Course Of Non-alcoholic Steatohepatitis Research Articles

Correction of the clinical course of non-alcoholic steatohepatitis and diabetic kidney disease in patients with type 2 diabetes

Background. The relevance of finding optimal methods to treat patients with a comorbid non-alcoholic steatohepatitis (NASH) that developed against the background of type 2 diabetes mellitus (T2DM) is due to the fact that these diseases have a number of common cause-and-effect mechanisms, and if diabetic kidney disease (DKD) develops, also mutual burden mechanisms. The purpose of the study was to find out the possible influence of a combination of metformin, rosuvastatin, essential phospholipids and quercetin on the clinical course of non-alcoholic steatohepatitis, diabetic kidney disease, type 2 diabetes mellitus, as well as on the state of the blood lipids, parameters of carbohydrate metabolism compensation, the degree of insulin resistance, which are factors for the progression of NASH and diabetic kidney disease. Materials and methods. Studies were conducted on the dynamics of treatment in 60 patients with NASH, T2DM and DKD stage I–III: 48 (80.0 %) of them had mild NASH, and 12 (20.0 %) had moderate NASH. A comorbid disease in 100 % of patients was moderate type 2 diabetes: 15 (25.0 %) people were diagnosed with diabetes in the stage of compensation, 45 (75.0 %) had subcompensated disease. Results. The positive effect of quercetin was noted by us in relation to the content of low-density lipoprotein cholesterol in the blood that was increased by 1.8 times (p < 0.05) before the treatment: a decrease after it was 1.7 times (p < 0.05) in group 2 and 1.3 times (p < 0.05) in group 1. Comprehensive therapy with the inclusion of quercetin contributed to a probable increase in anti-atherogenic high-density lipoprotein (by 1.3 times, p < 0.05) with the normalization of the indicator after the treatment, while traditional therapy in this contingent did not lead to any probable changes. Conclusions. The combination therapy for type 2 diabetes mellitus and NASH with the addition of quercetin contributed to the elimination of the main clinical and laboratory symptoms of NASH exacerbation, a probable reduction in the liver inflammation (a decrease in markers of cytolysis, mesenchymal inflammation), reversal of hepatic steatosis due to the optimization of cholesterol and triacylglycerols in the blood, a probable increase in high-density lipoproteins, normalization of glycemia, reduction of insulinemia, a decrease in the degree of insulin resistance. The effectiveness of treatment for DKD was also increased: the rate of proteinuria and the degree of hypercreatinemia decreased, and the glomerular filtration rate increased.

The glycemic profile in patients with non-alcoholic steatohepatitis and type 2 diabetes depending on diabetic kidney disease

Background. State of carbohydrate metabolism and severity of insulin resistance in the comorbid course of non-alcoholic steatohepatitis (NASH) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (DM2) is due to the cascade of possible transformation of NASH into liver cirrhosis. The purpose is to study the interaction of changes in glucose and insulin homeostasis, the degree of insulin resistance and insulin sensitivity, the degree of hemoglobin glycosylation on the clinical course of NASH associated with DM depending on the presence of DKD and its stage. Materials and methods. One hundred and eight patients with NASH and comorbid DM2 were examined. The average age of patients was 58.2 ± 6.1 years. There were 63 women (58.3 %) and 45 men (41.7 %). Depending on the presence of DKD, 4 groups of patients were formed, who were randomized by age, sex, activity of cytolytic syndrome. The comparison group consisted of 30 healthy individuals of the appropriate age and sex. The degree of hepatic steatosis and its nature were determined using SteatoTest, ASH and NASH-Test kits (BioPredictive, France). The stage of liver fibrosis was determined using FibroTest (BioPredictive, France), a set of markers for quantitative biochemical evaluation of fibrosis. Results. In patients with NASH, DM2 and DKD stage I–II, we found a significant decrease in serum albumin by 9.0 % (p < 0.05); glomerular filtration rate (GFR) and urine albumin, on the contrary, increased significantly, by 1.5 times (p < 0.05) compared to those in the control group, which indicates the phenomenon of hyperfiltration and is specific to the initial stage of DKD. When NASH is combined with DM2 and DKD stage III, a significant decrease in serum albumin by 1.2 times (p < 0.05) is reported; GFR and albuminuria were significantly increased, by 1.4 and 11.7 times (p < 0.05), respectively, compared to the control group. In patients with NASH, DM2 and DKD stage IV, we found a significant decrease in serum albumin by 1.4 times (p < 0.05), it was significantly increased by 30.2 times (p < 0.05) compared to the indicator in the control group, and the GFR, on the contrary, was significantly reduced by 1.7 times (p < 0.05), which indicates the progression of DKD. Conclusions. Disorders of glucose homeostasis due to insulin resistance are one of the probable risk factors for the progression of non-alcoholic steatohepatitis and type 2 diabetes mellitus in the presence of stage I–IV diabetic kidney disease.

