Hepatocyte Cytolysis Research Articles

Biliary tract dysfunctions: Possibilities of combined drugs of plant origin as advantage therapy

Introduction. Non-alcoholic fatty liver disease (NAFLD) is caused by excess accumulation of fats in hepatocytes. An increasing percentage of adipose tissue is associated with chronic inflammation and developing oxidative stress. These pathological conditions can lead to the progression of steatosis to steatohepatitis with the further development of fibrosis and cirrhosis.Aim. To evaluate the indicators of lipid peroxidation and antioxidant defence factors in steatosis and steatohepatitis in patients with NAFLD.Materials and methods. During the work, 116 patients with NAFLD were examined, of which 65 had steatosis, and 51 had steatohepatitis. The study of biochemical markers of metabolism of proteins, fats and carbohydrates was performed on a Mindray BS-380 biochemical analyzer. The indicators of the LPO-AOD system (MDA, SOD, catalase, ceruloplasmin) were assessed using spectrophotometric methods. Statistical data processing was carried out in the STATISTICA and SPSS 26 programs using nonparametric tests.Results. Patients with steatohepatitis had more severe dyslipidemia, blood triglyceride, total cholesterol levels and LDL were significantly higher (p > 0.05). Impaired cholesterol metabolism was reflected by a high atherogenic index of 3.46. In patients with steatosis, changes in the lipid profile were less pronounced. No disturbances in protein and carbohydrate metabolism were detected. Increased levels of liver markers were noted only in patients with steatohepatitis. The change in the balance in the LPO- AOD system was more pronounced in patients with steatohepatitis; they had a high level of MDA, a high concentration of catalase; in patients with steatosis, only a decrease in the level of MDA and an increase in the level of ceruloplasmin were noted.Conclusion. Dyslipidemia, hepatocyte cytolysis and liver fibrosis are detected in patients with steatohepatitis. Disturbances in the LPO-AOD system have been identified in both forms of NAFLD, but in steatosis they are compensated. In steatohepatitis, disturbances in “LPO-AOD” in the form of an increase in pro-oxidants and a decrease in antioxidants cause the development of oxidative stress.

Traits of the lipid peroxidation – antioxidant defence system in non-alcoholic fatty liver disease

Introduction. Non-alcoholic fatty liver disease (NAFLD) is caused by excess accumulation of fats in hepatocytes. An increasing percentage of adipose tissue is associated with chronic inflammation and developing oxidative stress. These pathological conditions can lead to the progression of steatosis to steatohepatitis with the further development of fibrosis and cirrhosis.Aim. To evaluate the indicators of lipid peroxidation and antioxidant defence factors in steatosis and steatohepatitis in patients with NAFLD.Materials and methods. During the work, 116 patients with NAFLD were examined, of which 65 had steatosis, and 51 had steatohepatitis. The study of biochemical markers of metabolism of proteins, fats and carbohydrates was performed on a Mindray BS-380 biochemical analyzer. The indicators of the LPO-AOD system (MDA, SOD, catalase, ceruloplasmin) were assessed using spectrophotometric methods. Statistical data processing was carried out in the STATISTICA and SPSS 26 programs using nonparametric tests.Results. Patients with steatohepatitis had more severe dyslipidemia, blood triglyceride, total cholesterol levels and LDL were significantly higher (p > 0.05). Impaired cholesterol metabolism was reflected by a high atherogenic index of 3.46. In patients with steatosis, changes in the lipid profile were less pronounced. No disturbances in protein and carbohydrate metabolism were detected. Increased levels of liver markers were noted only in patients with steatohepatitis. The change in the balance in the LPO- AOD system was more pronounced in patients with steatohepatitis; they had a high level of MDA, a high concentration of catalase; in patients with steatosis, only a decrease in the level of MDA and an increase in the level of ceruloplasmin were noted.Conclusion. Dyslipidemia, hepatocyte cytolysis and liver fibrosis are detected in patients with steatohepatitis. Disturbances in the LPO-AOD system have been identified in both forms of NAFLD, but in steatosis they are compensated. In steatohepatitis, disturbances in “LPO-AOD” in the form of an increase in pro-oxidants and a decrease in antioxidants cause the development of oxidative stress.

