This review summarizes current data on the pathogenetic mechanisms of fibrosis in chronic liver diseases . Controlled inflammation and transdifferentiation of hepatic stellate cells into myofibroblasts is a key element of fibrogenesis , however , further study of the role of each of the macrophage populations is required . The initiation and progression of liver fibrosis is promoted by a complex interaction of different types of liver cells , mediated by cytokines , growth factors , miRNAs . Repeated cycles of apoptosis and regeneration of hepatocytes contribute to the pathogenesis o f f ibrosis . Modern e xperimental w ork h as p roven t he r ole o f m esenchymal s tem c ells i n l iver r egeneration b y i nhibiting t he e xpression o f t he p roapoptotic BAX g ene . The i nvolution o f l iver f ibrosis i s a ssociated w ith m onocytes o f t he p rorestorative p henotype LY6Clow. On i n v ivo m odels , r egression o f f ibrosis a nd u tilization o f t he e xtracellular m atrix d epot b y i nhibition o f miRNA-221-3p o f h epatocytes h ave b een p roven .

Патогенетическая связь между состоянием микробиоты кишечника и заболева ниями печениАНАЛИТИЧЕСКИЕ ОБЗОРЫ 1 Федеральное государственное бюджетное учреждение «Детский научноклинический центр инфекционных болезней Федерального медико-биологического агентства», 197022, г.Санкт-Петербург, Российская Федерация 2 Федеральное государственное бюджетное образовательное учреждение высшего образования «Санкт-Петербургский государственный педиатрический медицинский университет

The article presents a case of an unusual course of chickenpox in a young child (1.5 months). The development of acute hepatitis against the background of the course of the disease is described.This clinical observation clearly demonstrates that the varicella zoster virus, like other viruses from the herpes family, is secondary hepatotropic and is capable of causing acute hepatitis. This experience allows us to recommend assessing liver function in patients with chickenpox, and, if abnormalities are found, supplement the standard therapy with the appointment of hepatoprotectors.

There is a close relationship between intestine and liver, so-called ‘gut liver’ axis, especially in patients suffered from chronic liver diseases with significant degree of fibrosis. Small intestinal bacterial overgrowth and disturbance in the microbiota composition lead to an increase in the permeability of the intestinal epithelium, the development of endotoxinemia, the activation of pro-inflammatory cytokines and, as a consequence, an additional damage to hepatocytes.Objective. To estimate the incidence of bacterial overgrowth syndrome (BOS) in the small intestine in adolescents with chronic hepatitis C (CHC), to identify the interaction between this syndrome and cytolytic activity, the degree of fibrosis.Materials and methods. There is a group of 33 patients aged 12—17 years old with CHC. All children underwent a hydrogen breath test with lactulose. The degree of fibrosis was assessed by the results of liver elastography (Fibroscan), cytolytic activity was determined by the level of alanine transaminase in serum.Results. The frequency of BOS was 81.8% in the study group. As a result of the correlation analysis, no relationship was found between the development of BOS and the degree of cytolytic activity of chronic hepatitis C (criterion χ2= 0.914, p > 0.05). Also, there was no correlation between excessive bacterial contamination and the degree of fibrosis in the liver tissue (criterion χ2= 0.914,p> 0.05).Conclusion. BOS in children with CHC occurs much more often than in adults. However, no relationship was found between this syndrome and the severity of cytolytic activity, the degree of fibrotic changes in the liver.

