The development of personalized medicine is inextricably linked with the study of the patient’s genetic profile, which determines not only the features of the course of the disease, but also the risks of its occurrence. Purpose. The aim of the work was to study possible associations between the genetic polymorphisms GSTT1, GSTM1, NAT2 and predisposition to the development of acute lymphoblastic leukemia in children of the East Siberian region. Material and methods. A total of 82 children with acute lymphoblastic leukemia and 227 healthy volunteers with no history of hematological pathology were examined. Deletion polymorphisms in the glutathione S-transferase GSTT1 and GSTM1 genes were detected by polymerase chain reaction (PCR) with electrophoretic detection of amplification products in agarose gel; the type of acetylation was determined by genotyping SNP rs1495741 of the NAT2 gene by conducting a polymerase chain reaction in real time. The material for the study was DNA samples isolated from buccal epithelium samples. Results. Statistical processing allowed us to draw the following conclusions: the rate of acetylation of xenobiotics does not affect the risk of acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. Conclusion. There is no associative relationship between deletions in the GSTM1 and GSTT1 genes and the risk of developing acute lymphoblastic leukemia in children of the Caucasian ethnic group of the East Siberian region. It was found that the risk of developing acute lymphoblastic leukemia in children was significantly higher with the variant of combinations of alleles of the rapid type of NAT2 acetylation and normal activity of GSST1 and GSTM1 (G/G, active, active).

The measurement of the level of mitochondrial DNA (mtDNA) in the blood is a difficult problem due to high variability of mitochondrial genes, deletions in the mitochondrial genome in some pathological conditions, different sources of mtDNA into the bloodstream (mtDNA from tissues, from blood cells, etc.). We designed primers and TaqMan probes for highly conserved regions of the ND1 and ND2 genes outside the mitochondrial deletions "hot zones". For standardizing the technique, the true concentration of low-molecular-weight mtDNA was determined by real-time PCR for two targets: a fragment of the ND2 gene (122 bp) and the ND1 and ND2 genes (1198 bp). The sensitivity and specificity of the developed approach were verified on a DNA pool isolated from the blood plasma of healthy donors of various nationalities. The concentration of low-molecular-weight mtDNA in the blood plasma of two patients with COVID-19 was monitored over two weeks of inpatient treatment. A significant increase in the content of low-molecular-weight mtDNA was observed during the first 5 days after hospitalization, followed by a drop to the level of healthy donors. The developed technique makes it possible to assess the blood level of low-molecular-weight mtDNA regardless of the quality of sampling and makes it possible to standardize this biological marker in a wide range of infectious and non-infectious pathologies.

Drug acetylation plays an important role in the medical practice. Modern methods of acetylation phenotype prediction are based on genotyping of polymorphisms in the second exon of the gene NAT2. Some disadvantages of these methods limit their application in the clinical practice. We developed a method of human genotyping based on identification of NAT2 gene polymorphism rs1495741 by real-time PCR. This method of genotype determination has a number of advantages: high sensitivity, simplicity, possibility of automated interpretation of the results, and feasibility in clinical laboratories.

