Non-alcoholic fatty liver disease (NAFLD) is a group of conditions closely associated with obesity that are among the most common and socially significant liver diseases in the modern Western world. The emergence and progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis with the subsequent development of fibrosis are the leading factors in the pathogenesis of a significant proportion of the most severe liver pathologies, such as cirrhosis and hepatocellular carcinoma, as well as extrahepatic metabolic complications of NAFLD, such as insulin resistance and type 2 diabetes mellitus. The inflammatory component is one of the most important factors in the pathogenesis of NAFLD, particularly in the context of the progression of simple steatosis to non-alcoholic steatohepatitis. At the same time, the role of the most important mediators of the inflammatory response, innate immunity receptors and the Toll-like receptors in particular, in the pathogenesis of NAFLD has been poorly studied. In the present work, we first used the bioinformatics analysis of the publicly available gene expression databases to demonstrate that only TLR1, TLR2, TLR3 and TLR4 were significantly expressed in the healthy human liver. We then used the reverse transcription PCR to measure the mRNA expression levels of TLR2, TLR3, and TLR4, as well as those of the important pro-inflammatory mediators tumor necrosis factor (TNF) and interleukin-6 (IL-6), in the liver biopsy specimens obtained from 20 patients with NAFLD (simple steatosis, n = 10; non-alcoholic steatohepatitis, n = 10), as well as from 4 obese patients with clinical suspicion for NAFLD but no histological signs of NAFLD in their liver biopsies. We found a significant increase in the expression of TLR2, TLR3 and TLR4 mRNA in liver biopsy samples obtained from patients with non-alcoholic steatohepatitis as compared to those obtained from controls without histological signs of NAFLD. We were also able to demonstrate the association between the hepatic levels of TLR2, TLR3 and TLR4 mRNAs with the histological degree of liver damage as evidenced by the degree of steatosis and balloon dystrophy of hepatocytes, as well as with the plasma levels of uric acid, the important endogenous stimulator of innate immunity. Our data indicate the possible involvement of innate immunity, particularly the Toll-like receptors, in the pathogenesis of NAFLD.

AIM:Study of the social consequences of cognitive disorders in minimal hepatic encephalopathy (MHE) in patients with chronic genotype 1 hepatitis C and the possibilities of their pharmacological correction with L-ornithine-L-aspartate (LOLA, Hepa-Merz). MATERIALS AND METHODS:The study group included 60 male patients diagnosed with chronic hepatitis C, genotype 1 with fibrosis stage F1 according to the METAVIR scale, and presented with MHE. The average age of the patients was 34.2±5.3 years. The control group included 20 healthy men aged 34.1±5.8 years without liver disease. Intermittent treatment with LOLA was given to the study group at 15 g once daily in the morning for 2 months with 2-month off-treatment intervals, with the total treatment duration of 12 months. In the course of treatment, MHE dynamics was assessed using the critical flicker fusion frequency (CFF) test and the number connecting test (NCT), as well as by serum concentrations of ammonium ion. The LOLA efficacy endpoint was the change in the frequency of violations of traffic rules (traffic code). RESULTS:A significant decrease in the concentration of ammonium ion was observed after 5 months of treatment (135.53 and 82.9 μmol/L, p=0.002) and maintained throughout the study. The results of the CFF test significantly improved by the end of the 1st month of LOLA treatment (p=0.008), remaining at the achieved level for 9 months. The NCT parameters reached their minimum values after 5 months (p<0.001) and remained at this level throughout the study. During the study period, the frequency of traffic code violations by participants decreased from 60 to 40% (р=0.03). CONCLUSION:Fractional treatment with LOLA leads to a decrease in the blood concentration of ammonium ion and, consequently, to an improvement in psychometric test results and a decrease in the frequency of traffic code violations. The result achieved can have an impact on the accident rate reduction.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and is considered to be the liver manifestation of metabolic syndrome. Currently, there is no etiotropic treatment of NAFLD, so an active research for new methods of treatment is underway. In the meantime, drugs are used to treat comorbid conditions, such as dyslipidemia, arterial hypertension, obesity, type 2 diabetes, which are present in varying degrees in patients. This review considers medications that are used in patients with NAFLD and related concomitant features, and also describes new strategies for regressing changes in liver tissue in NAFLD. In our opinion, one of the promising groups of drugs are agonists of the farnesoid X receptor (FXR). FXR belongs to the group of nuclear receptors, which are ligand-activated transcription factors that regulate the genes involved in metabolism. FXR agonists can claim to be a new promising drug for the treatment of NAFLD and related diseases influencing carbohydrate metabolism, fat metabolism, bile acid metabolism, as well as inflammatory processes in the liver to ensure metabolic homeostasis.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and is considered to be the liver manifestation of metabolic syndrome. Currently, there is no etiotropic treatment of NAFLD, so an active research for new methods of treatment is underway. In the meantime, drugs are used to treat comorbid conditions, such as dyslipidemia, arterial hypertension, obesity, type 2 diabetes, which are present in varying degrees in patients. This review considers medications that are used in patients with NAFLD and related concomitant features, and also describes new strategies for regressing changes in liver tissue in NAFLD. In our opinion, one of the promising groups of drugs are agonists of the farnesoid X receptor (FXR). FXR belongs to the group of nuclear receptors, which are ligand-activated transcription factors that regulate the genes involved in metabolism. FXR agonists can claim to be a new promising drug for the treatment of NAFLD and related diseases influencing carbohydrate metabolism, fat metabolism, bile acid metabolism, as well as inflammatory processes in the liver to ensure metabolic homeostasis.

