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 Republic of Sakha (Yakutia) is the largest administrative-territorial unit in the world, more than 40% of its territory is located beyond the Arctic Circle. At the same time, the population of the republic is the lowest among all subjects of the Russian Federation (0.32 people/km2). All this together significantly distinguishes this region from other territories of Russia. The purpose of this study: to assess the main manifestations of the epidemic process of chronic hepatitis C on the territory of the Republic of Sakha (Yakutia) at the stage of implementation of the national program for the elimination of viral hepatitis. Materials and methods. An epidemiological analysis of chronic hepatitis C and liver cancer was carried out for the period from 2000 to 2019. The incidence of liver cancer was assessed according to ICD-10, in which malignant neoplasms of the liver and intrahepatic bile ducts are summarized under code C22. Statistical analysis was carried out in the application package R. The study of differences in the distribution of incidence rates of chronic hepatitis C and malignant liver diseases between the Russian Federation and the Republic of Sakha (Yakutia) was carried out using the method of nonparametric assessment of the weighted average median of the Mann-Whitney test. Results and discussion. The decrease in the intensity of the incidence of acute and chronic hepatitis C in Russia was unidirectional in nature with a fairly close manifestation of their long-term movement. In contrast, in the Republic of Sakha (Yakutia) there was a significantly less pronounced decrease in the incidence of acute hepatitis C (4.9 times, rate of increase -6.2%), and the incidence of chronic hepatitis C in general for the entire analyzed period was cyclical and had a pronounced upward trend (2.4 times growth, rate of increase +2.6%). It was shown that there are statistically significant differences (p<0.01) between the median incidence rates of chronic hepatitis C and malignant liver diseases between the Russian Federation and the Republic of Sakha (Yakutia). Conclusion. To achieve the appropriate targets for hepatitis C elimination in the country, it is necessary to take into account the specific natural, climatic, social and ethnic characteristics of the Republic of Sakha (Yakutia). Keywords: epidemiology, morbidity; hepatitis C; liver cancer; The Republic of Sakha (Yakutia).

In order to detect an association of the type of acetylation with the development of inflammatory liver diseases under the influence of external factors, rs1495741 polymorphism genotypes were compared in the group of patients with cryptogenic cirrhosis, non-alcoholic fatty liver disease and in the control group. Significant differences were found in the group of patients eating fried and smoked food. At the same time, the risks of developing inflammatory liver diseases increase at an older age. The rs1495741 polymorphism of the NAT2 gene and the associated type of acetylation do not affect the development of liver disease under the exposure to the external factors.

Slow acetylation of substrate is associated with drug-induced liver damage and transformation of viral and alcohol hepatitis in cirrhosis. Increasing xenobiotic load is a significant factor in development of metabolic associated liver diseases. This interaction between genotype and environment should be studied to reveal disease pathogenesis. We analysed polymorphism rs1495741 genotypes in control group and in patients with cryptogenic liver cirrhosis and non-alcohol fatty liver disease to evaluate association of acetylation type with liver disease development. As part of the study, patients filled the questionnaire to assess xenobiotic load. The rs1495741 polymorphism was detected by real-time PCR. Significant differences were revealed in the criptogenic liver cirrhosis and non-alcoholic fatty liver disease groups in patients consuming fried and smoked foods (OR: 5,49 at p<0,05); in combination with older age (>55) the risk increases by 7.57 times (p<0,05). However, no association of the rs1495741 polymorphism with the development of liver diseases was identified. Keywords: N-acetyltransferase 2, polymorphism, cryptogenic liver cirrhosis, non-alcoholic fatty liver disease.