THE MAIN CLINICAL AND PATHOGENETIC FEATURES OF THE COMORBID COURSE OF NON-ALCOHOLIC STEATOHEPATITIS, OBESITY AND HYPERTENSION

SUMMARY. The incidence of nonalcoholic steatohepatitis (NASH) in the population is 20–40 %, in obese patients – 50–90 %. The presence of NASH significantly reduces the quality of life of patients. The presence of concomitant arterial hypertension in patients can cause a cascade of reactions of mutual burdens, which will lead to the progression of all comorbid diseases. The aim – to investigate the differences between clinical and laboratory parameters in the comorbid course of NASH on the background of obesity. In addition, we studied the state of hepatic circulation and the functional state of the endothelium depending on the presence of comorbid hypertension. Material and Methods. Systematic review with further analysis, comparison, systematization and generalization of scientific literature in MEDLINE, Cochrane and PubMed databases of relevant articles on the study of psychological characteristics of women of childbearing age diagnosed with psychogenic infertility. Results. In recent years, NASH has increasingly been seen as an additional independent risk factor for cardiovascular disease and a predictor of its complications. The course of NASH under conditions of comorbidity with obesity in comparison with the isolated course is characterized by a predominance of hypertension of II degree (60.0 %), increased variability of systolic blood pressure (SBP) during the day with increasing duration of “pressure load” during the day. The comorbid course of NASH with obesity and hypertension (HT) there is a significant activation of the processes of liver tissue fibrosis, the content of protein-bound oxyproline in the blood, fibronectin, hexosamines, sialic acids, fucose, not bound to protein due to the activation of fibroblast growth factor, in response to which there is usually inadequate compensatory activation of collagenolysis (increase in the content of free oxyproline in the blood, which was inhibited by excessively activated proteinase-inhibitory system). Conclusions. The comorbidity of NASH with HT and obesity is a powerful pathogenetic factor that worsens the quality of life of patients to a much greater extent than the severity of a single disease. It's crucial to have multidisciplinary approach in the treatment of people with comorbidity of HT with NASH on the background of obesity.

High prevalence of periodontal disease in patients with NASH- possible association of poor dental health with NASH severity

Introduction and ObjectivesRecent translational research indicated a bidirectional relationship between NASH (non-alcoholic steatohepatitis) and periodontitis; however, few clinical cohorts have studied this in detail. Thus we investigated this assumed association in a well-defined cohort. Materials and MethodsData were generated prospectively for 132 patients (32 patients with NASH and 100 unselected, consecutively collected, anonymized controls from a local dental practice): detailed periodontal parameters, i.e., pocket-probing-depths (PPD), bleeding-on-probing (BOP), plaque-index, and utilization of dental care were assessed and correlated with relevant hepatic parameters (liver stiffness via fibroscan, AST, ALT, bilirubin, and MELD-score). Gingiva samples were tested for Porphyromonas gingvalis (P.g.) and Actinobacillus actinomyctemcomitans (A.a.) by PCR. Results87.5% of NASH patients and 47% of controls suffered from moderate to severe periodontitis (p=0.01). Liver stiffness was significantly correlated with elevated PPD (p=0.02) and BOP (p=0.03). 34 % of the NASH patients did not make use of regular dental health care. In these patients, AST (p=0.04), MELD score (p<0.01), and liver stiffness (p=0.01) were significantly elevated compared to those who see a dentist regularly. The severity of NASH was not associated with the intraoral detection of P.g. and A.a. ConclusionsThe present study suggests that NASH might be associated with periodontitis, irrespective of the intraoral presence of P.g. and A.a. Moreover, regular dental care utilization might mitigate the course of NASH, and patients should be reminded by their hepatologists of the importance of regular dental visits. Future studies should investigate the role of regular dental care and additional anti-inflammatory treatments of the oral cavity.

Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.

CCN6 improves hepatic steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis.

CCN6 is a secretory protein with functions of maintaining mitochondrial homeostasis and anti-oxidative stress; and yet, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) is still obscure. We investigated the role and mechanism of CCN6 in the development of NASH. Human liver tissue samples were collected to detect the expression profile of CCN6. High-fat-high-cholesterol (HFHC) and methionine choline-deficient (MCD) diet were applied to mice to establish NASH animal models. Liver-specific overexpression of CCN6 was induced in mice by tail vein injection of adeno-associated virus (AAV), and then the effect of CCN6 on the course of NASH was observed. Free fatty acid (FFA) was applied to HepG2 cells to construct the cell model of steatosis, and the effect of CCN6 was investigated by knocking down the expression of CCN6 through small interfering RNA (siRNA) transfection. We found that CCN6 expression was significantly downregulated in the liver of NASH. We confirmed that liver-specific overexpression of CCN6 significantly attenuated hepatic steatosis, inflammation response and fibrosis in NASH mice. Based on RNA-seq analysis, we revealed that CCN6 significantly affected the MAPK pathway. Then, by interfering with apoptosis signal-regulating kinase 1 (ASK1), we identified the ASK1/MAPK pathway pairs as the targets of CCN6 action. CCN6 protects against hepatic steatosis, inflammation response and fibrosis by inhibiting the activation of ASK1 along with its downstream MAPK signalling. CCN6 may be a potential therapeutic target for the treatment of NASH.