Цель. Изучение социальных последствий когнитивных расстройств при минимальной печеночной энцефалопатии (МПЭ) у больных хроническим гепатитом С (генотип 1) и возможностей их фармакологической коррекции L-орнитином-L-аспартатом (LOLA, Гепа-Мерц). Материалы и методы. Исследуемая группа включала 60 пациентов мужского пола, с диагнозом «хронический гепатит С, генотип 1» со стадией фиброза F1 по шкале METAVIR и наличием МПЭ. Средний возраст обследованных составил 34,2±5,3 года. В контрольную группу вошли 20 здоровых мужчин в возрасте 34,1±5,8 года без заболеваний печени. Основной группе проводилась интермиттирующая терапия LOLA по 15 г утром однократно в течение 2 мес с 2-месячным перерывом общей продолжительностью 12 мес. В процессе лечения оценивалась динамика МПЭ с помощью теста критической частоты слияния мельканий (КЧСМ) и теста связи чисел (ТСЧ), а также сывороточной концентрации иона аммония. Конечной точкой оценки эффективности LOLA являлась динамика частоты нарушений правил дорожного движения (ПДД). Результаты и обсуждение. Значимое снижение концентрации иона аммония отмечено через 5 мес терапии (135,53 и 82,9 мкмоль/л; р=0,002) и поддерживалось на протяжении всего исследования. Результаты КЧСМ-теста достоверно улучшились к окончанию 1-го месяца терапии LOLA (р=0,008), сохраняясь на достигнутом уровне в течение 9 мес. Показатели ТСЧ достигли минимальных значений через 5 мес (р<0,001) и сохранялись на этом уровне в течение всего исследования. За период проведения исследования частота нарушений ПДД участниками снизилась с 60 до 40% (р=0,03). Выводы. Дробная терапия LОLА ведет к снижению концентрации иона аммония в крови и, как следствие, к улучшению психометрических тестов и снижению частоты нарушений ПДД. Достигнутый результат может оказать влияние на снижение аварийности.