Objective. To determine environmental and genetic factors associated with fibrosis progression after virus elimination as a result of direct-acting antiviral therapy by follow-up dispensary observation of patients with chronic hepatitis C with moderate and severe liver fibrosis (F2–F3 according to the METAVIR scoring system). Patients and methods. This study included 301 patients (166 men and 135 women) aged 20-64 years with chronic hepatitis C virus (HCV). A sustained virologic response was achieved in all patients after therapy with direct-acting antiviral agents. Patients were followed up for an average of 38 weeks (16–64). Patients were divided into two groups in order to perform comparative evaluation: group I included 257 patients with regression of liver fibrosis and group II – 44 patients with progression of liver fibrosis. Questionnaire and clinical and laboratory data were assessed. In addition, genetic studies of 24 singlenucleotide polymorphisms of genes involved in intracellular immune signaling pathway activation, interferon synthesis, metabolic regulation and cell proliferation were performed in both groups. Results. It was revealed that validated predictors of liver fibrosis progression in patients with chronic HCV after successful virus elimination as a result of therapy with direct-acting antiviral agents are the presence of concomitant type 2 diabetes mellitus, low ALT activity and serum osteopontin levels over 80 ng/mL at the beginning of therapy. Genetic predisposition to liver fibrosis progression is mediated by carriage of the AA genotype of HNF4α rs4812829 (OR = 3.55; 95% CI 1.21–10.41; p = 0.015). Additionally, the G-allele of NAT2 rs1495741, which marks fast xenobiotic acetylation, was found to have protective properties in the dominant genetic model. Carriers of GG- and GA-genotypes had an almost 2-fold lower risk of liver fibrosis progression after antiviral therapy than AA-genotype carriers (OR = 0.49; 95% CI 0.25–0.94; p = 0.029). Conclusion. The risk after successful hepatitis C virus elimination is significantly higher in patients with concomitant type 2 diabetes mellitus. ALT activity and serum osteopontin levels at the beginning of therapy can be estimated as predictors of liver fibrosis progression among laboratory parameters. Moreover, some genetic markers in the form of single-nucleotide polymorphisms of the HNF4α and NAT2 genes were established, which can be used to predict the development of liver fibrosis in patients with hepatitis C after therapy with direct-acting antiviral agents. Key words: hepatitis C, liver fibrosis, predictors, risk factors, diabetes mellitus, osteopontin, single-nucleotide polymorphisms, HNF4α gene, NAT2 gene

Журнал для непрерывного медицинского образования врачей Гепатоцеллюлярная карцинома, ассоциированная с гепатитами В и С, у монголоидов и европеоидов Северо-Восточной Азии ОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯ 1 Монгольский национальный университет медицинских наук, 14210, г.Улан-Батор, Монголия 2 Монгольская академия медицинских наук, Улан-Батор, Монголия 3 Федеральное государственное бюджетное образовательное учреждение высшего образования «Иркутский государственный медицинский универ-

We evaluated the possibility of using an experimental model of hepatocellular carcinoma to study oncomarkers of primary liver cancer and compared the diagnostic efficacy of alpha-fetoprotein and osteopontin in the experiment and in clinical practice. Experimental studies were performed on a model of hepatocellular carcinoma induced by administration of diethyl nitrosamine to Fisher-344 rats. In addition, the levels of α-fetoprotein and osteopontin were determined in 35 patients with hepatocellular carcinoma detected at stages I-II according to TNM classification. The proposed model of liver cancer in rats reflects the sequence of stages characteristic of hepatocellular carcinoma in humans: liver fibrosis—cirrhosis—cancer. This model is applicable for the study of tumor markers at the early stage of tumor development. Osteopontin was found to have a more powerful diagnostic potential then alpha-fetoprotein.

The objective: to assess the effect of parenteral viral hepatitis on the manifestations of respiratory tuberculosis and the nature of surgical interventions for tuberculosis.Subjects and methods. An ambispective observational study was conducted with a continuous sampling of 475 respiratory tuberculosis patients over 18 years old who underwent surgical interventions. The patients are divided into two groups: the group of RTB+PVH consisted of 92 patients with concurrent respiratory tuberculosis and chronic parenteral viral hepatitis; the group of RTB included 383 patients with respiratory tuberculosis and no parenteral viral hepatitis.Results. It was found that compared with RTB group, in RTB+PVH group (regardless of the type of hepatitis virus), a chronic course of tuberculosis was registered significantly more often (42.4%; p = 0.005; OS = 2.0); more often bacillary excretion was documented (68.5%; p = 0.035; OR = 1.7), including those with multiple and extensive drug resistance (52.4% of cases with positive sputum tests, p = 0.048; OR = 1.8). Radical (69.6%; p = 0.05; OS = 1.7) and small-scale surgical interventions (64.1%; p = 0.037; OS = 1.8) were significantly less frequently performed in RTB+PVH patients; and such patients often developed postoperative complications (8.7%; p = 0.009; OS = 2.9).

