted that in some patients with amyloidosis, the appearance of this syndrome, provoked by an intercurrent infection, cooling, trauma, drug effects, vaccination, or exacerbation of the underlying disease, may also seem sudden. If the previous stage of amyloidosis was not detected in time, edema and pronounced proteinuria can be mistakenly assessed as signs of acute glomerulonephritis or exacerbation of chronic. The occurrence of nephrotic syndrome, as in other nephropathies, indicates the severity of kidney damage. Its course in amyloidosis is characterized by persistence and early resistance to various diuretics. Spontaneous remissions, although described, are rare. In addition to proteinuria, a number of other changes in urine are detected, constituting the urinary syndrome. They are less significant and, compared with other nephropathies, are poorly expressed. Usually, in accordance with the degree of proteinuria, hyaline and, less often, granular cylinders are detected, giving a sharply positive PAS reaction. They do not have the main properties of amyloid: metachromasia with crystal violet and dichroism. Relatively often, persistent microhematuria is detected, sometimes macrohematuria. Leukocyturia can occur with or without concomitant pyelonephritis. In amyloidosis, lipiduria with the presence of birefringent crystals in the urine sediment can be detected.

The damage to the renal tubular apparatus in amyloidosis has not been sufficiently studied, but amyloid deposition in the renal medulla can lead to polyuria and resistance to vasopressin, difficulty in water reabsorption in the collecting ducts, and tubular acidosis that is not amenable to correction with bicarbonate. In amyloidosis, renal dysfunction does not always reflect the degree of histological amyloid loading. Excretory renal function may be preserved in nephrotic syndrome, which indicates significant amyloid deposits. Usually, renal failure in amyloidosis is no different clinically from chronic renal failure of other etiologies and is characterized by slowly developing azotemia with all its known symptoms. It often occurs in combination with high proteinuria and the absence of nephrogenic arterial hypertension. A rapid decline in glomerular filtration in amyloidosis may be associated with renal vein thrombosis, which may be facilitated by severe dehydration as a result of uncontrolled use of diuretics. Clinical manifestations of kidney damage in hereditary forms of amyloidosis are in many ways reminiscent of nephropathy in secondary amyloidosis, but are usually combined with damage to other organs and systems (symptoms of periodic disease, hypertension syndrome, various allergic manifestations).

Until recently, involvement of the kidneys in the process of primary amyloidosis was not considered characteristic, since damage to other organs and systems (heart, nervous system, gastrointestinal tract) is usually noted. In primary amyloidosis, with the exception of local, the process is always generalized, often with a predominant pathology of one or another organ or system.

Cardiovascular system damage is observed in all patients with primary amyloidosis. Arterial and venous vessels of any caliber may be involved in the process. Heart pathology is characterized by a large number of non-specific signs: shortness of breath, palpitations, chest pain, changes in boundaries and tones, arrhythmias, symptoms of one or another heart defect or myocardial infarction, pericarditis. The ECG picture is also varied and non-specific. It is important to emphasize that heart damage is typical for primary generalized amyloidosis, and heart failure is often the direct cause of death. In case of unclear etiology of heart failure, especially in elderly patients, and its resistance to treatment, cardiac amyloidosis should always be considered.

Lung damage is observed in half of patients and is manifested by dyspnea, hemoptysis, hemorrhagic infarctions, recurrent pneumonia, pulmonary insufficiency, development of fibrosing alveolitis and alveolar-capillary block. Combination with heart failure aggravates the picture of the disease and complicates the diagnosis of pulmonary pathology, however, progressive dyspnea, recurrent pneumonia along with other clinical signs allow us to suspect pulmonary amyloidosis.

More than half of patients have changes in the gastrointestinal tract: abdominal pain, constipation alternating with diarrhea, flatulence, vomiting, nausea, intestinal and gastric atony, amyloid ulcers with the development of peritonitis, etc. Macroglossia with cracks and bedsores is especially typical, the length of the tongue can reach 15 cm or more. An enlarged tongue can lead to dysarthria, salivation, dysphagia, and even complete inability to chew and swallow food.

Lesions of the spleen and lymph nodes also occur in half of the patients. A marked increase in lymph nodes usually serves as a basis for suspecting lymphogranulomatosis, sarcoidosis, tuberculosis, but it is also worth considering the probability of amyloid genesis of the enlargement of the latter. Involvement of the liver and spleen in the process is characterized by an increase and compaction of the organs with little pain and relative preservation of functions. Casuistic cases may include the occurrence of portal hypertension and liver failure. Lesions of the adrenal glands can be suspected with persistent hypotension and adynamia. Arterial hypertension is extremely rare because kidney damage, unlike secondary amyloidosis, is less common (about 40%) and less pronounced.

When the pancreas is affected, latent diabetes mellitus and changes in the activity of pancreatic enzymes may develop. Neurological symptoms characteristic of certain forms of hereditary primary amyloidosis may appear in the terminal (uremic) stage of the disease in secondary amyloidosis.

In amyloidosis, hyperfibrinogenemia, thrombocytosis, anemia (more often in chronic renal failure or as a manifestation of the disease in which amyloidosis developed), bone marrow plasmacytosis, an increase in the content of hexosamines and a decrease in the level of calcium in the blood serum are also observed.

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