The majority of deaths related to complications of liver cirrhosis would have been preventable with timely diagnosis and proper treatment. However, absence of the population-based screening programs for hepatitis, an asymptomatic course of the majority of liver disorders, failures in the registration of etiologically confirmed cases of liver cirrhosis, low population awareness of its risks and of current diagnostic and management opportunities do impede the collection of reliable epidemiological data on the incidence and prevalence of liver disorders including their end-stages, and on the related mortality of the population; as a consequence, all these factors hinder a comprehensive assessment of the medical and social burden of hepatic disorders. Medical registries are the single system for their registration and follow-up. Analysis of data from the Moscow Regional Registry of patients with liver disease has shown that the leading cause of liver cirrhosis is HCV infection (66%), with alcoholic liver cirrhosis ranking second (16.1%). There is a trend towards higher proportions of liver cirrhosis as an outcome of HCV hepatitis among newly referred patients (7.2% in 2012 and 10.6% in 2016). HCV genotype characteristics determine the rates of the disease progression: in those with genotype 3, liver cirrhosis would occur at an earlier age (51.8% of patients aged from 26 to 45) than with genotype 1 (58.7% of patients aged from 46 to 65). In older patients, various comorbidities can contribute to the development of liver cirrhosis. Among patients with HBV infection, 4.9% have liver cirrhosis, and most of patients receive antiviral treatment with nucleoside/nucleotide analogues. The highest percentage of liver cirrhosis has been found in the patients with chronic D hepatitis (46/116, 39.7%). In 10.3% of the patients with chronic D hepatitis, the aggressive course of the disease leads to primary liver cancer. Thus, the necessity of the development of prevention measures and early detection of liver disorders, as well as modernization of the public healthcare system at all stages of medical care should be recognized as the short-term goals, in addition to the search for highly effective etiologic treatment and making it available within the state-financed programs.

Autoimmune hepatitis is a progressive immune-mediated liver disease of unknown etiology. Its key characteristics include hyper-gammaglobulinemia, circulating autoantibodies, and periportal inflammation seen in a liver biopsy sample. It is not infrequent that the lack of unified diagnostic tests makes the verification of the disease very challenging. Most patients respond well to standard immunosuppressive therapy; however, a significant proportion of them demonstrate side effects and disease relapses after treatment withdrawal. A wide range of side effects of systemic steroids and eventual disruptions with azathioprine (the agent of choice in the treatment algorithms for autoimmune hepatitis) supplies to the Russian market make it relevant to use alternative treatment regimens. In the real world practice, alternative treatment regimens are rarely used in such patients due to the absence of hard evidence of their efficacy. Low prevalence of autoimmune hepatitis, multiplicity of its clinical types, as well as a lack of understanding of its pathogeneticmechanisms hinder the synthesis of new agents and performing trials with already known immunosuppressants with a statistical power necessary to obtain persuasive data. One of solutions of the problem could be the accumulation of clinical data into registries for further systematization of the knowledge and formulation of new clinical guidelines.

AIM:To identify predictors for the high efficiency of short-term interferon-containing antiviral therapy (AVT) using direct-acting antivirals (DAAs) in patients with chronic hepatitis C (CHC) virus (HCV) type 1 (CHC-1). MATERIAL AND METHODS:A total of 2,798 case histories of patients aged 18 to 60 years who received AVT using peginterferon, ribavirin in combination with DAAs for CHC-1, which was stopped at 10 to 14 weeks, were selected from the archives of the healthcare facilities of the Moscow Region. The inclusion criteria were aviremia achieved when AVT was discontinued; therapy using the dose recommended in compliance with the international standards; and adherence during treatment. RESULTS:The analysis included 179 case histories, including 158 cases of discontinuation of triple AVT using a protease inhibitor (telaprevir) and 22 cases of that of quadruple treatment (QT) with asunaprevir and daclatasvir. There were two main factors predicting a high probability of achieving a sustained virological response (SVR) in patients with HCV-1 during short-term triple AVT: viremia at 28 days of AVT, which was registered by a highly sensitive polymerase chain reaction (PCR) assay (its analytical sensitivity was 12 IU/ml), and the genotype CC of interleukin-28B (IL-28B) rs12979860. With a combination of these two factors, recovery was observed in 100% of cases. SVR was observed in all cases of QT discontinuation, regardless of the stage of fibrosis and the subtype of CHC genotype. However, the resulting sample was unrepresentative. CONCLUSION:Triple AVT using a protease inhibitor may be reduced in patients with CHC-1 and the CC allelic variant in IL-28B if viremia is achieved at 28 days of AVT, as evidenced by highly sensitive PCR assay. Short-term QT needs further investigation.