Microbial DNA enrichment promotes liver steatosis and fibrosis in the course of non-alcoholic steatohepatitis.

Low-grade inflammation is the hallmark of non-alcoholic fatty liver diseases (NAFLD) and non-alcoholic steatohepatitis (NASH). The leakage of microbiota-derived products can contribute to liver inflammation during NAFLD/NASH development. Here, we assessed the roles of gut microbial DNA-containing extracellular vesicles (mEVs) in regulating liver cellular abnormalities in the course of NAFLD/NASH. We performed studies with Vsig4-/- , C3-/- , cGAS-/- , and their wild-type littermate mice. Vsig4+ macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut mEVs were adoptively transferred into Vsig4-/- , C3-/- , cGAS-/- , or littermate WT mice, and hepatocyte inflammation and HSC fibrogenic activation were measured in these mice. Non-alcoholic fatty liver diseases and non-alcoholic steatohepatitis development was concomitant with a diminished liver Vsig4+ macrophage population and a marked bacterial DNA enrichment in both hepatocytes and HSCs. In the absence of Vsig4+ macrophages, gut mEVs translocation led to microbial DNA accumulation in hepatocytes and HSCs, resulting elevated hepatocyte inflammation and HSC fibrogenic activation. In contrast, in lean WT mice, Vsig4+ macrophages remove gut mEVs from bloodstream through a C3-dependent opsonization mechanism and prevent the infiltration of gut mEVs into hepatic cells. Additionally, Vsig4-/- mice more quickly developed significant liver steatosis and fibrosis than WT mice after Western diet feeding. In vitro treatment with NASH mEVs triggered hepatocyte inflammation and HSC fibrogenic activation. Microbial DNAs are key cargo for the effects of gut mEVs by activating cGAS/STING. Accumulation of microbial DNAs fuels the development of NAFLD/NASH-associated liver abnormalities.

Сравнительное исследование эффективности препарата Прогепар у пациентов с неалкогольным стеатогепатитом

Неалкогольная жировая болезнь печени (НАЖБП) является одним из самых распространенных заболеваний печени в развитых странах. В среднем ее частота достигает 20 %. У части пациентов ­НАЖБП протекает с наличием воспаления, вакуолизации гепатоцитов и последующим развитием фиброза и цирроза. Такой вариант течения НАЖБП называют неалкогольным стеатогепатитом (НАСГ). Пациенты с НАСГ подвержены более высокому риску развития осложнений, например возникновению гепатоцеллюлярной карциномы или варикозного расширения вен пищевода. Специфическая терапия НАСГ на сегодняшний день еще не разработана. Основные рекомендации для пациентов заключаются в изменении стиля жизни, что имеет определенную эффективность в снижении уровня стеатоза и активности воспаления. Однако быстро прогрессирующее течение НАСГ не всегда возможно контролировать одним только снижением калорийности диеты и увеличением уровня физической активности. Для лечения пациентов с НАСГ также используется неспецифическая терапия, которая способна замедлять прогрессирование заболевания и снижать уровень воспаления. Так как основным механизмом патогенеза НАСГ является оксидативный стресс, исследователи активно изучают действие различных антиоксидантов и их комбинаций. На сегодняшний день представлено большое количество результатов исследований подобных препаратов. Существенным ограничением большой части данных исследований является отсутствие тщательного мониторинга комплайенса и длительности выполнения пациентами рекомендаций по изменению образа жизни. Ведь в данной ситуации особый интерес должны представлять именно те пациенты, у которых высокая степень активности НАСГ сохраняется, несмотря на строгую приверженность к рекомендациям по изменению стиля жизни. В связи с этим требуется проведение дополнительных исследований по оценке эффективности фармакологической терапии у пациентов с НАСГ на фоне длительного изменения образа жизни. В этой статье мы приведем описание и результаты одноцентрового контролируемого исследования по оценке эффективности препарата Прогепар у пациентов с НАСГ с персистенцией активности воспалительного процесса на фоне модификации образа жизни.

Features of correction of markers of hepatocyte cytolysis and the degree of hepatocyte steatosis in patients with nonalcoholic steatohepatitis and type 2 diabetes with diabetic kidney disease

