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15. Bandazhevskyi Yu.I., Dubova N.F. The Role of Genome of Folate Metabolism in the Occurrence of Hyperhomocysteinemia in Children from the Areas Affected by the Chornobyl Nuclear Power Plant Accident. Scientific and Practical Collection «Chornobyl: Ecology and Health». Ivankiv: PI Coordination and Analytical Center «Ecology and health» ; Dnipro: Serednyak T.K. ; 2017 ; 6 : 27-35.
16. Zhang X., Liu T., Li Y and Li S. Association between MTHFR 677C/T and 1298A/C Gene Polymorphisms and Breast Cancer Risk. Genet. Mol. Res. 2015 ; 14 (4) : 16425-16430.
17. Grechanina E.Ya., Malaton R., Grechanina Yu.B. et al. Nasledstvennye narusheniya obmena serosoderzhashchikh aminokislot [Hereditary Metabolic Disorders of Sulfur-Containing Amino Acids]. Rossiyskiy vestnik perinatalogii i pediatrii. 2008 ; 6 : 57-65 (in Russian).
18. Vayner A.S., Kudryavtseva E.A., Zhechev D.A. et al. Issledovaniye assotsiatsii polimorfizma genovfolatnogo obmena s riskom vrozhden-nykh anomaliy razvitiya [Study of the Association of Folate Metabolism Gene Polymorphism with the Risk of Congenital Malformations]. Mat I ditya v Kuzbasse. 2011 ; 3 (46) : 10-16 (in Russian).
19. Bandazhevskyi Yu.I. and Dubova N.F. Pozhezhi lisu v Chornobylskii zoni vidchuzhen-nia ta zdorovia ditei [Forest Fires in the Chornobyl Exclusion Zone and Children's Health]. Ivankiv, Ukraine : Coordination Analytical Center «Ecology and Health»; Dnipro, Ukraine : Serednyak T.K. ; 2020 : 42 p. (in Ukrainian).
Haa 'Mwno go pegaKW 14.11.2020
УДК 612.354:616.36-055: 616-001.28
https://doi.org/10.32402/ dovkil2021.01.035
ЗАКОНОМ1РНОСТ1 ФОРМУВАННЯ ЗАХВОРЮВАНЬ ПЕЧ1НКИ У ПОСТРАЖДАЛИХ ВНАСЛ1ДОК АВАР11 НА ЧОРНОБИЛЬСЬК1Й АЕС
Чумак А.А., Сарюсова Е.О., Альохша С.М., Медведовська Н.В., Овсяншкова Л.М., Малишевська 6.М.
PATTERNS OF LIVER DISEASE FORMATION IN VICTIMS OF THE CHORNOBYL NUCLEAR POWER PLANT ACCIDENT
1CHUMAK A.A., 1SARKISOVA E.O., 1ALEKHINA S.M., 2MEDVEDOVSKA N.V., 12OVSIANNIKOVA L.M., 12MALYSHEVSKA Y.M 1State Institution «National Research Center for Radiation Medicine of the NAMS of Ukraine» 2Scientific Coordination Department of the National Academy of Medical Sciences , of Ukraine
Non-alcoholic fatty liver disease (NAFLD) is a problem not only of modern hepatology, but also has a global importance for the state of human health, which is both due to the broad reach and the consequences of the progression of this pathology - the development of the liver cirrhosis, hepato-cellular carcinoma, liver-cell deficiency [1].
ЗАКОНОМ1РНОСТ1 ФОРМУВАННЯ ЗАХВОРЮВАНЬ ПЕЧ1НКИ У ПОСТРАЖДАЛИХ ВНАСЛ1ДОК АВАР11 НА ЧОРНОБИЛЬСЬКЙ АЕС 1 Чумак А.А., 1 Сарюсова Е.О., 1Апьохна С.М., 2Медведовська Н.В., 1,2Овсяннкова Л.М., 12Мапишевська €.М.
1ДУ «Нацональний науковий центр ралашйно! медицини НАМН Укра)ни», м. Ки)в
2Науково-координашйне управлння НАМН Укра)ни, м. Ки)в
Метою доспдження стало визначення механ'зм'в форму-вання та прогре^ентност хро^чних дифузних захворювань печiнки у постраждалих внаслдок авар) на ЧАЕС з розробкою д1агностичних критерпв фiброзних змн з цею патологею. Матер'апами доспдження були результати обстеження та лiкування в умовах клiнiки ДУ «ННЦРМ НАМН Укра)ни» постраждалих внасл'щок Чорнобильсько) катастрофи, 57 з яких, за критерiями включення та виключення, було в'щне-сено до основно) групи.