Неалкогольная жировая болезнь печени (НАЖБП) и сахарный диабет 2 типа (СД2) – патологические состояния, ассоциированные друг с другом и достигающие размеров эпидемии. Одним из наиболее значимых факторов риска развития как СД2, так и НАЖБП является ожирение, которое усиливает имеющуюся инсулинорезистентность (ИР). Последняя является основным патогенетическим звеном СД2 и НАЖБП, связывая эти два патологических состояния. В настоящее время повышен интерес к поиску неинвазивных методик исследования; для оценки фиброза и определения показаний для биопсии печени неинвазивным методом используется Шкала оценки стадии фиброза при НАЖБП (NAFLD fibrosis score), расширенная панель фиброза печени (ELF) и транзиентная эластография. Однако золотым стандартом диагностики остается биопсия печени. Ввиду того, что у пациентов с СД чаще выявляется НАЖБП, чем в общей популяции, а также учитывая, что наличие СД является фактором риска прогрессии НАЖБП, данная когорта пациентов должна находиться под более тщательным контролем клиницистов. Данная обзорная работа посвящена поиску причинно-следственных связей таких коморбидных заболеваний, как НАЖБП и различные нарушения углеводного обмена, а также приоритетным направлениям диагностики НАЖБП.

Material and methods. The original study included overall 120 patients with ALD, who were randomized in two identical groups. The patients of the main group (group A) received 2 courses of therapy: the first - Phosphogliv 5 mg/day as intravenous bolus injection for 2 wks, followed by the oral intake of 2 capsules t.i.d. for 10 wks (the total treatment duration was 24 wks). Patients of the control group (group B) received placebo in the same regimen. The dynamics of serum alanine transaminase (ALT), aspartate transaminase (AST), liver scores by noninvasive FibroMax test was applied to assess the treatment efficacy and safety, along with change in quality of life of patients. Results. In 24 wks in group A in comparison to the group B significantly lower mean ALT level was found: 35,2±29,4 U/l vs 48,4±36,1 U/l (р =0,044), AST level became normal in higher rate of patients: 69,4% vs 47,7% (р =0,034), that had more prominent decrease in gamma-glutamyltranspeptidase (GGT) level - 47,4±36,5% vs 25,1±63,9% (р =0,039), the rate of patients with Aktitest A2-A3 range decreased - 8,5% vs 21,4% (p<0,05) with no patients remained in FibroTest F3-F4 range; significantly more pronounced improvement by the vitality and social functioning scales of «SF-36» questionnaire was registered. The safety profile was comparable in both groups. Conclusions. Expected effects of the drug include reduction of inflammatory activity in the liver, improvement of cholestasis at longer follow-up period, decrease in fibrosis severity, improvement of quality of life at favorable safety profile.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are pathological conditions that are co-occurring, and have been reaching epidemic proportions. One of the most significant risk factors for the development of both T2DM and NAFLD is obesity, which increases existing insulin resistance (IR). IR thought to be one of the main pathogenic causes linking T2DM and NAFLD. In recent years, there has been increased interest in obtaining non-invasive methods for assessing fibrosis and determining indications for liver biopsy, such as the NAFLD fibrosis score, extended liver fibrosis panel, and transient elastography. However, liver biopsy remains the gold standard for diagnosing NAFLD. Given that patients with T2DM are at higher risk of NAFLD than the general population, and that the presence of diabetes is a risk factor for the progression of NAFLD, patients with T2DM should be more closely monitored by clinicians. The present review paper is devoted to the search for cause-effect relationships of concurrent diseases such as NAFLD and disorders of carbohydrate metabolism, and priority areas of diagnosis of NAFLD.

The structure of HCV genotypes/subtypes and dynamics of its changes in a cohort of adult patients with chronic hepatitis C (n = 17229) was studied during 2008-2015 in the Moscow region. The prevalence of subtypes 1b and 3A HCV, whose relative density have made 47.5% (95%CI 46.8 - 48.3%) and 39.4% (95% CI 38.7 - 40.2 per cent) respectively was revealed. The average proportion of subtype 1A HCV was 5.4% (95%CI of 5.1 - 5.8%) and genotype 2 - 7.2% (95% CI 6,8 - 7,6%). It was established that the dynamics of 1b subtype HCV relative density was characterized by a moderate decline rate of 1.3% per year, while the proportion of subtype 3A HCV increased (+2.9% per year). The differences in the ratio of subtypes 1b and 3A HCV were revealed when dividing the patients by gender. The subtype 1b HCV was more frequently identified in women during the observation period. In the cohort of male patients a shift of the leading HCV subtype was detected - since 2010, the 3A subtype HCV was identified with a higher frequency than subtype 1b HCV. It was shown that in patients under 30 years the proportion of subtype 3A HCV was higher than in the age group older than 30 years, regardless of gender.