The relevance of the problem of the comorbid course of nonalcoholic steatohepatitis, type 2 diabetes and diabetic kidney disease lies in the rapid progression of all comorbid diseases, decompensation of carbohydrate metabolism processes, and the development of hepatocellular and renal failure. The specified comorbid diseases have a number of mutually burdening mechanisms, the elimination of which will contribute to achieving clinical remission of diseases, compensation of the functional potential of the liver and kidneys. The aim of the study was to find out the probable effect of the complex of metformin, rosuvastatin and bicyclol on the markers of hepatocyte cytolysis in patients with non-alcoholic steatohepatitis and type 2 diabetes with diabetic kidney disease, the degree of hepatocyte steatosis and the stage of liver fibrosis, which are markers of the progression of non-alcoholic steatohepatitis. Materials and methods. Depending on the prescribed treatment, the examined patients were randomly divided into 2 groups: (1 group – control: 28 people) received a hypocaloric diet taking into account the restrictions of diet No. 9, essential phospholipids (Essentiale forte H 300 mg 2 capsules 3 times a day ) for 90 days in order to treat active non-alcoholic steatohepatitis, for type 2 diabetes and hyperlipidemia metformin hydrochloride (Metformin-Teva 1000 mg per day, rosuvastatin (Rosuvastatin-Teva 5 mg once a day) was prescribed for 90 days. Group 2 consisted of patients (32 people), who, in addition to similar dietary recommendations, hypoglycemic and hypolipidemic therapy, instead of essential phospholipids, additionally received the drug Bicyclol 25 mg 3 times a day for 90 days. The average age of the patients was (53,8±3,52) years. Group comparison for the presentation of reference values of homeostasis indicators was made by 30 healthy persons of the appropriate age. Research results and their discussion. The analysis of indicators of cytolytic syndrome activity indicates that the activity of ALT increased before treatment (by 3,6 times, p&lt;0,05) – after treatment it decreased in patients of groups 1 and 2: by 2.2 and 3,7 times, respectively (p&lt;0,05) with the presence of a probable intergroup difference (p&lt;0,05). At the same time, the increased indicator of steatosis of hepatocytes before treatment, which exceeded the reference values by 4,0 times (p&lt;0,05) – under the influence of treatment also probably decreased in patients of 1 and 2 observation groups – by 1.2 and 1.8 times, respectively (p&lt;0,05) with the presence of a probable intergroup difference (p&lt;0,05). Thus, both traditional treatment with essential phospholipids and the drug Bicyclol actively affect and during 90 treatments contribute to the reduction of the main components of the pathological process in the liver in non-alcoholic steatohepatitis – cytolysis and fatty dystrophy of hepatocytes, but Bicyclol as part of complex hypoglycemic and hypolipidemic therapy has a more intense effect. It should also be pointed out that the effect of traditional therapy and the activity of liver fibrosis, according to previous studies, was probably lower than the proposed Bicyclol therapy. Thus, the significantly increased FibroTest indicator before treatment (3,2 times, p&lt;0,05) in patients with non-alcoholic steatohepatitis with comorbid diabetes mellitus and diabetic kidney disease in the dynamics of treatment in patients of group 1 decreased by 10,7% (p&lt; 0,05), and in patients of group 2 – by 40,0% (р&lt;0,05) with the presence of a probable intergroup difference (р&lt;0,05). The obtained data indicate a favorable anti-inflammatory effect of Bicyclol, which is aimed at inhibiting and preventing liver fibrosis. Conclusions from the study. Complex therapy with metformin, rosuvastatin in combination with bicyclol in people with comorbid non-alcoholic steatohepatitis, type 2 diabetes and diabetic kidney disease for 3 months contributed to the elimination of hepatocyte cytolysis syndrome, a significant decrease in steato-test and fibrotest indicators (p&lt;0.05), probable reducing the intensity of liver tissue fibrosis.

FEATURES OF CORRECTION OF MARKERS OF HEPATOCYTE CYTOLYSIS AND THE DEGREE OF HEPATOCYTE STEATOSIS IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS AND TYPE 2 DIABETES WITH DIABETIC KIDNEY DISEASE