Методи доспдження: загальноклМчне обстеження, iнструментальнi дослдження (ультразвукова дiагностика органе черевно) порожнини), бiохiмiчнi, медико-статистич-нi, iнформацiйно-аналiтичнi.
Резупьтати доспдження. Доведено, що у постраждалих внасл'щок Чорнобильсько) катастрофи основною патологею печiнки е неалкогольна жирова хвороба печiнки (НАЖХП), на тл'1 яко) розвиваеться виражене порушення жирового обм '1ну, достов'рне зниження холестерину, бета-лпопроте)-дiв, що можна вважати маркером розвитку цирозу в УЛНА, хворих на НАЖХП; наведено чинники прогресування цирозу з манiфестацiею захворювання на стади декомпенсацИ Кпючовi спова: постраждап'1 внаспдок Чорнобипьсько/ катастрофи, хронiчнi дифузш захворювання печнки, НАЖХП, НАСГ.
© ЧумакА.А., Сарюсова Е.О., Апьохна С.М., Медведовська Н.В., Овсяннкова Л. М., Мапишевська е. М. СТАТТЯ, 2021.
Nowadays, the incidence on NAFLD has reached an epidemic scale: it is diagnosed in approximately 20-30% of the adult population, in 70-90% of people with obesity or diabetes, which determines its leading positions in the structure of liver diseases. The disease begins with the development of steatosis, in 12-40% of patients the pathological process proceeds to the next stage, which is characterized by the development of steato-hepatitis and moderate fibro-sis [2].
Risk factors for the progression of NAFLD along with the development of steatohepatitis and fibrosis are considered to be the following: age over 45 years old, obesity (body mass index - BMI >30), diabetes mellitus type 2 (MD), arterial hypertension (AH), hyper-triglyceridemia, as well as the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) greater than
1. It has been proven that for persons with non-alcoholic steatohepatitis (NASH) compared to hepatic steatosis, the prognosis may be less positive due to the high risk of liver cirrhosis [3, 4].
NAFLD usually accompanies metabolic syndrome (MS), in which insulin resistance (IR) becomes the leading link. The WHO Working Group (1998) determined the following group of symptoms as constituent components of the MS: visceral (abdominal, central, android) obesity, IR, hyperinsulinemia, impaired glucose tolerance or MD type 2, dyslipidemia, hemostasis disorders, hyperuricemia, microalbuminuria [5].
Research of the pathogene-sis, etiological factors, and the clinical picture demonstrate that NAFLD is a component of MS, and some scientists consider this pathology to be a factor in the development of MS. Pathological changes in the liver with NASH are associated with activation of lipid peroxidation (LPO) along with inhibition of the functional activity of the antioxidant defense system. This process, together with the formation of active radicals, leads to mitochondria and cell membrane damage [6].
LPO processes are initiators in the progression of systemic inflammation and forced athe-rogenesis, even in the absence of obesity. They have immuno-genic properties and potentiate processes of oxidative modification of biomolecules, both in the hepatocytes themselves and in the peripheral bloodstream, while activating mo-nonuclear phagocytes that release anti-inflammatory mediators. The activity of the main antioxidant protection enzymes (superoxide dismutase and catalase) increases during the NAFLD progression; however, their depletion occurs during the transition to the fibrosis and cirrhosis stage [7].
Thus, oxidative stress against the backdrop of lipid encumbrance on the body contributes to the manifestations of the effects of cytotoxicity and inhibition of fatty acid oxidation, which activates the processes of LPO. The disorder in the composition of lipid membranes is significant for the development of IR and the manifestation of lipotoxicity effects due to the formation of fatty bodies in insulin-dependent tissues, that activate anti-inflammatory and pro-athero-genic mechanisms, thus producing a systemic inflammatory response that aggravates NAFLD with comorbid conditions, involving different organs and the body as an entire system.
