Amyloidosis is a general, systemic disease of the body, in which a specific glycoprotein (amyloid) is deposited in organs and tissues with impaired function of the latter. With amyloidosis, the kidneys (nephrotic syndrome, edematous syndrome), heart (heart failure, arrhythmias), gastrointestinal tract, musculoskeletal system, skin can be affected. Possible development of polyserositis, hemorrhagic syndrome, mental disorders. Reliable diagnosis facilitated by the detection of amyloid in biopsy samples of affected tissues. For the treatment of amyloidosis, immunosuppressive and symptomatic therapy is performed; according to indications, peritoneal dialysis, kidney and liver transplantation.
ICD 10
E85 Amyloidosis
Meaning
Amyloidosis is a disease from the group of systemic dysproteinosis that occurs with the formation and accumulation in tissues of a complex protein-polysaccharide compound – amyloid. The prevalence in the world is largely geographically determined: for example, periodic disease is more common in the countries of the Mediterranean basin; amyloid polyneuropathy – in Japan, Italy, Sweden, Portugal, etc. The average frequency of amyloidosis in the population is 1 case per 50 thousand population. The disease usually develops in people older than 50-60 years. Considering the fact that almost all organ systems are affected the disease is studied by various medical disciplines: rheumatology, urology, cardiology, gastroenterology, neurology, etc.
Causes
The etiology of primary amyloidosis has not been fully studied. At the same time, it is known that secondary amyloidosis is usually associated with chronic infectious (tuberculosis, syphilis, actinomycosis) and purulent-inflammatory diseases (osteomyelitis, bronchiectatic disease, bacterial endocarditis, etc.), less often – tumor processes (lymphogranulomatosis, leukemia, cancer of visceral organs). Reactive amyloidosis can develop in patients with atherosclerosis, psoriasis, rheumatology (rheumatoid arthritis, Bekhterev’s disease), chronic inflammation (ulcerative colitis, Crohn’s disease), multisystem lesions (Whipple’s disease, sarcoidosis). Among the factors contributing to the development of amyloidosis, hyperglobulinemia, impaired functioning of cellular immunity, genetic predisposition, etc. are of paramount importance.
Pathogenesis
Among the numerous versions of amyloidogenesis, the theory of dysproteinosis, local cellular genesis, immunological and mutational theories have the largest number of supporters. The theory of local cellular genesis considers only the processes occurring at the cellular level (the formation of fibrillar precursors of amyloid by the macrophage system), while the formation and accumulation of amyloid occurs outside the cell. Therefore, the theory of local cellular genesis cannot be considered exhaustive.
According to the theory of dysproteinosis, amyloid is a product of abnormal protein metabolism. The main links in the pathogenesis of amyloidosis – dysproteinemia and hyperfibrinogenemia contribute to the accumulation of coarse fractions of protein and paraproteins in plasma. The immunological theory of the origin of amyloidosis links the formation of amyloid with the antigen-antibody reaction, in which the antigens are foreign proteins or decay products of their own tissues. In this case, the deposition of amyloid occurs mainly at the sites of the formation of antibodies and an excess of antigens. The most universal is the mutational theory of amyloidosis, which takes into account a huge variety of mutagenic factors that have the ability to cause abnormal protein synthesis.
Amyloid is a complex glycoprotein consisting of fibrillar and globular proteins closely related to polysaccharides. Amyloid deposits accumulate in the intima and adventitia of blood vessels, stroma of parenchymal organs, glandular structures, etc. With minor deposits of amyloid, changes are detected only at the microscopic level and do not lead to functional disorders. Pronounced accumulation of amyloid is accompanied by macroscopic changes in the affected organ (increase in volume, greasy or waxy appearance). In the outcome of amyloidosis, stroma sclerosis and atrophy of the parenchyma of organs develop, their clinically significant functional insufficiency.
Classification
According to the causes, primary (idiopathic), secondary (reactive, acquired), hereditary (familial, genetic) and senile amyloidosis are distinguished. There are various forms of hereditary amyloidosis: Mediterranean fever, or periodic illness (attacks of fever, abdominal pain, constipation, diarrhea, pleurisy, arthritis, skin rashes), Portuguese neuropathic amyloidosis (peripheral polyneuropathy, impotence, cardiac conduction disorders), Finnish type (corneal atrophy, cranial neuropathy), Danish variant (cardiopathic amyloidosis) and many others.
Depending on the predominant lesion of organs and systems, nephropathic (amyloidosis of the kidneys), cardiopathic (of the heart), neuropathic (of the nervous system), hepatopathic (of the liver), epinephropathic (of the adrenal glands), ARP-amyloidosis, of the skin and a mixed type of disease are distinguished. In addition, in international practice it is customary to distinguish between local and generalized (systemic) amyloidosis. Localized forms, usually developing in elderly people, include amyloidosis in Alzheimer’s disease, type 2 diabetes mellitus, endocrine tumors, tumors of the skin, bladder, etc. Depending on the biochemical composition of amyloid fibrils, the following types are distinguished among the systemic forms:
- AL – Ig light chains in the fibrils (in Waldenstrom’s disease, myeloma, malignant lymphomas);
- AA – in the composition of fibrils acute-phase serum α-globulin, similar in its characteristics to C-reactive protein (with tumor and rheumatic diseases, periodic illness, etc.);
- Aß2M– in the composition of fibrils β2-microglobulin (with chronic renal failure in patients on hemodialysis);
- ATTR is a transport protein transtyretin in the fibrils (in familial hereditary and senile forms of amyloidosis).