Peculiarities of pharmacological prevention strategy of pancreatic complications after endoscopic papillosphincterotomy for choledocholithiasis

The most frequent complication of endoscopic papillosphincterotomy (EPST) is acute pancreatitis. This complication is supposed to be based on mechanical, chemical, hydrostatic, enzymatic and thermal impact on pancreatic ducts and parenchyma. According to different literature data, the incidence of post-EPST pancreatitis (PEP) varies from 30 to 40%, and the mortality rate is 2-10%. The aim of the investigation was to expand information about peculiarities of early diagnostics and prevention of post-EST pancreatitis at the present stage. To reach the set goal we analyzed 559 case histories of patients with diagnosed cholelithiasis, 319 of them underwent EPST. During the study it was found out, that elevated neutrophils/lymphocytes ratio over 4,96 (p=0,001), high LDH level over 250 IU/ml (p=0,01), as well as C-reactive to albumin index over 0,180 (p=0,001) are reliable markers of early diagnosis. Also, indirect diagnostic markers of PEEP are biochemical signs of cholestasis and cytolysis of hepatocytes, as well as hyperglycemia combined with glucosuria. We consider the inclusion of intraoperative injections of papillotomy wound margins with Epinephrine in combination with subsequent Somatostatin administration in combination with rectal Diclofenac and intravenous hydration with Reamberin to be the most effective strategy for PEP prevention. Thus, we can conclude that despite the ongoing research and the search for effective algorithms for the prevention and early diagnosis of PEP, their data often contradict each other or simply do not confirm their effectiveness. The problem of prevention and diagnosis of PEP remains complex and requires further study. There are discrepancies, sometimes significant ones, in the current literature, which provides grounds for the development and research of new methods of early diagnosis and prevention.

Peculiarities of pharmacological prevention strategy of pancreatic complications after endoscopic papillosphincterotomy for choledocholithiasis

The most frequent complication of endoscopic papillosphincterotomy (EPST) is acute pancreatitis. This complication is supposed to be based on mechanical, chemical, hydrostatic, enzymatic and thermal impact on pancreatic ducts and parenchyma. According to different literature data, the incidence of post-EPST pancreatitis (PEP) varies from 30 to 40%, and the mortality rate is 2–10%. The aim of the investigation was to expand information about peculiarities of early diagnostics and prevention of post-EST pancreatitis at the present stage. To reach the set goal we analyzed 559 case histories of patients with diagnosed cholelithiasis, 319 of them underwent EPST. During the study it was found out, that elevated neutrophils/ lymphocytes ratio over 4.96 (p = 0.001), high LDH level over 250 IU/ml (p = 0,010), as well as C-reactive to albumin index over 0,180 (p = 0.001) are reliable markers of early diagnosis. Also, indirect diagnostic markers of PEEP are biochemical signs of cholestasis and cytolysis of hepatocytes, as well as hyperglycemia combined with glucosuria. We consider the inclusion of intraoperative injections of papillotomy wound margins with epinephrine in combination with subsequent Somatostatin administration in combination with rectal diclofenac and intravenous hydration with Reamberin to be the most effective strategy for PEP prevention. Thus, we can conclude that despite the ongoing research and the search for effective algorithms for the prevention and early diagnosis of PEP, their data often contradict each other or simply do not confirm their effectiveness. The problem of prevention and diagnosis of PEP remains complex and requires further study. There are discrepancies, sometimes significant ones, in the current literature, which provides grounds for the development and research of new methods of early diagnosis and prevention.

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism

Background & AimsThe constitutive androstane receptor (CAR) is a nuclear receptor that binds diverse xenobiotics and whose activation leads to the modulation of the expression of target genes involved in xenobiotic detoxification and energy metabolism. Although CAR hepatic activity is considered to be higher in women than in men, its sex-dependent response to an acute pharmacological activation has seldom been investigated. MethodsThe hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or with vehicle. ResultsAlthough 90% of TCPOBOP-sensitive genes were modulated in a sex-independent manner, the remaining 10% showed almost exclusive female liver specificity. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation, and extracellular matrix organisation. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and was associated with a decrease in hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a potential role in the control of TMAO homeostasis, CAR activation decreased platelet hyper-responsiveness in female mice supplemented with dietary choline. ConclusionsMore than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic responses such as platelet aggregation. CAR activation may be an important mechanism of sexually-dimorphic drug-induced liver injury. Impact and implicationsCAR is activated by many drugs and pollutants. Its pharmacological activation had a stronger impact on hepatic gene expression and metabolism in females than in males, and had a specific impact on liver toxicity and trimethylamine metabolism. Sexual dimorphism should be considered when testing and/or prescribing xenobiotics known to activate CAR.