In recent decades, patho-genetic mechanisms have been identified, confirming that
NAFLD ought to be considered as a multisystem disease. Comorbid pathology occurs in 80-95% of patients over the age of 60 years old. There is no exception as to those who experienced the effects of the Chornobyl accident factors, which became a negative cause in changes to the state of health of the population over large territories of three countries - Ukraine, Belarus and the Russian Federation. Certain studies based on the analysis of official medical statistics and registers reported on the deterioration in health, increase in number of non-neoplastic diseases, development of respiratory organs, cardiovascular, digestive and endocrine system diseases among the Chornobyl accident clean-up personnel and in population of radiologi-cally contaminated areas [9].
A characteristic feature of the state of health of the Chornobyl accident clean-up personnel is the presence of several chronic diseases, ranging from 5 to 13 diseases recorded concurrently. Among the evacuated population, there is also a noted increase in risks and a reliable increase in the number of non-neoplastic diseases with an increase in the level of doses of external radiation. According to Mironenko T.V. et al (2010), when assessing the somatic status of the Chornobyl accident clean-up personnel who received a dose radiation of up to 0.3 Gy and who suffer from dyscirculatory encephalopathy, there were 4-5 somatic diseases per person examined. Among them, cardiovascular system (65,5-80,0%) and gastrointestinal system (65,075,0%) diseases, muscu-loskeletal system (30,0-50,0 %) and thyroid gland (40,055,0%) pathologies were observed most often [8, 17].
There are reports on a possible dependence between the severity of somatic and mental disorders and the level of dose burden in persons affected by ionizing radiation as a result of the Chornobyl accident [8].
The results of the clinical data
PATTERNS OF LIVER DISEASE FORMATION IN VICTIMS OF THE CHORNOBYL NUCLEAR POWER PLANT ACCIDENT 1ChumakÂ.Â., 1Sarkisova E.O., 1AlekhinaS.М., 2Medvedovska N.V., 1, 2Ovsiannikova L.M., 1,2Malyshevska Y. M 1 State Institution «National Research Center for Radiation Medicine of the NAMS of Ukraine», Kyiv, Ukraine 2Scientific Coordination Department of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
The aim of the study is to determine the mechanisms for the formation and progressivi-ty of chronic diffuse liver diseases in victims of the Chornobyl Nuclear Power Plant accident with the development of a diagnosis criteria for fibrous changes in this pathology. The materials were the results of examination and treatment in the clinic of the State Institution «NRCRM of the NAMS of Ukraine» of victims of the Chornobyl Nuclear Power Plant accident, 57 of which, according to the criteria for switching on and off, were
assigned to the main group. The research methods were: general clinical examination, instrumental studies (ultrasound diagnostics of abdominal organs), biochemical, medical statistics, analytical.
According to the results of the study, it was proved that in the victims of the Chornobyl Nuclear Power Plant accident, the main liver pathology was non-alcoholic fatty liver disease. It has been shown that in patients affected by the Chornobyl disaster, NAFLD develops a pronounced violation of fat metabolism with a reliable decrease in cholesterol and beta-lipoproteins in cirrhosis - a sign of a long-term course of the disease, accompanied not only by the development of fibrosis, but also by a fatty rebirth of liver tissue with low cholesterol and beta-lipoproteins; this can be considered a marker of cirrhosis in the Chornobyl accident clean-up personnel with NAFLD.
Keywords: victims of the Chornobyl Nuclear Power Plant accident, chronic diffuse liver diseases, NAFLD, NASH.
analysis of the changes in the main systems of the organisms of the Chornobyl accident clean-up personnel indicate that they are more often poly-syndromic in nature (hema-toimune, cardiovascular, gas-troenteral, bronchopulmonary and polyneuropathic syndromes with the development of metabolic syndromes of oxidative destruction, insulin and leptin resistance, carbohydrate and lipid metabolism disorders, hormonal changes).
In the period after the accident, there is a persistent tendency towards an increased prevalence of comorbid diseases, the pathogenetic basis of which is considered to be a systemic inflammatory reaction with the alteration of microcir-culatory vessels against the background of oxidative stress, endothelial dysfunction, immu-nopathological and destruc-tive-dystrophic changes [16].
Thus, the above is a convincing evidence as to the relevance of determining the mechanisms for the formation of chronic diffuse liver diseases that lead to irreversible changes in the state of health of the Chornobyl Nuclear Power Plant accident victims.