The relevance of the problem of the comorbid course of nonalcoholic steatohepatitis, type 2 diabetes and diabetic kidney disease lies in the rapid progression of all comorbid diseases, decompensation of carbohydrate metabolism processes, and the development of hepatocellular and renal failure. The specified comorbid diseases have a number of mutually burdening mechanisms, the elimination of which will contribute to achieving clinical remission of diseases, compensation of the functional potential of the liver and kidneys. The aim of the study was to find out the probable effect of the complex of metformin, rosuvastatin and bicyclol on the markers of hepatocyte cytolysis in patients with non-alcoholic steatohepatitis and type 2 diabetes with diabetic kidney disease, the degree of hepatocyte steatosis and the stage of liver fibrosis, which are markers of the progression of non-alcoholic steatohepatitis. Materials and methods. Depending on the prescribed treatment, the examined patients were randomly divided into 2 groups: (1 group – control: 28 people) received a hypocaloric diet taking into account the restrictions of diet No. 9, essential phospholipids (Essentiale forte H 300 mg 2 capsules 3 times a day ) for 90 days in order to treat active non-alcoholic steatohepatitis, for type 2 diabetes and hyperlipidemia metformin hydrochloride (Metformin-Teva 1000 mg per day, rosuvastatin (Rosuvastatin- Teva 5 mg once a day) was prescribed for 90 days. Group 2 consisted of patients (32 people), who, in addition to similar dietary recommendations, hypoglycemic and hypolipidemic therapy, instead of essential phospholipids, additionally received the drug Bicyclol 25 mg 3 times a day for 90 days. The average age of the patients was (53,8±3,52) years. Group comparison for the presentation of reference values of homeostasis indicators was made by 30 healthy persons of the appropriate age. Research results and their discussion. The analysis of indicators of cytolytic syndrome activity indicates that the activity of ALT increased before treatment (by 3,6 times, p&lt;0,05) – after treatment it decreased in patients of groups 1 and 2: by 2.2 and 3,7 times, respectively (p&lt;0,05) with the presence of a probable intergroup difference (p&lt;0,05). At the same time, the increased indicator of steatosis of hepatocytes before treatment, which exceeded the reference values by 4,0 times (p&lt;0,05) – under the influence of treatment also probably decreased in patients of 1 and 2 observation groups – by 1.2 and 1.8 times, respectively (p&lt;0,05) with the presence of a probable intergroup difference (p&lt;0,05). Thus, both traditional treatment with essential phospholipids and the drug Bicyclol actively affect and during 90 treatments contribute to the reduction of the main components of the pathological process in the liver in non-alcoholic steatohepatitis – cytolysis and fatty dystrophy of hepatocytes, but Bicyclol as part of complex hypoglycemic and hypolipidemic therapy has a more intense effect. It should also be pointed out that the effect of traditional therapy and the activity of liver fibrosis, according to previous studies, was probably lower than the proposed Bicyclol therapy. Thus, the significantly increased FibroTest indicator before treatment (3,2 times, p&lt;0,05) in patients with non-alcoholic steatohepatitis with comorbid diabetes mellitus and diabetic kidney disease in the dynamics of treatment in patients of group 1 decreased by 10,7% (p&lt; 0,05), and in patients of group 2 – by 40,0% (р&lt;0,05) with the presence of a probable intergroup difference (р&lt;0,05). The obtained data indicate a favorable anti-inflammatory effect of Bicyclol, which is aimed at inhibiting and preventing liver fibrosis. Conclusions from the study. Complex therapy with metformin, rosuvastatin in combination with bicyclol in people with comorbid non-alcoholic steatohepatitis, type 2 diabetes and diabetic kidney disease for 3 months contributed to the elimination of hepatocyte cytolysis syndrome, a significant decrease in steato-test and fibrotest indicators (p&lt;0.05), probable reducing the intensity of liver tissue fibrosis.

Влияние кверцетина на клиническое течение неалкогольного стеатогепатита и диабетической болезни почек на фоне комплексного лечения больных сахарным диабетом типа 2

Цель исследования — установление возможного влияния комплекса средств — метформина, розувастатина, эссенциальных фосфолипидов и кверцетина на клиническое течение неалкогольного стеатогепатита (НАСГ), диабетической болезни почек, сахарного диабета (СД) типа 2, а также на состояние липидного спектра крови, параметры компенсации углеводного обмена, степень инсулинорезистентности, которые являются факторами прогрессирования НАСГ и диабетической болезни почек. Материалы и методы. Проведенные исследования в динамике лечения у 60 больных НАСГ с СД типа 2 и диабетической болезнью почек I–III стадии, среди которых у 48 пациентов был установлен НАСГ легкой активности, а у 12 — умеренной активности. Коморбидным заболеванием у всех пациентов с НАСГ был СД типа 2 средней степени тяжести, у 15 человек он был в состоянии компенсации, у 45 — субкомпенсированный. Состояние углеводного обмена устанавливали по уровню гликемии натощак и через 2 часа после еды глюкозооксидазным методом, по содержанию в крови инсулина натощак (DRG System) методом иммуноферментного анализа, содержанию в крови гликированного гемоглобина с помощью стандартных наборов реактивов «Simko Ltd» (Львов). Результаты. Через месяц от начала терапии астеновегетативный синдром значительно меньшей интенсивности сохранялся лишь у одного человека (3,13 %) второй группы, тогда как в первой группе он оставался у 9 больных (32,1 %). В то же время у большинства больных второй группы исчезли ощущение тяжести и боль в правой подреберной области (соответственно у 31 (96,9 %) против 16 (57,1 %) в первой группе (р &lt; 0,05), а также практически не беспокоили диспептические явления (24 больных второй группы (75,0 %) против 11 человек (39,3 %) в первой группе). Через месяц от начала лечения не было зарегистрировано клинических проявлений синдрома холестаза у 20 (62,5 %) больных второй группы и только у 10 больных (35,7 %) в первой группе (р &lt; 0,05). Отмечено положительное влияние дополнительного к комплексной терапии назначения кверцетина на регрессию гепатомегалии, которая после лечения в течение одного месяца оставалась лишь у 5 лиц второй группы (15,6 %). Выводы. Комплексная терапия эссенциальными фосфолипидами, розувастатином, метформином в сочетании с кверцетином у лиц с коморбидными НАСГ, СД типа 2 и диабетической болезнью почек способствует устранению основных клинико-лабораторных симптомов обострения НАСГ, снижению интенсивности воспалительного процесса в печени, обратному развитию явлений стеатоза печени, способствует нормализации гликемии. Комплексная терапия с добавлением кверцетина достоверно способствовала повышению эффективности лечения диабетической болезни почек на фоне СД типа 2, уменьшению частоты выявления протеинурии, повышению скорости клубочковой фильтрации, снижению степени гиперкреатининемии.