Methods of early diagnosis and pharmacological prevention of pancreatitis after endoscopic papillosphincterotomy

Introduction. The most frequent complication of endoscopic papillosphincterotomy (EPST) is acute pancreatitis. This complication is supposed to be based on mechanical, chemical, hydrostatic, enzymatic and thermal impact on pancreatic ducts and parenchyma. According to different literature data, the incidence of post-EPST pancreatitis (PEP) varies from 30 to 40 %, and the mortality rate is 2–10 %.The aim of the investigation was to expand information about peculiarities of early diagnostics and prevention of post-EST pancreatitis at the present stage.Materials and methods. To reach the set goal we analyzed 559 case histories of patients with diagnosed cholelithiasis, 319 of them underwent EPST.Results. During the study it was found out, that elevated neutrophils/lymphocytes ratio over 4,96 (p = 0,001), high LDH level over 250 IU/ml (p = 0,01), as well as Creactive to albumin index over 0,180 (p = 0,001) are reliable markers of early diagnosis. Also, indirect diagnostic markers of PEEP are biochemical signs of cholestasis and cytolysis of hepatocytes, as well as hyperglycemia combined with glucosuria. We consider the inclusion of intraoperative injections of papillotomy wound margins with Epinephrine in combination with subsequent Somatostatin administration in combination with rectal Diclofenac and intravenous hydration with Reamberin to be the most effective strategy for PEP prevention.Conclusions. Thus, we can conclude that despite the ongoing research and the search for effective algorithms for the prevention and early diagnosis of PEP, their data often contradict each other or simply do not confirm their effectiveness. The problem of prevention and diagnosis of PEP remains complex and requires further study. There are discrepancies, sometimes significant ones, in the current literature, which provides grounds for the development and research of new methods of early diagnosis and prevention.

Предиктори цитолізу гепатоцитів інсулінорезистентних щурів за умов пре- та постнатального йододефіциту

Carbohydrate metabolism markers, thyroid profile indexes, transaminase activity and structural features of liver were studied, taking into account sexual dimorphism, in rats which were keeping on a high-fructose diet under conditions of adequate iodine supply and pre- and postnatal iodine deficiency. It was found that under fructose loading of animals with iodine deficiency the risk of insulin resistance (IR) development increases (HOMA-IR index in insulin-resistant male rats under conditions of pre- and postnatal iodine deficiency increases respectively by 22 and 13% compared to the data in animals that received a high-carbohydrate diet and adequate iodine supply). It is important, that in males and females with IR, the secretion of free triiodothyronine decreased by 36 and 40%, thyroid-stimulating hormone – by 28 and 34%, respectively, compared to the data of intact animals. The development of IR was accompanied by the activation of aminotransferases in blood serum (more in males). In particular, in male rats with IR under conditions of pre- and postnatal iodine deficiency, the activity of aspartate aminotransferase increased by 2.7 and 2.4 times, alanine aminotransferase – by 3.9 and 2.7 times, respectively, which led to a decrease of the de-Ritis index (more significantly against the background of prenatal iodine deficiency – by 25%) in relation to the data in animals that were on a standard diet. The activity of aminotransferases in rats with IR under conditions of iodine deprivation was higher than in animals with isolated iodine deficiency – by 11-56% and IR – by 13-47 %. In animals with IR, the presence of binucleated hepatocytes with a diffuse decrease in the number of glycogen granules in them and accumulation of glycoproteins in the wall of liver vessels were found. The foci of fatty dystrophy and pronounced zonal character of dystrophic processes in hepatocytes were identified in females, diffuse dystrophy prevailed in males. In the cytoplasm of hepatocytes of animals with IR under conditions of prenatal iodine deficiency, the lightening and the granularity, single granules of glycogen were observed. Under these conditions, the average perimeter (by 74%) and area (by three times) of hepatocytes, the average area of nucleus (by 3.1 times), the average perimeter (by 50%) and area (by 66%) of the nucleolus were increased compared to the control values. The structural changes were consistent with an increase of the transaminase activity. Thus, fructose loading and the development of IR acts as a trigger for cytolysis of hepatocytes, which increases under conditions of iodine deficiency, especially prenatal.

