Generation of an induced pluripotent stem cell line ICGi030-A from a Wilson's disease patient carrying a frameshift mutation p.Lys1013fs and missense mutation p.H1069Q in the ATP7B gene.

Wilson's disease is a rare autosomal recessive disorder of copper metabolism. The copper accumulation in the viscera appears due to the functional impairment of copper-transporting ATPase, which is encoded by the ATP7B gene. In this study, PBMCs of a patient with two ATP7B mutations were reprogrammed. The first mutation is a missense mutation p.H1069Q, which is the most frequent mutation in the human population. At the same time, the second one is a frameshift mutation p.Lys1013fs. The generated iPSC line had a normal karyotype, maintained the original genotype, expressed pluripotency markers, and demonstrated the ability to differentiate into derivatives of the three germ layers.

[Efficacy and safety of bulevirtide in patients with chronic hepatitis D and compensated cirrhosis].

AIM: To study the efficacy and safety of bulevirtide, the HBV and HDV entry inhibitor. MATERIALS AND METHODS: Analysis of the results of using bulevirtide in randomized controlled open-label comparative studies MYR202 and MYR203 in 56 patients with chronic hepatitis D and compensated cirrhosis, in monotherapy and combination with pegylated interferon alpha-2a (PEG-IFN). RESULTS: Monotherapy with bulevirtide for 24 weeks in the MYR202 study in 46 patients with compensated liver cirrhosis demonstrated: 1) a high rate of virological (100%) and biochemical response (alanine aminotransferase normalization rate 45.7%), 2) superiority of bulevirtide in efficacy over the control group (tenofovir), 3) comparability of treatment efficacy in patients with and without cirrhosis, 4) no progression of liver fibrosis with elastometry in most patients. Treatment with bulevirtide in monotherapy and combination with PEG-IFN for 48 weeks in 10 patients with compensated liver cirrhosis in the MYR203 study was accompanied by a high rate of virological response (80%) and normalization of alanine aminotransferase (70%). Bulevirtide was well tolerated, there was no deterioration in tolerability compared with patients without cirrhosis, there were no serious adverse events and cases of treatment cancellation due to adverse events. CONCLUSION: Bulevirtide is recommended as the first line of treatment for chronic hepatitis D in patients with compensated cirrhosis in monotherapy and combination with PEG-IFN.

Generation of two induced pluripotent stem cell lines from peripheral blood mononuclear cells of a patient with Wilson's disease.

Wilson's disease is an inherited disorder associated with copper accumulation in the liver, brain and other vital organs. Wilson's disease is caused by mutations in the ATP7B gene. Over 300 mutations of ATP7B have been described. Despite the disease is autosomal recessive, the patient whose PBMCs were reprogrammed in the study harbours heterozygous mutation c.3207C > A (p.H1069Q). Detailed analysis of the ATP7B complete gene sequencing data has not revealed other known disease associated mutation. The generated iPSC lines maintained the original genotype, expressed pluripotency markers, had normal karyotype and demonstrated the ability to differentiate into derivatives of the three germ layers.

Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018).

The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications.

Pharmacotherapy of chronic pancreatitis in terms of current clinical recommendations.

The article reflects the main positions of the latest Russian and pan-European clinical recommendations on the diagnosis and treatment of chronic pancreatitis (CP), devoted to the pharmacotherapy of this disease. The main objectives of pharmacotherapy for CP are to reduce or arrest pain abdominal syndrome and prevent or compensate for functional pancreatic insufficiency.

Important problems in the diagnosis and treatment of autoimmune hepatitis (based on the Russian consensus 2017).

The analysis of publications devoted to the Russian Consensus on the Diagnostic and Treatment of Autoimmune Hepatitis (AIH), which was considered at the 43rd annual Scientific Session of the CNIIG From Traditions to Innovation (March 4, 2017) is carried out. The presence of clear algorithms and recommendations for the diagnosis and treatment of AIH significantly help the doctor in real clinical practice, but do not exclude a personified approach to the patient.

[Predictors of the efficiency of short-term interferon-containing therapy using direct-acting antiviral drugs in patients with chronic hepatitis C virus genotype 1]. / Prediktory éffektivnosti korotkogo kursa interferonsoderzhashchei terapii s primeneniem preparatov priamogo protivovirusnogo deistviia u patsientov s khronicheskim gepatitom, vyzvannym virusom gepatita S 1-go genotipa.

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.

[Nonalcoholic fatty liver disease without obesity: the problem to be solved]. / Nealkogol'naia zhirovaia bolezn' pecheni bez ozhireniia: problema, ozhidaiushchaia resheniia.