Features of iron homeostasis in patients with steatohepatitis of alcoholic and non-alcoholic etiology and its correlation with the intensity of oxidative stress and apoptosis

Features of iron homeostasis in patients with steatohepatitis of alcoholic and non-alcoholic etiology and its correlation with the intensity of oxidative stress and apoptosis

INTENSITY OF OXIDATIVE STRESS AS A UNIVERSAL MECHANISM OF TISSUE DAMAGE IN NONALCOHOLIC STEATOHEPATITIS AND DIABETIC KIDNEY DISEASE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS. QUERCETIN CORRECTION EFFECTIVENESS

The objective of the research was to determine the intensity of the effect of a complex of Metformin, Rosuvastatin, Essentiale Forte N and Quercetin on the state of oxidative-antioxidant homeostasis, as well as the intensity of hepatocyte apoptosis by cytokeratin-18 in the blood that are the factors in the progression of nonalcoholic steatohepatitis and diabetic kidney disease. Material and methods. 75 patients with non-alcoholic steatohepatitis with type 2 diabetes mellitus and stage I­–III diabetic kidney disease were studied over time. According to the prescribed treatment, the examined patients were divided into 2 groups: (group 1 ­– the controls: 37 patients) received a low-calorie diet with dietary restrictions No.9, essential phospholipids (Essentiale forte H 300 mg 2 caps. 3 times a day) for 30 days for the treatment of active non-alcoholic steatohepatitis, Metformin Hydrochloride (Metformin-Teva) 1000 mg per day, Rosuvastatin (Rosuvastatin-Teva 5 mg once daily) for 1 month for concomitant type 2 diabetes mellitus and hyperlipidemia. Group 2 consisted of patients (38 people) who in addition to similar dietary recommendations and therapy received additionally Quercetin and Povidone (Corvitin) 500 mg intravenously per 100 ml of isotonic chloride for 10 days. Results. It was found that the comorbid course of nonalcoholic steatohepatitis and diabetic kidney disease in patients with type 2 diabetes mellitus is accompanied by a significant increase in the intensity of oxidative stress, accompanied by an increase in blood intermediate and final products of lipid peroxidation. The damaging effect of oxidative stress in patients with type 2 diabetes mellitus leads to the activation of apoptosis of hepatocytes with an increase in blood cytokeratin-18 (7.5 times, p &lt; 0.05), the content of which correlates with the degree of oxidative stress, the intensity of liver damage and stage of diabetic kidney disease (p &lt; 0.05). Oxidative stress increases the risk of endothelial damage by atherosclerotic process due to hyperproduction of homocysteine (3.9 times, p &lt; 0.05), which contributes to the progression of diabetic kidney disease. The use of Quercetin in the complex therapy of non-alcoholic steatohepatitis and type 2 diabetes mellitus with diabetic kidney disease contributes to the reduction of oxidative stress, increased activity of antioxidant defense factors (content of reduced glutathione in erythrocytes, reduction of cytokeratin-18 content by 1.7 times) and endothelial damage (reduction of homocysteine content in blood by 1.9 times) (p &lt; 0.05). Conclusions. The comorbid course of nonalcoholic steatohepatitis and diabetic kidney disease in patients with type 2 diabetes mellitus is accompanied by a significant increase in the intensity of oxidative stress, and in the content of intermediate and final products of lipid peroxidation and oxidative modification of proteins (p &lt; 0.05).

Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments.

Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.

Peculiar features of glucose homeostasis in patients suffering from non-alcoholic steatohepatitis with comorbid obesity and osteoarthritis on the background of metadoxine and guar gum administration

To determine the probable effect of metadoxine and guar gum on glucose homeostasis during the comorbid course of non-alcoholic steatohepatitis (NASH) with obesity and osteoarthritis (OA).Material and methods. 60 patients (30 men and 30 women) with the indicated comorbidity were examined and divided into three groups: patients of group 1 - control (C) (n = 20) took Essentiale H 1 capsule 3 times a day, patients in group 2 - main group 1 (M1) (n = 20) - received metadoxine (Liveria IC) at 0.5 g twice daily, in 3 - main group 2 (M2) (n = 20) - in addition to metadoxine patients received guar gum (Guarem) 1 sachet (5 g) 2 times a day. The groups were randomized to age, sex, obesity and cytolytic syndrome activity. The control group consisted of 30 practically healthy individuals of the same age and gender. The average age of patients was (62,3 ± 5,7) years.Conclusions. The conducted analysis showed that the course of treatment with metadoxine and guar gum proved the ability to achieve stable normalization of carbohydrate metabolism over a long period of time, since guar gum together with metadoxine enhance rapid compensation of carbohydrate metabolism with impaired carbohydrate tolerance, ability to resensitize insulin receptors and eliminate insulin resistance syndrome.

Diagnostics of progression of liver fibrosis in patients with non-alcoholic steatohepatitis combined with obesity and chronic calculous cholecystitis.