Comparative Evaluation of the Effect of Hepatoprotectors on Oxidative Homeostasis in the Blood of Patients with Alcoholic Hepatitis: A Randomized Experimental Study

Background. An analysis of published results on the chemical structure, pharmacodynamics and pharmacokinetics of hepatoprotective agents, as well as their practical application, shows that a holistic view on the pharmacology of hepatoprotective agents is yet to be developed. Thus, the relationship between antioxidant activity and the effectiveness of reducing hepatocyte cytolysis remains unclear. Another difficult question concerns indications for the application of hepatoprotectors, selection of a particular drug and treatment duration.Objectives. To investigate the effects of hepatoprotective agents with different mechanisms of action on the indicators of oxidative metabolism in the blood of patients with alcoholic hepatitis.Methods. Four groups of patients were involved in the study. The 1st group consisted of relatively healthy male patients (n = 15). The remaining groups (10 individuals in each) were represented by patients with moderate alcoholic hepatitis. Patients of the 2nd group received remaxol; patients of the 3rd group received ademetionine; patients of the 4th group received ursodeoxycholic acid. Prior to and following treatment, the indicators of cytolysis and oxidative stress in blood were determined. Statistical data processing was carried out using the StatPlus v 7 (AnalystSoft Inc.) software package.Results. According to the observed changes in the cytolytic syndrome marker enzymes, all three hepatoprotectors under study expressed comparable efficacy. After treatment according to any of the applied schemes, the ALT and AST activity in the blood plasma decreased by 56–68% and 75–81%, respectively, compared to their initial values. In comparison with the control group, the total antioxidant activity of the blood plasma decreased by 20–27%; the content of TBA-reactive products in the erythrocyte suspension increased by 61–87%. The remaxol, ademethionine or ursodeoxycholic acid therapy led to a partial normalization of the abovementioned parameters without significant differences between the experimental groups. The concentration of reduced glutathione in the erythrocyte suspension and the content of thiol groups in the blood plasma of patients were reduced in comparison with the control group by 16% and 26%, respectively. After therapy, these indicators also increased by 12–15%, although no predominant effect of either of the studied hepatoprotectors was revealed.Conclusion. The conducted comparative study indicated the absence of a specific antioxidant effect among the pharmacological mechanisms of action of remaxol, ademethionine and ursodeoxycholic acid. In this regard, further research should be carried out to investigate the effect of hepatoprotective drugs on pathobiochemical changes and to analyse a relationship between the antioxidant effect and the efficacy of reducing the level of hepatocyte cytolysis.

FEATURES OF CHANGES IN INTEGRATIVE INDICATORS OF ENDOGENOUS INTOXICATION, REACTIVITY, INFLAMMATION ACTIVITY IN PATIENTS WITH CHRONIC VIRAL HEPATITIS AND CHRONIC RENAL FAILURE