Aim of the research . To study the epidemic manifestations of HCV infection in the Republic of Sakha (Yakutia) in order to develop recommendations for improving the effectiveness and quality of treatment and prevention measures. Materials and methods . The paper uses materials from the official statistics of the Territorial Department of Rospotrebnadzor of the Republic of Sakha (Yakutia) for 1994–2018, and data from the electronic register «Chronic viral hepatitis in the RS (Ya)» (2019). Molecular and biological studies of the genotype of the hepatitis C virus were performed jointly on the basis of the Federal state budgetary Institution «Central research Institute of epidemiology» of Rospotrebnadzor (2007–2011, n = 75). To assess the epidemiological situation, the rate of increase in morbidity is calculated on the basis of data equalized by the method of least squares. Statistical processing was performed using the SPSS 17 program. The critical significance level is assumed to be 0.05. Results. Thus, the study of long-term dynamics of the incidence of viral hepatitis shows that in the Republic of Sakha (Yakutia) a consistently high level of incidence of HCV with adverse trends in the development of the epidemic process remains. Analysis of the distribution of different variants of HCV genotypes allowed us to establish the prevalence of genotype 1b, which can determine the high frequency of cirrhosis and primary liver cancer. The current situation in the Republic regarding the incidence of viral hepatitis requires detailed monitoring, improvement of epidemiological surveillance and introduction of modern treatment methods. It is also necessary to improve the quality of health education among the population of the Republic.

Objective. To analyze associations between single-nucleotide polymorphisms (SNPs) in some genes located on the X chromosome and risks for hepatocellular carcinoma (HCC) in Yakut males with chronic hepatitis C infection (HCV). Patients and methods. We examined 140 Yakut males with chronic HCV in the stage of liver cirrhosis formation. In 41 of them, chronic hepatitis was complicated by HCC. All patients were tested for SNPs in the genes located on the X chromosome, including TLR7 (rs179008); TLR7 (rs179009); TLR8 (rs3764879); TLR8 (rs3764880); IRAK1 (rs3027898); MECP2 (rs1734791); TAB3 (rs1000129516); ELK1 (rs1000619237); GPC3 (rs2267531). Results. We found no significant differences in the frequencies of specific alleles of genes involved in TLR7 signaling between patients with chronic HCV and patients with HCC. However, there were significant differences in the distribution of variable sites in the rs2267531 locus of the GPC3 gene. The GPC3 gene encodes glypican-3 known as a regulator of cell proliferation and a highly specific HCC tumor marker. GPC3 mutations are inherited as an X-linked recessive trait and only males manifest this condition. The number of C-allele carriers among HCC patients was 1.5 higher than that among HCV patients without HCC. We found that chronic HCV patients carrying the C-allele are 2.7 times more likely to develop HCC than G-allele carriers (p = 0.0095). Conclusion. We found a SNP in the GPC3 gene, which C-allele was associated with an increased risk of HCC in Yakut males with chronic HCV. This genetic marker can be used for personalized prognosis of the disease course and as a predictor of HCC development in patients with liver cirrhosis. Key words: hepatitis C, hepatocellular carcinoma, glypican-3, single-nucleotide polymorphisms, Toll-like receptors, X chromosome, Yakuts

Relevance. In 2016, a resolution was adopted at the 69th World Health Assembly, the goal of which is to eliminate parenteral hepatitis in the world by 2030. In the Republic of Sakha (Yakutia), as in the Russian Federation as a whole, it is necessary to determine the starting positions for the prevalence and incidence of hepatitis B, C, and D, as the leading factors in the development of hepatocellular carcinoma. Aim: to give a clinical and epidemiological characterization of hepatocellular carcinoma in the Republic of Sakha (Yakutia) at the initial stage of the program for the elimination of viral hepatitis for subsequent analysis of its effectiveness. Materials & Methods. A clinical and epidemiological analysis of morbidity, mortality, cumulative survival in hepatocellular carcinoma in the Republic of Sakha (Yakutia) over a 10-year period (2009-2018) was carried out. Predictors for the development of hepatocellular carcinoma were analyzed based on primary medical records and a survey of 125 patients. Results and discussion. The incidence rate of hepatocellular carcinoma in the Republic of Sakha (Yakutia) over the past 10 years is 2.0 3.9 times higher than the corresponding indicator in the Russian Federation. The highest mortality from the studied pathology is noted in the Central and Polar zones of the republic. According to the materials of the cancer registry, the median cumulative survival of patients with carcinoma was 13.7 months from the date of diagnosis, which is significantly higher than ten years ago. The main risk factors have been identified, among which the leading role is played by infection with hepatitis C, B, and D. viruses. Also, alcohol abuse, diabetes mellitus, overweight, and smoking are important. Conclusion. The Republic of Sakha (Yakutia) is a hyperendemic region of the Russian Federation in terms of the incidence of hepatocellular carcinoma with a predominance of the male population in its structure. The rate of decrease in the incidence of liver cancer in the country will depend on the effectiveness of the regional program for the elimination of viral hepatitis and the decrease in the incidence of cirrhosis of the liver of non-infectious etiology.