The aim of the work is to investigate the diagnostic value of laboratory blood biomarkers – alanine aminotransferase, aspartate aminotransferase, oxyproline and prothrombin time in comparison with morphological indicators for diagnosis of the degree of liver fibrosis in patients with comorbid course of non-alcoholic steatohepatitis (NASH) combined with obesity and chronic calculous cholecystitis. The data of 22 patients with NASH combined with obesity and chronic calculous cholecystitis was analyzed by laboratory and morphological indicators. There were 6 (27.2%) men and 16 (72.8%) women among the patients. Liver biopsy was performed intra-operatively on performing surgical treatment of calculus cholecystitis. METAVIR and Е. Brunt criteria were used in the histological diagnosis of NASH, as well as for determination of the stage of liver fibrosis (LF). Hepatic tissue fibrogenesis was assessed by serum values of total (OPT), free (OPF) and protein-bound (OPB) oxyproline, activity of indirect fibrosis markers – alanine ami­notransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio and prothrombin time (РТТ). As a mathematical tool for modeling, stepwise discriminant analysis was used. Fibrosis of the first stage (F1) was observed in 5 (22.7%) patients, the second stage of fibrosis (F2) – in 7 (31.8%), F3 stage of fibrosis - in 10 (45.5%) patients. Analysis of the morphological study of liver biopsy samples in examined patients with NASH indicates that established histological changes combine the signs of fatty and protein degeneration of hepatocytes, inflammation and necrosis in the lobules. Among the indicators included in the mathematical model the highest diagnostic significance can be attributed to the AST / ALT ratio (F = 9.03; p = 0.003) and the level of OPF (F = 5.67; p = 0.016), whereas OPB level has the lowest value (F = 2.94; p = 0.086). Evaluation of the accuracy of the method for determining of the LF phase based on the proposed algorithm showed that the frequency of correct detecting of F1 and F2 stages of LF was 100%, for the F3 stage - 90% (1 case attributed to the F2 stage). In general, the accuracy of the method was 95.5% (95% CI 86.8-100%), sensitivity – 90.0% (95% CI 71.4-100%), specificity – 100% (95% CI 92,5 – 100%), validity - 90.0%. Evaluation of the stage of LF in patients with NASH combined with obesity and chronic calculous cholecystitis, which was determined using discriminant functions calculated from laboratory data (OPT, OPF, OPB, ALT, AST / ALT ratio and PTT), is very much in line with the corresponding results of histopathological studies of liver biopsy samples.

Clinical course features of non-alcoholic steatohepatitis on obesity background in comorbidity with chronic obstructive pulmonary disease

Objective: to elucidate clinical, ultrasonographic, and biochemical features of the course of non-alcoholic steatohepatitis (NASH) for comorbidity with grade 1 obesity, chronic obstructive pulmonary disease (COPD) of 2–3 D stages compared with NASH during obesity without COPD by studying the frequency and intensity of leading clinical and biochemical syndromes of NASH, comparison of ultrasonographic (USG) characteristics of NASH depending on the presence of COPD. Material and methods. 105 NASH patients were examined: 52 NASH patients with grade 1 obesity (1 group) (there were 18 men, 24 women); 53 NASH patients with comorbid grade 1 obesity and COPD of 2–3 D stages (group 2) (there were 28 men, 13 women). In order to determine the dependence of NASH on the presence of COPD, groups of patients were randomized by the age and the degree of obesity. The average age of the patients was (55,7 ± 3,22) years. The functional condition of the liver was determined by the generally accepted lists of enzyme activity, markers of pigment and nitrogen metabolism, proteinograms, lipidograms, ionograms, calculation of de Ritis ratio, and the USG was performed. In order to quantify the changes in liver echogenicity we have used the method of echodensitometry with the calculation of the hepatorenal index. Results. The symptoms of astheno-vegetative syndrome, dyspepsia and feeling of heaviness or pain while palpating in the right hypochondrium were observed in 2,1 times, 1,7 times and 2,5 times (p<0,05) more often in patients of the 2nd group in comparison with patients of the 1st group. Clinically, in NASH patients the syndrome of cholestasis was found in 28.8%, in comparison with NASH patients and COPD (in 62,3%). In patients of the 2nd group, the frequency of splenomegaly exceeded the indicator in the 1st group, respectively, in 2.7 times (p<0.05). Among the biochemical syndromes in the examined patients of the 2nd group was found cytolytic (100,0%), cholestatic (73,6%) syndromes, which exceeded the frequency in the 1st group in 2,3 times (p<0,05), mesenchymal inflammatory, which occurred more often as compared to the 1st group — in 1.9 times (p<0,05), and hepatocellular failure (HF) syndrome (50,9%), which occurred more often in comparison with the 1st group — in 2,6 times (p<0,05). Conclusion. The clinical course of non-alcoholic steatohepatitis for comorbidity with obesity is characterized by a high frequency and intensity of clinical syndromes, the manifestation of which increases significantly with the addition of COPD 2–3 D namely: astheno-vegetative, abdominal pain, portal hypertension, splenomegaly, cholestasis, as well as the frequency and intensity of biochemical syndromes namely: mesenchymal inflammation, cholestasis, hepatocellular failure.