The aim: to study the peculiarities of changes in integrative indicators of endogenous intoxication, reactivity and activity of inflammation in patients with chronic viral hepatitis B and C, and with chronic renal failure undergoing hemodialysis. Materials and methods. 19 patients with chronic viral hepatitis B (HBV) and chronic viral hepatitis C (HCV) with chronic renal failure and patients with chronic kidney disease (KD) were examined. Comparison group included 40 healthy blood donors. Epidemiological, clinical and laboratory examination was performed. Indicators of endogenous intoxication, nonspecific reactivity and inflammatory activity were calculated and analyzed using statistical criteria (M±m, Student's test and Mann–Whitney test). Results: an increase in the integrative indicators of endogenous intoxication in patients with the combined pathology of chronic KD and chronic viral hepatitis (VH) is a consequence of the activation of tissue disintegration, cytolysis of hepatocytes and a significant impairment of liver function. A change in the indices of non-specific inflammation indicate expressed activity of the inflammatory process and immunological disorder of reactivity. These changes also suggest decompensated endotoxicosis, as a possible consequence of a chronic infectious process and decompensated endogenous intoxication. Indicators of leukocyte intoxication index (LII), leukocyte shift index (ISL), hematological intoxication index (HII), intoxication index severity (IIS), immunoreactivity index (IR), neutrophil-monocyte ratio (NMR) are increased in all patients with chronic KD, which may be related to the actual cause of development – glomerulonephritis, chronic pyelonephritis, concomitant pathology. More pronounced deviations were found in men of both groups than in women, which may be related to greater adherence to diet, water load between hemodialysis procedures in the latter. Conclusions. Patients receiving invasive manipulations, including hemodialysis, belong to the risk group and are more susceptible, taking into account immunodeficiency, to infection with hepatitis viruses than the general population. CVH is one of the most common types of lesions in them. The obtained changes, namely, a more pronounced increase in the integrative indicators of endogenous intoxication, in patients with the combined pathology of CKD and CVH indicate the activation of the processes of tissue decay, cytolysis of hepatocytes and significant liver function impairment. At the same time, a change in indices of non-specific inflammation indicates a pronounced activity of the inflammatory process and an immunological disorder of reactivity. A clear systemic reaction to inflammatory processes in the body of patients is determined, the probable development of decompensated endogenous intoxication, which is possible consequence of a chronic infectious process. A simultaneous increase in ISL and a decrease in ILG was established, which is associated with the development of endogenous intoxication and a violation of immunological reactivity due to autointoxication of the body. A decrease in Ilymph indicates an active adaptive reaction of white blood cells and a cell-type immunodeficiency, in particular, a decrease in non-specific anti-infective protection. Indicators of LII, ISL, HII, IIS, IR, NMR are increased in all patients with CKD, which may be related to the actual cause of development – glomerulonephritis, chronic pyelonephritis, etc. The difference of integrative indicators between men and women was established, more pronounced deviations from normal were found in men of both groups than in women, which may be associated with greater adherence to diet, water load between hemodialysis procedures in the latter.

On the toxicity of gold nanoparticles: Histological, histochemical and ultrastructural alterations.

Gold nanoparticles (Au NPs) are used in diagnostic and therapeutic applications together with a variety of industrial purposes and in many biomedical sectors with potential risks to human health. The present study aimed to the histological, histochemical, and ultrastructural alterations induced by Au NPS in vital organs. Healthy male Wistar Albino rats (Rattus norvegicus) were subjected to 20 injections of 10-nm Au NPs at a daily dose of 2mg/kg. Liver, kidney, heart, and lung biopsies from control and Au NPs-treated rats under study were subjected to histological and histochemical examinations. In comparison with the control rats, the renal tissue of Au NPs-treated rats demonstrated glomerular congestion, interstitial inflammatory cell infiltration, renal tubular hydropic degeneration, cloudy swelling, necrosis, and hyaline cast precipitation. In addition, Au NPs induced the following hepatic alterations: hepatocyte cytolysis, cytoplasmic vacuolation, hydropic degeneration, and nuclear alterations together with sinusoidal dilatation. Moreover, the hearts of the treated rats demonstrated myocarditis, cardiac congestion, hyalinosis, cardiomyocyte hydropic degeneration, myofiber disarray and cardiac congestion. The lungs of Au NPs-treated rats also exhibited the following pulmonary alterations: alectasis, emphysema, inflammatory cell inflammation, thickened alveolar walls, pulmonary interstitial edema, congestion, hypersensitivity, fibrocyte proliferation, and honeycombing. In conclusion, exposure to Au NPs induced histological, histochemical and ultrastructural alterations in the vital organs that may alter the function of these organs. Additional efforts are needed for better understanding the potential risks of Au NPs to human health.

Clinical and diagnostic characteristics of the development of hepatocardial syndrome in black and white cows in the early lactation period.