The aim of the study is to determine the mechanisms for the formation and progressivity of chronic diffuse liver diseases in victims of the Chornobyl Nuclear Power Plant accident with the development of a diagnosis criteria for fibrous changes in this pathology.
The subject of the study was the hepatobiliary system in patients examined and treated at the SI «NRCRM of the NAMS of Ukraine» clinic.
Research materials and methods. The contingent of respondents was represented by the Chornobyl accident
clean-up personnel, evacuees from the 30-km zone and the city of Pripyat and inhabitants of the territories with the strengthened radiation control (territory with the contamination density with isotopes 137Cs from 185 kBk/m2 to 555 kBk/ m2 and/or 90Sr from 5.55 kBk/ m2 to 111 kBk/m2).
The main group included 57 people with NASH and SH and who were affected by the Chornobyl accident. Respondents were represented by males between the ages of 31 and 70 (table 1). The average age of patients was (57,3 ± 1,1)
Table 1
Distribution of patients affected by the Chornobyl Nuclear Power Plant accident, NAFLD stage and complications
Nosology form ICD cipher Number of patients
absolute quantity %
STEATOHEPATOSIS K76 33 57,9
NON-ALCOHOLIC STEATOHEPATITIS OF MINIMAL ACTIVITY K73.9 13 22,8
STEATOSIS HEPATOSPLENOMEGALY K76 R16.2 4 7
NON-ALCOHOLIC STEATOHEPATITIS OF MINIMAL ACTIVITY HEPATOSPLENOMEGALY K73.9 R16.2 6 10,5
NON-ALCOHOLIC STEATOHEPATITIS OF MINIMAL ACTIVITY VARICOSE VEINS OF THE ESOPHAGUS K73.9 R16.2 1 1,8
years old with the predominance of those aged from 51 to 60 years old (43,9%).
Research methods - general clinical examination, instrumental studies (ultrasound diagnostics of abdominal organs), biochemical, medical statistics, analytical.
Ultrasound diagnostics of the abdominal organs was carried out on the following devices: Shiwadzy 410B (Japan), Aloka-2000 (Japan), Aloka-650 (Japan) in accordance with the standard procedure.
The diagnosis of NAFLD was established in patients with signs of metabolic syndrome during an ultrasound examination of the liver: distal echo signal attenuation («bright liver»); increased liver echogenicity compared to kidneys; fuzzy vascular pattern.
The condition of the patients' liver was examined according to the following indicators and conventional laboratory methods: total protein level - by the biuret-ic method, protein fractions - by electrophoresis on cellulose acetate pellice, albumin - by color reaction with bromo-cresol green, bilirubin - by colorimetric method (diazomethode) by Jendrashik, aspartate amino-transferase (AST) and alanine aminotransferase (ALT) activity - by colorimetric kinetic method (Thermo Scientific kits, Finland), gamma-glutamyl transpepti-dases - by colorimetric method («GT liquicolor» set, Human, Germany), alkaline phospha-tase - by the kinetic method on
the Kone Ultra-918 biochemical analyzer, the number of platelets was determined by the unified method of counting in blood smears for Fonio, prothrombin time - by the Quick method, erythrocyte sedimentation rate (ESR) - by the standard method. Serum cholesterol content was determined by Ilk method, thymol sample was carried out by Burstein method.
The status of the LPO processes was evaluated by a method based on spectropho-tometric measurements of iso-propanol extracted unsaturated lipids and lipid peroxidation products (ether-bound phos-pholipid peroxidation products, which are basic POL substrates) from plasma and peripheral blood erythrocytes followed by calculation by formula of conditional quantitative parameters [10-15].
The content of secondary POL products reacting with thiobar-bituric acid (TBA) was determined by the formation of a chromogenic trimethyl complex during the interaction of mal-onic dialdehyde with TBA [11].
Statistical processing of the results of the studies was carried out using the statistical package SPSS (v.16.0 for Windows). The distribution form in the data series was checked using the Kolmogorov-Smirnov test for a single sample. Deviation from the normal distribution was considered significant at p<0,05.
Study results and discussions. According to the abdom-
Table 2
Frequency of detection of signs of liver structure change based on results of ultrasound of abdominal organs of NAFLD patients affected by the Chornobyl Nuclear Power Plant accident
Indicator Number of cases
absolute quantity %
Liver Size Increase 48 84,2
Increased liver echogenicity 50 87,7
Coarse-grained liver pattern 21 36,8
Depletion of vascular pattern 18 31,6
Ultrasonic signal attenuation 5 8,8
Heterogeneous structure 4 7,0
Portal System Wall Compaction 2 3,5
Bright vascular pattern 2 3,5
inal ultrasound of NAFLD patients, liver enlargement was determined in 48 (84,2%) cases (Table 2).