Введение. Хронический гепатит С (ХГС) занимает лидирующую позицию среди всех хронических гепатитов. Около 71 миллиона человек в мире инфицированы вирусом гепатита С (ВГС), среди них, по разным оценкам, от 2,1 до 5 млн составляют дети до 15 лет. В большинстве случаев заболевание в детском возрасте протекает бессимптомно, однако с возрастом повышается риск развития фиброза и связанных с ним осложнений, что требует динамического контроля и своевременного назначения противовирусной терапии. Цель исследования. Определить эпидемиологические особенности и характер течения вирусного гепатита С у детей, инфицированных в раннем возрасте; проанализировать эффективность новых схем терапии препаратами прямого противовирусного действия в сравнении с терапией препаратами интерферона. Материалы и методы. В группу наблюдательного исследования вошли 559 детей с установленным диагнозом ХГС. Диагноз был подтвержден серологически (методом ИФА) и молекулярно-генетически (методом полимеразной цепной реакции - ПЦР). Степень фиброза оценивалась по результатам эластографии печени (Fibroscan). Результаты. Преобладающее большинство детей были инфицированы ВГС в результате перинатального контакта. Спонтанный клиренс отмечался не более чем в 20% случаев. По полученным данным, девочки заражались чаще мальчиков, однако с большей частотой элиминировали вирус. ХГС в детском возрасте характеризовался гладким, малосимптомным течением, однако 12% пациентов имели начальную стадию фиброза. УВО при использовании интерфероновых (ИФН) схем был достигнут у 40-53% пациентов с 1-м генотипом, у 92-100% пациентов со 2-м и 3-м генотипами. Эффективность терапии α-ИФН с рибавирином (РВ) составила 72%, пег-ИФН с РВ - 81,8%, комбинацией пег-ИФН + РВ в сочетании с каскадной плазмофильтрацией - 89,2%. Применение препаратов интерферона сопровождалось развитием нежелательных явлений, наиболее тяжело переносили введение препарата подростки старше 12 лет. Среди побочных реакций чаще всего наблюдался гриппоподобный, астеновегетативный синдромы (до 97%), несколько реже отмечались диспептические расстройства, снижение массы тела, алопеция, нервно-психические расстройства. В единичных случаях был спровоцирован дебют аутоиммунных заболеваний. На базе нашего центра подтверждено влияние полиморфизма генов rs8099917 и rs12979860 IL28B на вероятность спонтанной элиминации вируса гепатита С, а также на эффективность ПВТ. С 2019 г. начата терапия препаратами прямого противовирусного действия (ПППД), которая показала 100% эффективность при развитии минимальных нежелательных явлений. Выводы. Заболеваемость ХГС в настоящее время остается на высоком уровне. Несмотря на малосимптомное течение заболевания у детей, с возрастом значительно повышается риск развития прогрессирующего фиброза печени, жизнеугрожающих осложнений. Применение препаратов прямого противовирусного действия у детей позволяет не только своевременно начать терапию ХГС, но также избежать серьезных нежелательных явлений, связанных с лечением препаратами интерферона. Introduction. Chronic hepatitis C (CHC) occupies a leading position among all chronic hepatitis. There are about 71 million people in the world infected with the hepatitis C virus (HCV). Among them there are 2.1-5 million children under 15 years of age according to various estimates. In most cases, the disease in childhood is asymptomatic, however, with age, the risk of fibrosis and associated complications increases, that`s why requires dynamic control and timely administration of antiviral therapy. Purpose of the study. To determine the epidemiological features and nature of the course of viral hepatitis C in children infected at an early age; to analyze the effectiveness of new regimens of therapy with direct antiviral drugs in comparison with interferon therapy. Materials and methods. There are 559 children with an established diagnosis of CHC included in the observational study group. The diagnosis was confirmed serologically (by ELISA) and molecular- genetically (by polymerase chain reaction - PCR). The degree of fibrosis was assessed by the results of liver elastography (Fibroscan). Results. The vast majority of children were infected with HCV as a result of perinatal contact. Spontaneous clearance was noted in no more than 20% of cases. According to the data obtained, girls became infected more often than boys, but eliminated the virus with a greater frequency. CHC in childhood was characterized by a smooth, low-symptom course, but 12% of patients had an initial stage of fibrosis. SVR after using interferon (IFN) regimens was achieved in 40-53% of patients with genotype 1, 92-100% in patients with genotypes 2 and 3. The effectiveness of therapy for a-IFN with ribavirin (RV) was 72%, peg-IFN with RV - 81.8%, the combination of peg-IFN + RV in combination with cascade plasma filtration - 89.2%. The use of interferon preparations was accompanied by the development of undesirable phenomena; adolescents over 12 years of age hardly tolerated the administration of the drug. More often observed adverse events were flu-like, asthenovegetative syndromes (up to 97%), dyspeptic disorders, weight loss, alopecia, and neuropsychiatric disorders were noted somewhat less frequently. In isolated cases, the debut of autoimmune diseases was provoked. On the basis of our center, the influence of the polymorphism of the rs8099917 and rs12979860 IL28B genes on the probability of spontaneous elimination of the hepatitis C virus, as well as on the effectiveness of the AVT, has been confirmed. Since 2019 therapy when direct antiviral therapy (DAA) was started, it showed 100% efficiency with minimal adverse events. Conclusions. The incidence of CHC currently remains at a high level. Despite the low-symptomatic course of the disease in children, the risk of developing progressive liver fibrosis and life-threatening complications increases significantly with age. The use of drugs with direct antiviral action in children allows not only to start therapy for CHC in a timely manner, but also to avoid serious adverse events associated with treatment with interferon drugs.

Liver transplantation today is the only radical method of treatment decompensating fulminant and chronic liver failure. The operation technic and patient care improvement made it possible to achieve a high survival rate. Transplantation has become an available and safe method for children, including patients weighing less than 10 kg. However, at the moment there are a number of unsolved problems. Postoperative complications can significantly affect the results of transplantation. This article provides a Russian and foreign literature overview, reflecting the achievements in the field of liver, identifying current problems and solutions.