It is known that during the early postpartum and lactation periods in dairy cows, metabolic disorders develop, that is, ketosis, which can lead to secondary damage to internal organs. Therefore, it is important to address the issues of changing the lactating cows' clinical, laboratory, and physiological parameters regarding the development of hepatocardial syndrome. This study aimed to provide clinical and diagnostic justification for developing hepatocardial syndrome in highly productive dairy cows. The study was conducted on 20 black and white cows in the early postpartum period (7-10 days after birth), with a milk production level of >4500 kg of milk during the previous lactation period, a positive result in the formol colloid sedimentary test, the presence of deafness and splitting of heart sounds, changes in the size, or increased pain sensitivity of the percussion field of the liver. Clinically healthy dairy cows in the early postpartum period were used as controls (n = 24). Clinical, electrocardiographic, echocardiographic, and biochemical parameters were also evaluated. Dairy cows with hepatocardial syndrome developed arterial hypertension and sinus tachycardia, which led to a significant decrease in PQ and QT intervals at ECG. A significant increase in the diastolic size of the interventricular septum, systolic size of the free wall of the left ventricle, and diastolic and systolic sizes of the left ventricle and a significant decrease in the shortening fraction of the left ventricular myocardium were observed in the cows due to the development of hepatocardial syndrome. The affected cows demonstrated a significant increase in serum activity of gamma-glutamyl transferase, alanine aminotransferase, lactate dehydrogenase, creatine phosphokinase, alkaline phosphatase, troponin, malondialdehyde, diene conjugates, and ceruloplasmin and a decrease in glucose concentration. In addition, they demonstrated decreased activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Hepatocardial syndrome in dairy cows occurs due to ketosis, characterized by arterial hypertension, sinus tachycardia, a moderate decrease in myocardial contractility, oxidative stress, and cytolysis of cardiomyocytes and hepatocytes. Therefore, the control and prevention of the development of hepatocardial syndrome will make it possible to maintain the productive health and longevity of dairy cows.

Anamnestic and biochemical predictors of obstetric and perinatal complications in intrahepatic cholestasis of pregnancy

Objective. To determine the anamnestic and biochemical predictors of obstetric and perinatal complications in women with intrahepatic cholestasis of pregnancy (ICP).Materials and methods. 59 women with ICP and 30 pregnant women included into the comparison group were examined. The characteristics of the reproductive history, anamnesis of the disease, complaints, biochemical parameters of liver function (syndromes of cholestasis and hepatocyte cytolysis, function of protein synthesis), features of the course and treatment of ICP were studied.Results. The main predictors of preterm birth in the women with ICP were: age (P(U)=0.027), multiple pregnancy (OR=17.5, p=0.033); alkaline phosphatase (ALP) blood level > 499 U/l (AUC=0.801; p=0.008); De Ritis Ratio value ≤ 0.49 (AUC=0.757; p=0.005). The main prognostic markers for meconium staining of amniotic fluid (MSAF) in the patients with ICP were: ICP in previous pregnancies (OR=7.1; p=0.029); serum bile acid concentration > 14 μmol/l (AUC=0.718; p=0.043); total bilirubin blood level > 13 μmol/l (AUC=0.773; p=0.007); ALP activity > 484 U/l (AUC=0.728; p=0.033); blood creatinine concentration ≤ 60 μmol/l (AUC=0.930; p=0.0001) in asymptomatic course. The development of respiratory disorders in children born to women with asymptomatic ICP was associated with a total protein concentration in the blood of 78 g/l or less (AUC=0.852; p=0.0001).Conclusion. The anamnesis of the disease and the determination of the levels of the biochemical parameters of liver function allows predicting obstetric and perinatal complications in ICP.

EFFICACY OF BICYCLOL APPLICATION IN COMPLEX TREATMENT OF NON-ALCOHOLIC STEATHOHEPATITIS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

The аim of research – to establish the probable eff ect of Bicyclol on the clinicalmanifestations of nonalcoholic steatohepatitis, markers of hepatocyte cytolysis,cholestasis, mesenchymal infl ammation in patients with nonalcoholic steatohepatitisnonalcoholic steatohepatitis, and diabetes mellitus of type 2, the degree of hepatocytesteatosis and the stage of liver fi brosis.Methods. Studies were conducted in the treatment dynamics of 60 patients with NASHwith diabetes mellitus of type 2 of moderate severity. Clinical, biochemical, sonographic,bibliosemantic, statistical methods were used.Results. The eff ectiveness of Bicyclol exceeded the intensity of therapeutic eff ect oftraditional therapy (essential phospholipids) by reducing the intensity of clinicalsyndromes of anonalcoholic steatohepatitis: astheno- vegetative, abdominal discomfort,dyspepsia, cholestasis, hepatomegaly (p<0,05), as well as the activity of biochemicalsyndromes: cytolysis, cholestasis, mesenchymal infl ammation (p<0,05), decreasedsteatosis (p<0,05), and contributed to the reversal of liver fi brosis (p<0,05).Conclusions. Bicyclol treatment is more eff ective than traditional nonalcoholicsteatohepatitis therapy against a background of diabetes mellitus of type 2 and may berecommended for use as fi rst-line therapy for 3 months 1 or 2 times a year.