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

This study aims to develop approaches for screening highly specific bacteriophages based on bio-informatic analysis of CRISPR-Cas structures of bacterial systems using the example of Corynebacterium diphtheriae. We proposed an algorithm for bioinformatic search and analysis of CRISPR-Cas structures of bacteria systems and phage screening through spacer sequences of CRISPR-cassette in genomes of Corynebacterium strains. 22 genome-wide sequences loaded from the GenBank database were selected as the target. 21 strains out of 22 had CRISPR-Cas systems. Using several search algorithms in CRISPR-Cas systems, one CRISPR-cassette was found in 23.8% of the tested strains and two in 76.2% of cases. Near the cassettes, a complete set of Cas-genes was identified, characteristic of two types of systems: Type-I Subtype-I-E and Type-II Subtype-II-C. The conducted analysis of the CRISPR-cassette spacer composition showed 3 to 42 spacers in the cassette. The cumulative total number of identified spacers amounted to 297, 64 spacers of which repeated in two or more CRISPR-cassettes, 159 spacers had no replicates. The three pairs of strains under study from this group had a complete match of spacer and consensus sequences, although they were isolated at different times and in multiple countries. A phylogenetic analysis was performed to confirm their common origin. Phages screening through the spacer sequences showed the highest compliance of the spacers with the phages protospacers, characteristic of the bacteria of the Mycobacteriaceae, Gordoniaceae, Streptomycetaceae, Corynebacteriaceae family belonging to the Actinobacteria type. One strain with multiple antibiotic resistance was identified, and its expected bacteriophage resistance was determined using this method. Thus, the developed bioinformatic analysis technology allowed the information on the expected resistance of the tested strains CRISPR-Cas system against the detected phages to be obtained, which in the long term enables the development of a platform of personalised bacteriophage treatment approaches.

The aim of the study was to identify the most effective serum tumor markers for early diagnosis of hepatocellular carcinoma based on the combination of diagnostic characteristics and correlations.Materials and Methods:There were observed 55 patients with chronic hepatitis C in the stage of liver cirrhosis with a verified diagnosis of hepatocellular carcinoma. The control group consisted of 55 patients with chronic hepatitis C at the stage of liver cirrhosis without hepatocellular carcinoma, comparable to the experimental group in terms of basic clinical profile. The following tumor markers were estimated in both groups: alpha-fetoprotein (AFP), alpha-fetoprotein-L3 (AFP-L3), annexin A2 (ANXA2), heparin-binding growth factor Midkine (MDK), glypican-3 (GPC3), des-gamma-carboxyprothrombin (DCP, PIVKA-II), dickkopf-related protein 1 (DKK-1), osteopontin (OPN), and Golgi protein 73 (GP73). There were also evaluated such indices as diagnostic sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio of a positive test, the possible correlation between alpha-fetoprotein and other tumor markers. The area under the ROC curve (AUC) was calculated at the 95% confidence interval.Results:The greatest sensitivity was revealed when using heparin-binding growth factor, annexin A2, osteopontin. Alpha-fetoprotein, alpha-fetoprotein-L3, glypican-3, des-gamma-carboxyprothrombin, dickkopf-related protein 1 had the best specificity. AUC>0.75 was found in annexin A2, heparin-binding growth factor, glypican-3, des-gamma-carboxyprothrombin, osteopontin, Golgi protein 73. The likelihood ratio of a positive test result was the highest for glypican-3. A significant correlation was found between alpha-fetoprotein and alpha-fetoprotein-L3, annexin A2, des-gamma-carboxyprothrombin.Conclusion:According to the aggregate indicators of diagnostic efficiency, heparin-binding growth factor, glypican-3, and osteopontin are the most promising tumor markers of those studied. When they are used, integral AUC values are above the average, the level of these tumor markers in the blood of patients with hepatocellular cancer does not correlate with alpha-fetoprotein. They are applicable for diagnosing liver cancer in AFP-negative patients. The combined use of AFP + GPC3, AFP + OPN has already shown their advantages. However, the efficacy of the combination of AFP + MDK, GPC3 + OPN has not been determined yet; therefore, significance of the combined use of these tumor markers in the diagnosis of liver cancer should be investigated in the near future.

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.