Background: Epidemiological characteristics of chronic hepatitis C virus (HCV) infection presented in the literature are not representative for the real situation with its incidence and prevalence in the Russian Federation. In the Moscow Region, which is the second largest population in the Russian Federation (7.2 million people), the Moscow Regional Registry of patients with hepatic disorders has been continuously maintained since 2010, as well as screening programs for anti-HCV positive individuals. Analysis of this data allows for generalization of the results obtain to the general population and for description of the prevalence of the infection among adult population of the Russian Federation. Aim: To analyze the epidemiological situation with chronic hepatitis C in the Moscow Region. Materials and methods: We analyzed data from the Moscow Regional Registry of patients with hepatic disorders as per April 2016, as well as the results of large scale screening of the population of the Moscow Region with oral express test for anti-HCV antibodies (OraQuick HСV Rapid Antibody Test). Based on the registry, we assessed the following parameters of the patient cohort with chronic HCV infection (n = 17 182): age, gender, HCV genotype, grade of liver fibrosis, allele variants of interleukin 28В. Within the large scale screening program among the population of the Moscow Region, 1447 individuals from 6 districts of the region were screened for anti-HCV antibodies. Results: As per April 2016, the proportion of patients with chronic viral hepatitis in the Registry was 75.3% (n = 12 938 of 17 182). The vast majority of them (80.3%, or n = 10 393) had chronic hepatitis C, with 84% (n = 8726) of referrals were patients of productive age (from 20 to 50 years). 8.4% (n = 873) of all HCV infected patients had liver cirrhosis. Although the proportion of patients with cirrhosis was negligibly low (< 1.5%) in patients below 30 years of age, it was progressively increasing with age, with a maximum of 23.8% in those above their 50-es. As far as the HCV genotype distribution is concerned, it was as follows: genotype 1, 54.1% (n = 5622) of patients, genotype 2, 7.2% (n = 747), genotype 3, 38.4% (n = 3990). According to the results of assessment of IL28B genetic polymorphisms (n = 3212), СС rs12979860, which is associated with the most favorable sensitivity to interferon α, was found in 27.5% (n = 883), СТ allele, in 58.4% (n = 1876), and ТТ in 14,1% (n = 453). Prevalence of HCV infection in the Moscow Region, assessed by the screening program, is 1.38% of adults, or 77 200 anti-HCV positive persons, whereas estimated number of patients with chronic hepatitis C may amount to 54 000 to 61 700. Conclusion: HCV infection is the most prevalent among other viral hepatites in the Moscow Region (80.3%), and the largest numbers of infected individuals are of productive age. Almost three quarters of these patients are referred for medical care at the stage of minimal liver injury, and antiviral therapy can be used on an elective basis. Knowing the proportion of patients with liver cirrhosis (8.4%) allows for planning of the need in emergency treatments. The true prevalence of HCV infection estimated from the results of the screening program is at least 5-fold higher than that in the Registry. This indicates the necessity to upgrade the system of primary assessments. In particular, it seems reasonable to include detection of anti-HCV antibodies into the list of obligatory screening laboratory tests.

Treatment of chronic hepatitis B during pregnancy is an extremely complicated issue. Despite implementation of immune prophylaxis, a significant proportion of babies born by mothers with high viral load are infected by hepatitis B virus. Cumulative data suggest that antiviral therapy in the 3 trimester of pregnancy is an effective intervention in the event of unsuccessful immune prord phylaxis. To minimize fetal effects of nucleoside and nucleotide analogues, antiviral therapy during pregnancy should be administered to mothers with high risk of disease progression and/or uncontrolled hepatitis B virus infection. The safety data obtained indicate that telbivudine and tenofovir can be used during pregnancy. Nevertheless, antiviral therapy requires a thorough assessment of the risk to benefit ratio.