In the clinical picture of NAFLD, for victims of the Chornobyl accident prevailed symptoms of the concomitant pathology of the digestive system - the stomach, duodenum, bile tract, with pain (78,381,6%) and dyspeptic (64,567,8%) syndromes. In NASH, astheno-vegetative syndrome (74,7%), increased blood pressure (74,7%), inflammatory processes (50%) were determined more often than in the comparison group (CG).
Concomitant cerebrovascular and cardiovascular pathology in NAFLD patients affected by the Chornobyl accident was determined concurrently in most cases (77,2%). The most frequent among cerebrovascular diseases (35,5%) cases was dyscirculatory encephalopathy, as well as chronic cerebral circulation disorder (CPMK) -(29,8%) cases. 7% of NAFLD patients suffered with the acute cerebral circulation disorder.
Concomitant cardiovascular pathology in the studied group of patients with NAFLD was represented by hypertension (17%). In 3,4% of patients with NAFLD, rhythm disorders were established - one case of paroxysmal form of atrial fibrillation and one case of extrasys-tolic arrhythmia. Coronary heart disease was detected in 31,6% of patients. Stage I heart failure had 36,8% of patients with NAFLD, stage II A - 5,2%. The diagnosis of aortic atherosclerosis was established in 10,5% of patients.
IA difference was found in the dynamics of inflammatory process indicators in the liver in NAFLD in patients of the main group and the comparison group (CG), the marker of which is the activity of transaminases. AST activity significantly increased in patients with NASH compared to those with SH as in victims of the Chornobyl accident (52,81 ± 3,77) U/L, and in CG (47,51 ± 2,78) U/L. ALT activity in NAFLD patients
ЗАКОНОМЕРНОСТИ ФОРМИРОВАНИЯ ЗАБОЛЕВАНИЙ ПЕЧЕНИ У ПОСТРАДАВШИХ ВСЛЕДСТВИЕ АВАРИИ НА ЧЕРНОБЫЛЬСКОЙ АЭС 1Чумак А.А., 1Саркисова Э.А., 1 Алёхина С.М. 2Медведовская Н.В., 1, 2Овсянникова Л. М., 1, 2Малышевская Е. М. 1ГУ «Национальный научный центр радиационной медицины НАМН Украины» 2Научно-координационное управление НАМН Украины
Целью исследования стало определение механизмов формирования и прогредиент-ности хронических диффузных заболеваний печени у пострадавших вследствие аварии на ЧАЭС с разработкой диагностических критериев фиброзных изменений при этой патологии.
Материалами исследования были результаты обследования и лечения в условиях клиники ГУ «ННЦРМ НАМН Украины» пострадавших вследствие Чернобыльской катастрофы, 57 из которых, по критериям
включения и исключения, были отнесены к основной группе.
Методы исследования: общеклиническое обследование, инструментальные исследования (ультразвуковая диагностика органов брюшной полости), биохимические, медико-статистические, информационно-аналитические.
Результаты исследования доказали, что у пострадавших вследствие Чернобыльской катастрофы основной патологией печени была неалкогольная жировая болезнь печени (НАЖБП), на фоне которой развивалось выраженное нарушение жирового обмена, достоверное снижение холестерина, бета-липопротеидов, что можно считать маркером развития цирроза печени у участников ликвидации последствий аварии на ЧАЭС, больных НАЖБП. Приведены факторы про-грессирования цирроза с манифестацией заболевания на стадии декомпенсации. Ключевые слова: пострадавшие вследствие Чернобыльской катастрофы, хронические диффузные заболевания печени, НАЖБП, НАСГ.
increased with NASH both in the main group (64,24 ± 2,93) U/L and in CG (71,08 ± 4,60) U/L, with a decrease in liver cirrhosis in patients of the main group (58,84 ± 23,35) U/L and in CG -(48,40 ± 16,57) U/L.