Symptoms
Clinical manifestations of amyloidosis are diverse and depend on the severity and localization of amyloid deposits, the biochemical composition of amyloid, the “length of service” of the disease, the degree of organ dysfunction. In the latent stage of amyloidosis, when amyloid deposits can only be detected microscopically, there are no symptoms. With the development and progression of functional insufficiency of an organ, clinical signs of the disease increase.
With amyloidosis of the kidneys, the long-term current stage of moderate proteinuria is replaced by the development of nephrotic syndrome. The transition to the advanced stage may be associated with an intercurrent infection, vaccination, hypothermia, exacerbation of the underlying disease. Edema gradually increases (first on the legs, and then on the whole body), nephrogenic arterial hypertension and renal insufficiency develop. Possible occurrence of renal vein thrombosis. Massive protein loss is accompanied by hypoproteinemia, hyperfibrinogenemia, hyperlipidemia, azotemia. Micro-, sometimes macrohematuria, leukocyturia are detected in the urine. In general, during kidney amyloidosis, an early non-edematous stage, an edematous stage, and a uremic (cachectic) stage are distinguished.
Amyloidosis of the heart proceeds according to the type of restrictive cardiomyopathy with typical clinical signs – cardiomegaly, arrhythmia, progressive heart failure. Patients complain of shortness of breath, swelling, weakness that occurs with minor physical exertion. Less often, amyloidosis of the heart develops polyserositis (ascites, exudative pleurisy and pericarditis).
The defeat of the gastrointestinal tract in amyloidosis is characterized by amyloid infiltration of the tongue (macroglass), esophagus (rigidity and violation of peristalsis), stomach (heartburn, nausea), intestines (constipation, diarrhea, malabsorption syndrome, intestinal obstruction). Gastrointestinal bleeding may occur at various levels. With amyloid infiltration of the liver, hepatomegaly, cholestasis, portal hypertension develops. The defeat of the pancreas in amyloidosis is usually masked as chronic pancreatitis.
Amyloidosis of the skin occurs with the appearance of multiple waxy plaques (papules, nodules) in the face, neck, and natural skin folds. According to external signs, the skin lesion may resemble scleroderma, neurodermatitis or lichen planus. For amyloid lesions of the musculoskeletal system, the development of symmetrical polyarthritis, carpal tunnel syndrome, shoulder periarthritis, myopathy is typical. Some forms of amyloidosis that occur with the involvement of the nervous system may be accompanied by polyneuropathy, paralysis of the lower extremities, headache, dizziness, orthostatic hypotension, sweating, dementia, etc.
Diagnostics
Various clinicians may encounter clinical manifestations of amyloidosis: rheumatologists, urologists, cardiologists, gastroenterologists, neurologists, dermatologists, therapists, etc. Of paramount importance for the correct diagnosis is a comprehensive assessment of clinical and anamnestic signs, conducting a comprehensive laboratory and instrumental examination.
In order to assess the functional state of the cardiovascular system, an EchoCG, an ECG is prescribed. Examination of the digestive tract organs involves ultrasound of the abdominal cavity, X-ray diagnostics (radiography of the esophagus, stomach, irrigation, radiography of the barium passage), endoscopic examinations (EGDS, rectoromanoscopy). Amyloidosis should be considered when combining proteinuria, leukocyturia, cylindruria with hypoproteinemia, hyperlipidemia (increased cholesterol, lipoproteins, triglycerides in the blood), hyponatremia and hypocalcemia, anemia, and a decrease in the number of platelets. Electrophoresis of blood serum and urine allows to determine the presence of paraproteins.
The final diagnosis is possible after the detection of amyloid fibrils in the affected tissues. For this purpose, a biopsy of the kidney, lymph nodes, gums, gastric mucosa, rectum can be performed. The establishment of the hereditary nature of amyloidosis is facilitated by a thorough medical and genetic analysis of the pedigree.
Treatment
The lack of completeness of knowledge about the etiology and pathogenesis of the disease causes difficulties associated with the treatment of amyloidosis. In secondary amyloidosis, active therapy of the background disease is important. Dietary recommendations suggest limiting the intake of table salt and protein, including raw liver in the diet. Symptomatic therapy of amyloidosis depends on the presence and severity of certain clinical manifestations. As pathogenetic therapy, drugs of the 4-aminoquinoline series (chloroquine), dimethyl sulfoxide, unithiol, colchicine can be prescribed. For the treatment of primary amyloidosis, treatment regimens with cytostatics and hormones (melfolan + prednisolone, vincristine + doxorubicin + dexamethasone) are used. With the development of CRF, hemodialysis or peritoneal dialysis is indicated. In some cases, the question of kidney or liver transplantation is raised.
Forecast
The course of amyloidosis is progressive, almost irreversible. The disease can be aggravated by amyloid ulcers of the esophagus and stomach, bleeding, liver failure, diabetes mellitus, etc. With the development of chronic renal failure, the average life expectancy of patients is about 1 year; with the development of heart failure – about 4 months. The prognosis of secondary amyloidosis is determined by the possibility of therapy of the underlying disease. A more severe course is observed in elderly patients.
Literature
- Gillmore JD, Hawkins PN. / Drug Insight: emerging therapies for amyloidosis. link
- Pepys MB. / Pathogenesis, diagnosis and treatment of systemic amyloidosis.
- Hirschfield GM, Hawkins PN. / Amyloidosis: new strategies for treatment. link
- Martinez-Rivas G, Bender S, Sirac C. / Understanding AL amyloidosis with a little help from in vivo models. link