Histological and histochemical features of the liver in patients with non-alcoholic steatohepatitis depending on the presence of coronary heart disease

The aim of the study — investigation of pathohistological and histochemical features of changes in liver tissue with nonalcoholic steatohepatitis (NASH) and comorbid obesity and coronary heart desease (CHD) in comparison with the course of NASH on the background of obesity.Material and methods. Eighteen specimens of the autopsy material of the liver of patients with NASH were taken for the study, including 9 persons with NASH and 9 — with NASH and comorbid CHD. The morphological examination of the liver was carried out according to the standard method. The sections were stained with hematoxylin and eosin for inspection purposes. To identify the components of connective tissue, we used the techniques of staining histological sections by chromotrope aqueous blue according to the method of N. Z. Slinchenko and bromphenol blue based on Mikel Calvo method.Results. In the presence of NASH with comorbid obesity and CHD, the percentage of hepatocytes with steatosis is 2.5 times higher (p&lt;0.05) compared to NASH without myocardial pathology. The comorbidity of NASH with CHD significantly increases the percentage of hepatocytes in the state of granular or hydropic dystrophy (in 1.2 times (p&lt;0.05)) and the percentage of hepatocytes with signs of death — mainly necrosis (1.6 times (p&lt;0.05))), sometimes apoptosis. In patients with NASH, the overall percentage of hepatocytes in the state of alteration (dystrophy, necrosis or apoptosis) is significantly lower (60.9%) (p&lt;0.05) than in patients with NASH and CHD (99.4%). Comorbidity of NASH, obesity and CHD in 100% of cases reported in hepatocyte lipofuscinosis compared to 33.3% of NASH cases without CHD (p&lt;0.009). Comorbid CHD with NASH and obesity leads to an increase in the connective tissue volume in the liver parenchyma — in 2.1 times compared with NASH (p&lt;0.05), as well as to a higher degree of its maturation.Conclusion. In patients with nonalcoholic steatohepatitis and coronary heart disease develop changes that are in close pathogenetic interconnection and manifested by venous stasis, liver hypoxia and sustained activation of free radical processes. These processes lead to persistent considerable morphological long standing changes in the liver tissue with growth and compaction, a greater degree of connective tissue maturation, and are associated with activation of liver fibroblasts.

The ultrasonographic and pathomorphological markers of liver steatosis in patients with non-alcoholic fatty liver disease depending on the presence of comorbid chronic kidney disease (chronic pyelonephritis) and obesity

Objective — to establish the peculiarities of ultrasonographic and pathomorphological changes of liver parenchyma in patients with non-alcoholic liver steatosis (NAS) and non-alcoholic steatohepatitis (NASH) depending on the presence of comorbid chronic kidney disease (CKD) and obesity Materials and methods. The examinations involved 384 patients with non-alcoholic fatty liver disease (NAFLD), from them 84 subjects with I degree obesity (1 group) were divided into 2 subgroups: 32 patients with NAS and 52 patients with NASH. The second group consisted of 270 patients with NAFLD with comorbid I degree obesity and CKD І—ІІІ stage and included 110 patients with NAS and 160 patients with NASH. The control group consisted of 90 patients with CKD of the І—ІІІ stage with normal body weight (group 3). The mean age of patients was (45.8 ± 3.81) years. Results and discussion. The study demonstrated that the comorbidity of obesity and NASH with CKD increases the degree of steatosis (the area of hepatocytes affected by fatty liver dystrophy), the degree of ballooning degeneration, hyaline-drop dystrophy; the dystrophic changes in the centrilobular zone (3) deepen in the middle of the lobe with the development of panacinar injury and the involvement of zone 1. The course of NASH with CKD is characterized by a significantly higher incidence and intensity of clinical syndromes and the degree of biochemical and histological activity, which leads to the progression of fibrotic changes in the liver F2—F3. Conclusions. The NASH and CKD comorbidity is characterized by a higher degree of liver steatosis (LSD) (hepatorenal index 1.3 times higher than in the group of patients with NASH, p < 0.05) and the higher diagnostic threshold of values of the hepatotoxic index, which in strong interdependence correlates with the degree of steatosis of the liver, determined by Steato-test (r = 0.87; p < 0.001). In patients with NAS and NASH without comorbid pathology, a significant degree of LSD was found, with NASH it exceeds the reference values by 3.3 times (p < 0.05) and with NAS — by 1.8 times (p < 0.05). In comorbidity with CKD in patients with NAS, LSD was 3.5 times higher (p < 0.05) and in patients with NASH — 4.6 times higher (p < 0.05) than the reference values (p < 0.05).

Клінічні особливості перебігу неалкогольного стеатогепатиту за коморбідності з ішемічною хворобою серця

Клінічні особливості перебігу неалкогольного стеатогепатиту за коморбідності з ішемічною хворобою серця