In SH patients, AST activity in Chornobyl victims was significantly higher than in CG (27,68 ± 0,93) U/L and (23,34 ± 11,15) U/L, and in liver cirrhosis, AST activity was significantly higher in CG patients - (122,86 ± 42,53) U/L and (86,76 ± 29,68) U/L.
For the Chornobyl disaster clean-up personnel suffering from NAFLD with the development of liver fibrosis, cytolytic syndrome activity was significantly increased with a progressive increase in transaminase activity - AST - (31,25 ± 0,62) U/L, (57,90 ± 11,64) U/L, (159,4 ± 35,21) U/L, ALT -(38,65 ± 1,32) U/L, (68,5 ± 4,20) U/L, (117,25 ± 25,73) U/L, and the Ritis coefficient -AST/ALT - (0,91 ± 0,02), (1,03 ± 0,08), (1,61 ± 0,18). Cholesterol levels were significantly reduce - (5,51 ± 0,17) Mmol/L, (5,34 ±0,33) Mmol/L. The same changes, namely a significant decrease in beta-lipoproteins level in blood were observed in these groups of
patients - (48,69 ± 3,08) U/L, (45,42 ± 3,25) U/L.
Cholestasis syndromes were formed with a reliable increase in the activity of the enzyme gamma-glutamyl transpeptidase (GGTP) - (39,15 ± 3,25) U/l, (82,41 ± 12,38) U/l, (139,92 ± 31,29) U/l, hepatic cell failure with a progressive increase in bilirubin (14,19 ± 0,53) Mmol/L, (17,07 ± 1,12) Mmol/L, (22,64 ± 3,16) Mmol/L, as well as impaired protein synthesizing liver function with reduced albumin (36,3 ± 1,86) g/l, and an increase in the acute phase protein alpha 2-macroglobulin (2,76 ± 0,45) g/l, which activates astrocytes and stimulates fibrogenesis, the development of dyspro-teinemia and mesenchymal-inflammatory changes with a gradual increase in the thymol sample with reliability at the stage of pronounced fibrotic changes (2,39 ± 0,53) units, (2,70 ± 0,28) units, (4,49 ± 0,77) units.
Activation of lipoperoxidation processes with accumulation of secondary TBA active products observed in most patients at risk of developing severe cardiovascular complications (76% of those examined).
Changes in the hepatobiliary system for the Chornobyl disaster clean-up personnel of those who died as a result of liver cirrhosis were characterized by the development of atrophy and fatty dystrophy of hepatocytes, lymphoid-lym-phocytic infiltration, pronounced and systemic development of fibrosis, often with massive growth of fibrotic tissue, not only in the liver.
Conclusions
1. It was established that the main liver pathology for victims of the Chornobyl accident at ChNPP is non-alcoholic fatty liver disease. The main trigger in the launch of the mechanism for the development of pathological processes in the liver is oxidative stress with a breakdown of the antioxidative protection of cells, accompanied by the development of the state of peroxidation, while disorders of energy metabolism and general cell metabolism occur.
2. It has been shown that in patients affected by the Chernobyl accident, NAFLD develops a pronounced violation of fat metabolism with a reliable decrease in cholesterol and beta-lipoproteins in cirrhosis - a sign of a long-term
course of the disease, accompanied not only by the development of fibrosis, but also by a fatty rebirth of liver tissue with low cholesterol and beta-lipoproteins; this can be considered a marker of cirrhosis in the Chornobyl accident cleanup personnel with NAFLD.
3. It was established that for the Chornobyl accident cleanup personnel with NAFLD and the development of liver fibrosis, cytolytic syndrome activity was significantly increased with a progressive increase in transaminase activity - AST and ALT, cholestasis, hepatic cell insufficiency were formed with a progressive increase in biliru-bin, as well as impaired protein synthetic liver function with a decrease in albumin and an increase in the acute phase protein alpha 2-macroglobulin, which activates astrocytes and stimulates fibrogenesis with the development of dysproteine-mia and mesenchymal-inflam-matory changes with a gradual increase in thymolic sample at the stage of pronounced fibrous changes.
4. Factors of the liver cirrhosis progression with disease manifestation at decompensation stage were: long steadily progressing processes of inflammation, asymptomatic or low-symptomatic course with minimal activity and/or absence of cytolytic syndrome, improper dynamic observation and uncontrolled course of the disease, significant amount of comorbidity of other organs and systems.
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Hag'Mwno go pegaKW 05.12.2020