This review is dedicated to nowaday methods of liver fibrosis diagnostic in children. The article presents various types of puncture biopsy of the liver. Implementation of the immunohistochemical method in the morphological analysis of biopsy samples allows us to expand our understanding of the pathogenesis of chronic liver diseases, the role of the concomitant infectious agent in the progression of the disease and its outcomes. Instrumental methods for visualizing fibrosis with an assessment of their diagnostic significance are observed in the article. Ultrasound is a screening method among instrumental examination. Computed and magnetic resonance imaging are obligate imaging methods for suspected fibrosis, but they are do not allow to verify its stage. The advantages and disadvantages of various types of elastography are presented. Promising directions of fibrosis diagnostics are associated with scintigraphy, acoustic structural quantitative analysis. Special attention is paid to serum markers for assessing the stage of liver fibrosis in children; data about the role of several fibrosis markers, such as hyaluronic acid, type IV collagen, transforming growth factor1, as well as APRI, FIB-4, FibroTest indices in children are presented. Further study of the pathogenetic aspects of fibrogenesis, exploration of new non-invasive techniques for differentiation the intermediate stages of liver fibrosis, and the development of its prognostic criteria are required.

Family hemophagocytic lymphohistiocytosis (hemophagocytic syndrome) is a rare hereditary disease, which is based on a disturbance of the regulation of the immune response, leading to proliferation and activation of histiocytes, phagocytosis of peripheral blood cells. The most common mutations include – PRF1, UNC13D, STX11. Two cases of familial hemophagocytic lymphogystyocytosis in children of an early age from a single family, features of the course are described.

This review presents the current possibilities of diagnosis of children’s liver disease: to define avidity of antibodies to hepatitis A, C for detection early infection, the development of non-invasive panel of serum markers of fibrosis and the introduction of elastography liver, as an alternative to needle biopsy. Indicated promising directions in the therapeutic tactics of viral hepatitis in children associated with the use of combined schemes of parenteral interferon (IF), including pegylated, in conjunction with similar nukleoz(t) ides, IF inducers.

We have performed primary examination of 50 children with neonatal hepatitis. Prevalence of herpes infection as the etiologic agent (40,0%) has been found, as well as parenteral hepatitis, both as an isolated (26,0%) and mixed infections. We conducted a comparative analysis of clinical and laboratory data at initial examination and determined the outcomes of neonatal hepatitis to 12 months of life depending on the etiology. Congenital CMV- etiology hepatitis characterized by more cytolysis, mainly due to aspartate aminotransferase and cholestasis, which is 33,3% of cases combined by acholia and urobiliya. In 50,0% of patients with CMV-hepatitis was detected fibrosis with a mean value of liver elastography 9,9 kPa, which is ІІІ degrees of fibrosis METAVIR scale, whereas in children with primary chronic hepatitis C and concomitant HCV + DNA-virus infection fibrosis was not registered. Despite on the large number of modern non-invasive techniques for determining the degree of hepatic fibrosis, the use of its in children during the first months of life is limited and does not allow to predict disease outcome.

We anylised results of elastography of 77 patients with chronic liver diffus lesions including: viruses hepatitis B, C, D – 50, autoimmune – 16, metabolic disease – 6, neonatal hepatities – 5 persons. Fibrosis stage was assessed on METAVIR scail. For patients with viruses hepatitis B, C with an averege duration of disease 9,8±0,7 years, a minimum fibrosis stage (F0-1) and low cytolytic activity were indicated. Patients with viruses hepatitis D were characterised by F2 fibrosis stage at the level of hyperenzemia to 4-5 rate, and history of the disease – 10,3±1,8 years. Patients with metabolic liver damage showed signs of modarate fibrosis at 10,3±1,8 years. Heavy fibrosis was marked in autoimmune hepatitis with duration of disease 5 years and indicators of ALT to 3 rate. Neonatal hepatities were characterised by the highest level of cytolysis and by development of fibrosis in 80% of cases with 0,9+0,3 year history of the disease.

Recently, the share of children with verified neonatal hepatitis induced by genetic predisposition, malformations of biliary tracts, inborn infections with affection of hepatobiliary system increased. The comprehensive biochemical examination of 62 children aged from 1.5 months to 2 years old with diagnosis of neonatal hepatitis. The changes of standard indicators of cytolysis, cholestasis and protein metabolism were on average moderate in group with reliable increase of protein concentration of acute phase of inflammation. The peak changes of biochemical indicators during primary examination are revealed in group of children with malformations of hepatobiliary system conditioned by viruses of herpetic group and in the process of development of expressed fibrosis of liver up to first year of life. The detection of proteins of acute phase makes it possible to objectively evaluate the presence of prolonged inflammatory process in liver and to promote prognosis of course of neonatal hepatitis in children of early age and timely correction of therapy and improvement of outcomes of disease. The detection of C-reactive protein, alpha2-macroglobulin and alpha1-antitripsin is recommended to be included into algorithm of examination of children with neonatal hepatitis.