Nowadays multiple heterogeneous chemicals affect the human body. They include drugs, household chemicals, dyes, food supplements and others. The human organism can modify, inactivate, and eliminate the chemicals by biotransformation enzymes. But it is well known that biotransformation can lead to toxification phenomenon. Individuals differ from each other by the rate of chemical modification that promotes accumulation of toxins and carcinogens in some patients. An N-acetyltransferase 2 enzyme participates in the aromatic amines second phase metabolism. This work reviews the acetyltransferase gene polymorphism possible role in diseases development including drug-induced organs damage.Gene of acetyltransferase has polymorphisms associated with two haplotypes of fast and slow substrate acetylation. Gene alleles combine in three genotypes: fast, intermediate, and slow acetylators. Acetylation rate plays a significant role in side effects development during tuberculosis treatment and cancer pathogenesis. Recently, new data described the role of enzyme in development of non-infectious diseases in the human. Scientists consider that slow acetylation genotype in combination with high xenobiotic load result in accumulation of toxic substances able to damage cells.Therefore, acetyltransferase genotyping helps to reveal risk groups of cancer and non-infectious disease development and to prescribe more effective and safe doses of drugs.

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

Aim. To establish the main external and genetically determined risk factors for the development of hepatocellular cancer in the ethnic group of male Yakuts living in the Republic of Sakha (Yakutia) [RS (Y)] in the epidemiologically unfavorable conditions of the incidence of viral hepatitis. Materials and methods. A total of 97 male Yakuts were examined, including 44 people diagnosed with hepatocellular cancer and 53 people diagnosed with chronic viral hepatitis. HCC risk factors were identified by analyzing medical records and questioning patients. In the experimental and control groups, genetic studies of single nucleotide polymorphisms of genes mapped on the X-chromosome and involved in the activation of antiviral immunity along the TLR7 signaling pathway were performed. Results and discussion. In 100% of patients with hepatocellular cancer, infection with hepatitis B, C, D viruses or co-infection with these agents was detected. Every fourth patient with HCC in the RS (Y) was infected with hepatitis D. The course of hepatocellular cancer associated with HDV was characterized by rapid progression of liver cirrhosis, development of portal hypertension, bleeding from varicose veins of the stomach and esophagus (36.4%) and edematous ascitic syndrome (63.6%). In addition to viral agents, additional risk factors for liver cancer were identified, such as alcohol abuse, overweight, diabetes mellitus, and smoking. Among the studied variation sites of genes localized on the X-chromosome and encoding the reaction of innate antiviral immunity, no genetic marker was found with a sufficient degree of confidence determining the likelihood of hepatocellular cancer developing. Conclusions. The high incidence of hepatocellular carcinoma of the male population in the RS (Y) is due to the widespread prevalence of parenteral viral hepatitis, especially viral hepatitis D. Due to the introduction of mass vaccination of the population against hepatitis B in the Russian Federation in the foreseeable future in the RS (Y) we should see a decrease in the proportion of hepatocellular cancer associated with hepatitis B and D viruses, and therefore the focus should be on the treatment and prevention of hepatitis C virus and noninfectious risk factors.

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.

Hepatocellular carcinoma (HCC) is the second leading cause of death in oncological patients. The prognosis of the disease outcome depends directly on its timely detection. Currently, in the majority of countries, the diagnostic algorithm at the preclinical stage of tumor development includes determination of alpha-fetoprotein in combination with instrumental imaging techniques. This approach allows the detection of about 65-80% of liver tumors at an early stage (A according to the BCLC classification), whereas at a very early stage (0 according to the BCLC classification) only 32-50% of cases, the result which cannot be considered satisfactory. In this regard, the search for effective biomarkers of hepatocellular carcinoma is an important challenge that faces the world healthcare. Advances in proteomics and genomics have led to the discovery of numerous promising markers which are now being clinically tested. Molecules of protein nature proposed as hepatocellular carcinoma tumor markers in different periods of time are described in this review. Comparative data on their effectiveness and specificity are also presented. The possibility of isolated or combined use of these biomarkers for risk assessment and early diagnosis of primary liver cancer is considered.