It is generally agreed that nonalcoholic fatty liver disease (NAFLD) is a component of metabolic syndrome and is frequently associated with obesity, type 2 diabetes mellitus, atherogenic dyslipidemia, and other components of the syndrome. However, there is no doubt that not all overweight people develop NAFLD and, conversely, the latter may be present in normal weight individuals. The prevalence of NAFLD without obesity in different countries is very variable from 3 to 30%. Its risk factors are considered to be both exogenous (for example, excess intakes of cholesterol and rapidly assimilable fructose) and genetically determined (allelic variants of the genes encoding adiponutrin, the cholesteryl ester transport protein, sterol-regulatory element-binding protein 2). The methods for the diagnosis of NAFLD without obesity do not differ in essence from those for classic NAFLD. Analysis of the conducted investigations gives grounds to claim that lifestyle modification as exercises and dietary restrictions improves biochemical parameters and histological pattern. The efficiency of drug treatments needs further investigation.

[Apoptosis of peripheral blood mononuclears and evaluation of the effectiveness of antiviral therapy of chronic C hepatitis].

The effects of combined antiviral therapy on the apoptosis of peripheral blood mononuclears (PBM) were investigated in 54 patients with chronic hepatitis C (CHC), including patients with chronic viral-and-alcohol hepatitis (CVAH). Simultaneously, serum concentrations of cytokines (tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukins 10 and 12) using flow cytofluorimetry were taken. The results demonstrate an increase in the intensity of PBM apoptosis in patients with CHC and CVAH vs. controls; there was a tendency of lesser apoptosis intensity in the CVAH subgroup. In both groups IFN-gamma and TNF-alpha concentrations were increased, and there was a direct correlation between the level of apoptosis and TNF-alpha concentration. The study found an increase in the intensity of apoptosis in CHC patients with primary virological response to antiviral therapy with IFN-alpha and riboflavin, which can be considered an additional prognostic factor of the effectiveness of treatment.

[Treatment of autoimmune hepatic diseases]. / Lechenie autoimmunnykh zabolevanii pecheni.

The immunosuppresive drugs, primarily glucocorticosteroids, serve as the basis for the pathogenetic treatment of autoimmune diseases of the liver. In autoimmune hepatitis, immunosuppressive therapy induces and maintains persistent remission in most patients while in primary biliary cirrhosis and primary sclerosing cholangitis, its capacities are substantially limited. Ursodeoxycholic acid is used as the basic drug in predominantly occurring intrahepatic cholestasis. The treatment of cross autoimmune syndromes generally requires the choice of a combination of drugs.

[The role of Fas/FasL system in induction of hepatocyte apoptosis in chronic viral hepatitides]. / Rol' sistemy Fas/FasL v induktsii apoptoza gepatotsitov pri khronicheskikh virusnykh gepatitakh.

The aim of the study was assessment of hepatocyte apoptosis depending on expression of Fas and FasL proteins by various liver cells in patients with chronic viral hepatitis B (CVHB) or chronic viral hepatitis C (CVHC). The symptoms of hepatocyte apoptosis were observed in 3 of 12 patients with CVHB and in 9 of 14 patients with CVHC, the proportion of apoptotic cells being 12-65%. Hepatocytes of healthy people and patients with hepatitis B or C express Fas protein in the cytoplasm diffusely, as granules or on cell membrane. In health, hepatocytes do not express FasL, but in CVH they do. The highest apoptosis was observed in Fas protein location as granules in cytoplasm or in their preferable location on the cell membrane. The severity of hepatocyte apoptosis in CVH directly correlated with FasL expression by the cells of the lymphoid-histiocytic infiltrate in the liver and inversely correlated with FasL expression by hepatocytes. Thus, a great part of hepatocytes in CVH are killed by the virus; Fas/FasL interaction is leading in damage to hepatocytes in CVH.

[The treatment of hepatic encephalopathy with Hepa-Mertz]. / Lechenie pechenochnoi éntsefalopatii preparatom gepa-merts.

A course of hepamerz treatment (7 intravenous drip infusions followed by oral administration for 14 days) was tried in 14 patients with hepatic cirrhosis to clarify hepamerz effects on hepatic encephalopathy and hyperammonemia which were judged by blood ammonium levels and time of psychomotor tests. All the patients responded. Fasting ammonium levels reduced in 67%, after meal in 82% of patients, 68% improved their psychomotor parameters. Transient nausea as a side effect occurred in 3 patients.

[Autoimmune liver diseases: the relation to other autoimmune pathology]. / Autoimmunnye zabolevaniia pecheni: sviaz' s drugoi autoimmunnoi patologiei.

The paper reviews literature on association of primary biliary cirrhosis and autoimmune chronic active hepatitis with other autoimmune diseases. Included are the data on statistics of a number of diseases with histological findings and autoantibodies detection. A basic role of immunological tolerance infringement in pathogenesis of systemic involvement in autoimmune liver diseases is emphasized. Mechanisms leading to development of systemic autoimmune processes are considered.