ANTIVIRAL THERAPY IN LIVER CIRRHOSIS

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

EXPRESSION OF TLR2, TLR3, TLR4 AND PROINFLAMMATORY TNF AND IL-6 CYTOKINES IN LIVER BIOPSIES OF NONALCOHOLIC FATTY LIVER DISEASE PATIENTS

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

ACE inhibitors in arterial hypertension management: zofenopril – class-specific effects and extra benefits

The review is devoted to ACE inhibitor therapy in arterial hypertension (AH) management. The mechanisms of ACE inhibitors’ effects on oxidative stress, endothelial dysfunction, insulin and glucose metabolism are discussed. The data on pharmacological characteristics of zofenopril and its use in AH are presented

Alternative treatment regimens in autoimmune hepatitis: how justified is their choice?

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

LATENT HEPATIC ENCEPHALOPATHY IN PATIENTS WITH MINIMUM HEPATIC FIBROSIS

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

Liver cirrhosis in the Moscow Region: figures and facts

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

CHRONIC HEPATITIS B VIRUS INFECTION IN PREGNANCY: STRATEGIES OF ANTIVIRAL THERAPY

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

Epidemiology of hepatitis C in the Moscow Region: data from the Moscow Regional Registry and screening for HCV antibodies

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

The Structure of Hepatitis C Virus Genotypes/Subtypes in Adult Patients with Chronic Hepatitis C in the Moscow Region

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

Combined antihypertensive therapy in patients with chronic obstructive pulmonary disease

Aim. To investigate endothelium-regulating and antioxidant effects of trandolapril and verapamil SR combination (Tarka) in patients with arterial hypertension (AH) and chronic obstructive pulmonary disease (COPD).Material and methods. In total, 42 COPD and AH patients, aged 48-70 years, were examined. All participants received continuous basis COPD treatment and 16-week Tarka therapy. At baseline and at the end of the study, lung function, systemic inflammation, oxidative stress and antioxidant potential parameters were measured.Results. All patients achieved office-measured target blood pressure (BP) levels. Bronchial conductivity increase was explained by therapy-associated improvement in pulmonary hemodynamics. The medication was safe and well-tolerated by patients with COPD and AH. Decrease in C-reactive protein levels, possibly explaining antiinflammatory medication effect, pointed to the suppression of endothelium-damaging influences. The treatment was also associated with decreased lipid peroxidation, reduced serum levels of acylhydroperoxides, and increased concentration and activity of antioxidant enzymes.Conclusion. AH and COPD therapy should include antihypertensive agents with pleiotropic effects, specifi- cally, suppressing systemic inflammation, correcting endothelial function, and enhancing antioxidant potential. These characteristics could act as additional criteria of AH treatment effectiveness in patients with combined cardiovascular and respiratory pathology