Management of patients with liver cirrhosis due to viral hepatitis is complicated; nevertheless, effective treatment is possible in the majority of diagnosed cases. Etiotropic treatment should be initiated as soon as liver cirrhosis is diagnosed. Antiviral therapy is the only evidence-based and justified treatment approach in such patients. Use of hepatoprotectors with doubtful efficacy significantly reduces chances of recovery and increases likelihood of poor outcomes. During the choice of antiviral regimen, considerations must be given to disease etiology and stage as well as liver functional status. Generally accepted scales for staging of liver cirrhosis (e.g. Child-Turcotte-Pugh and MELD) are helpful in the choice of up-to-date therapy regimen, assessment of the disease prognosis and planning of radical interventions.

Treatment of chronic hepatitis B during pregnancy is an extremely complicated issue. Despite implementation of immune prophylaxis, a significant proportion of babies born by mothers with high viral load are infected by hepatitis B virus. Cumulative data suggest that antiviral therapy in the 3 trimester of pregnancy is an effective intervention in the event of unsuccessful immune prord phylaxis. To minimize fetal effects of nucleoside and nucleotide analogues, antiviral therapy during pregnancy should be administered to mothers with high risk of disease progression and/or uncontrolled hepatitis B virus infection. The safety data obtained indicate that telbivudine and tenofovir can be used during pregnancy. Nevertheless, antiviral therapy requires a thorough assessment of the risk to benefit ratio.

The structure of HCV genotypes/subtypes and dynamics of its changes in a cohort of adult patients with chronic hepatitis C (n = 17229) was studied during 2008-2015 in the Moscow region. The prevalence of subtypes 1b and 3A HCV, whose relative density have made 47.5% (95%CI 46.8 - 48.3%) and 39.4% (95% CI 38.7 - 40.2 per cent) respectively was revealed. The average proportion of subtype 1A HCV was 5.4% (95%CI of 5.1 - 5.8%) and genotype 2 - 7.2% (95% CI 6,8 - 7,6%). It was established that the dynamics of 1b subtype HCV relative density was characterized by a moderate decline rate of 1.3% per year, while the proportion of subtype 3A HCV increased (+2.9% per year). The differences in the ratio of subtypes 1b and 3A HCV were revealed when dividing the patients by gender. The subtype 1b HCV was more frequently identified in women during the observation period. In the cohort of male patients a shift of the leading HCV subtype was detected - since 2010, the 3A subtype HCV was identified with a higher frequency than subtype 1b HCV. It was shown that in patients under 30 years the proportion of subtype 3A HCV was higher than in the age group older than 30 years, regardless of gender.

Study objective. To evaluate effect of peroral administration of L-ornitin-L-aspartate (LOLA) on the frequency of road traffic accidents in persons with hepatic disease at the pre-cirrhotic stage. Material and methods. The study included 42 patients – men aged 25-45, drivers with the driving experience no less than 3 years acknowledged guilty of 3-4 road traffic accidents in the recent 3 years. All patients were diagnosed with chronic hepatitis C (genotype 1), with minimum or low activity of aminotransferase and the minimum hepatic fibrosis. Diseases that could affect performance of the road traffic accident as well as external factors (state of the car, road surfacing, weather conditions). LOLA therapy at a dosage 9 g per day was done by 2-month cycles with 2-month intervals, by the present moment the total duration reached 5 months. Each month biochemical blood analysis, blood ammonium ion concentration determination and psychometric tests were performed. Results. Ammonium ion concentration was reduced in a month after start of LOLA (from 145.4 μmol/l to 130.3 μmol/l, р = 0,016) maintaining stable tendency to reduction during the therapy until achievement of the medium level 90.4 μmol/l (р = 0.003) by the 6th month. Results of the flicker fusion frequency test significantly improved by the end of the first course LOLA (р = 0,003), remaining at the achieved level during the therapy. The results of the number connection test significantly improved by the end of the first month of therapy (р < 0.001), with maintenance of the trend on the background of the ubsequent courses. In the specified period of observation no road traffic accidents through the fault of persons included in the study, according to the data of the STSI. Conclusions. The intermitting LOLA therapy in patients with chronic hepatitis C and the minimum fibrosis reconditions quick reduction of the ammonium ion concentration in the blood and significant improvement of psychometric tests values.