Liver cirrhosis in the outcome of hepatitis C is the leading cause of hepatocellular carcinoma (HCC) in the world. Early diagnosis and timely treatment of HCC are important for reducing mortality and increasing life expectancy of patients with hepatocellular carcinoma. To assess the risk of HCC, the definition of alpha-fetoprotein (AFP) in the blood is most widely used, but low sensitivity limits its diagnostic value. In 2012, a new HCC biomarker - osteopontin (OPN), which is a secreted phosphoprotein that has a high affinity for integrins was proposed. The level of acute renal failure begins to rise in the early stages of malignancy, before the period of HCC detection by imaging methods, and has significantly better sensitivity than AFP. The purpose of this study is to evaluate the diagnostic efficacy of the combined determination of alpha-fetoprotein and osteopontin in prospective monitoring of patients with chronic hepatitis C in the advanced phase of liver fibrosis. Monitoring of 588 patients with hepatitis C was carried out from February 2013 to February 2019. HCC was detected in 55 of them (2.6% per year). The combination of 2 biomarkers showed better diagnostic efficacy than alpha-fetoprotein and osteopontin separately: AUC 0.85 (95% CI 0.80-0.90) versus AUC 0.63 (95% CI 0.57-0, 70) and AUC 0.82 (95% CI 0.77-0.88), respectively. This combination showed a sensitivity of 85.5% and made it possible to diagnose HCC with a prognostic level of a positive result of 72.3% at 19,4±0,8 weeks before the diagnosis was confirmed by instrumental imaging methods (ultrasound, MRI, CT). In the combined variant, ARF made the greatest contribution to the increase in diagnostic efficacy (AUC). At an early and very early stage of HCC development, isolated HCC elevations were found in only 5.4% of patients. Conclusion: the combined use of alphafetoprotein and osteopontin as a diagnostic panel can be recommended for monitoring patients with liver cirrhosis in the outcome of hepatitis C and predicting HCC at an early stage of development.

From all group of infectious pathology viral hepatitises, from which the most priority are the parenteral hepatitises B and С, are essential for health of mankind, also the Irkutsk region isn’t an exception. The aim of the study: to assess an epidemiological situation in sharp and chronic forms of the viral hepatitises B and С in the territory of the Irkutsk region for the long-term period. Materials and methods. The retrospective analysis of an epidemiological situation on viral hepatitises B and C in Russia, Siberian Federal District and in the Irkutsk region for 2008–2016 is carried out. Results. The expressed decrease in incidence of acute viral hepatitis B is noted, at a chronic form of this disease rates of decrease had less expressed character that can be connected with carrying out by mass vaccinal prevention. The carried-out ranged distribution of territories for all forms of viral hepatitis B and viral hepatitis C in the Irkutsk region has allowed to reveal territories of risk. Conclusion. Parenteral viral hepatitises (sharp and chronic forms) are widespread in the territory of the Irkutsk region. From 43 administrative territories of the area, 24 belong to unsuccessful on incidences from which five are to territories of high epidemiological risk: cities of Irkutsk, Angarsk and Ust-Ilimsk and also Katangsky and Shelekhovsky districts.

Aim. The current study is aimed at determining differences of epidemiological and clinical profiles associated with HCC in patients belonging to ethnic groups of Asians from Mongolia and Caucasians from Asian region of Russia. Materials and methods. The studies were carried out in the cross-border regions of Mongolia and Asian part of Russia (Irkutsk region). 300 patients with hepatocellular carcinoma (HCC) of the Caucasian and Mongolian races were enrolled in the study. The level of alpha-fetoprotein (AFP) in the serum was determined by the chemiluminescence technique. Results. The long-term dynamics of the HCC incidence shows more unfavourable trends in the territory of Mongolia compared to Irkutsk region. In both groups, male patients over 60 years of age predominated. Patients from Mongolia often have a history of jaundice and alcohol abuse. Out of the etiological factors, HCC is more often associated with the hepatitis B virus in Mongolia than in the Asian part of Russia. At the same time, in Caucasians, HCC develops primarily on the background of liver cirrhosis. In patients with HCC, AFP level higher than 20 ng / ml were significantly more frequent in the ethnic group of Caucasoids than in Mongoloids. Conclusions. Mongolia in terms of the incidence of HCC belongs to the hyperendemic regions of the world. In this country, among the risk factors for the development of the disease, hepatitis B virus plays a major role, which significantly differs from the Asian part of Russia. For the purpose of early diagnosis of HCC, it is necessary to search for new molecular markers or their combinations due to the insufficient diagnostic efficiency of AFP determination.

Introduction.The chronic hepatitis C is essential for health care of the Siberian federal district in the territory of which now the incidence of the specified pathology significantly exceeds similar indicators across the Russian Federation. Materials and methods. The retrospective analysis of an epidemiological situation onе the chronic hepatitis C in the Siberian federal district for 2006–2015 included case rate assessment with use of official statistical materials. For integrated assessment of an epidemiological situation indicators of a case rate of the chronic hepatitis C and statistical criteria are used: a standard deviation and rate of a gain of a case rate and also an algorithm of calculation of an integrated indicator in the form of presentation coefficient. A genotypical variety of a virus of hepatitis C (HCV) during 2001‒2017 was studied according to the Irkutsk regional clinical consulting and diagnostic center on the basis of the analysis of 13236 PCR-positive blood samples of the sick. The chronic hepatitis C living in the territory of the Irkutsk region. Results and discussion. Assessment of the movement of a case rate of the chronic hepatitis C for the surveyed long-term period on the federal districts of Russia from the West on the East taped its body height in the designated direction. Complex assessment of indicators of a case rate in the administrative territories which are a part of the Siberian federal district in some cases significantly differs from its standard estimates and the most safe territories the Republic of Buryatia and the Omsk region. The Republic of Tyva moved from the first to the eighth rank place. Integrated approach of studying of the key epidemiological indicators allows to carry out deeper comparative assessment of the situation. In distribution of the main genotypes of HCV significant depression of the first and augmentation of the third of genotypes of the chronic hepatitis C originator is observed in recent years.Conclusions. 1 Siberian federal district is the territory of risk for chronic hepatitis C. 2 The generalized case rate indicator reflects implications of epidemic process more objectively. 3 The offered methodical approach, besides a case rate, can be used for profound assessment and other indicators. 4 Processes of globalization and social conditions promote evolution in distribution of the main genotypes of HCV.

CHRONIC VIRAL HEPATITIS C IN THE FAR EASTERN FEDERAL DISTRICT N.N. Chemezova1, 2, V.A. Astafiev1, 2, S.I. Malov1, 3, I.V. Malov3, E.L. Kichigina1, E.D. Savilov1, 2 1 Irkutsk State Medical Academy of Postgraduate Training (100 Yubileinyi Dist. Irkutsk 664049 Russian Federation), 2 Scientific Centre for Family Health and Human Reproduction Problems (16 Timiryazeva St. Irkutsk 664003 Russian Federation), 3 Irkutsk State Medical University (1 Krasnogo Vosstaniya St. Irkutsk 664003 Russian Federation) Objective. The epidemiological situation on chronic viral hepatitis C was assessed in Far Eastern Federal District. Methods. Incidence rate data characterizing the epidemiological situation of chronic viral hepatitis C for 2006–2015 was used. Results. It was established that the most unfavorable epidemiological situation of all territories of the Russian Federation is primarily noted in the eastern regions of the country (Ural, Siberia, Russian Far East) and Northwestern Federal District. Integral criterion of main epidemiological factors enables to conduct more deep comparative analysis of epidemiological situation. According to this approach it was established that unfavorable situation of chronic viral hepatitis C in the Russian Far East was registered in Chukotka Autonomous Region, and the most favorable was registered in Jewish Autonomous Region and Primorskiy Territory. Conclusions. The proposed generalized incidence rate more objectively reflects the manifestations of the epidemic process, without distorting the standard value of the average value, and takes into account the main risks of the development of morbidity.