Clinical case of fulminant hepatitis in a child with hepatolenticular degeneration

The article presents a detailed analysis of the diagnostic search for Wilson’s disease in childhood. Polymorphism of clinical symptoms of the disease has led to various descriptions of this pathology and its manifestations. Despite more than a century of experience in studying the peculiarities of hepatolenticular degeneration, at the present stage the diagnosis of the disease, especially in children, remains a difficult issue. According to the literature data, there are no characteristic symptoms and typical clinical picture of this disease, which is the reason for the late diagnosis of this pathology in children. The earlier treatment is started, especially if at the preclinical stage, the higher is the efficacy and the more favorable the prognosis will be observed. The article summarizes information about the objective difficulties of proper diagnosis of this disease. In a specific clinical case presented in the article, the onset of hepatolenticular degeneration arose in the form of fulminant hepatitis with the development of acute liver failure, in which cytolysis of hepatocytes led to the release of copper that increased the content of the microelement in the blood. Particular attention should be paid to the symptoms that should alert the practitioner to Wilson’s disease, exactly such as the presence of jaundice of unknown origin, bleeding gums or multiple ecchymoses on the skin of the chest and back, a specific type of stripes (white, periodically changing color to reddish-blue) on thighs and axillary areas; hormonal disorders in the form of amenorrhea or dysmenorrhea in girls, as well as decreased intelligence and mental changes in the form of mood swings, or attacks of aggression, problems with school performance. Particular attention is paid to the role of an edema-ascites syndrome, in the absence of signs of portal hypertension, which is a pathognomonic sign of the onset of abdominal hepatolenticular degeneration, which is associated with early liver dysfunction.

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<0,05) – after treatment it decreased in patients of groups 1 and 2: by 2.2 and 3,7 times, respectively (p<0,05) with the presence of a probable intergroup difference (p<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<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<0,05) with the presence of a probable intergroup difference (p<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<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< 0,05), and in patients of group 2 – by 40,0% (р<0,05) with the presence of a probable intergroup difference (р<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<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<0,05) – after treatment it decreased in patients of groups 1 and 2: by 2.2 and 3,7 times, respectively (p<0,05) with the presence of a probable intergroup difference (p<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<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<0,05) with the presence of a probable intergroup difference (p<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<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< 0,05), and in patients of group 2 – by 40,0% (р<0,05) with the presence of a probable intergroup difference (р<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<0.05), probable reducing the intensity of liver tissue fibrosis.

ДИНАМИКА ИЗМЕНЕНИЙ ПОКАЗАТЕЛЕЙ ОКИСЛИТЕЛЬНОГО ГОМЕОСТАЗА В ПРОЦЕССЕ РЕПЕРФУЗИИ ПЕЧЕНИ КРЫС ПОСЛЕ ВАСКУЛЯРНОЙ ЭКСКЛЮЗИИ

Changes in the state of the antioxidant protection system and the intensification of free radical processes are the leading pathobiochemical mechanism for the development of reperfusion damage to cells. The aim of this paper is to determine the features of changes in markers of oxidative stress at different periods of development of the acute reperfusion after total vascular exclusion of rat liver. The study was carried out on 100 white nonlinear sexually mature male rats weighing of 200-250 grams. The animals of the experimental groups were simulated with a 20-minute vascular isolation of the liver. Blood in a volume of 2-3 ml was taken from the inferior vena cava for 5, 15, 30, 60, 120, 180 minutes, 8 hours and a day after the restoration of blood flow. The results of the study showed that in the early stages of the reperfusion period (5-60 minutes), changes are observed due to cytolysis of hepatocytes during the period of organ ischemia and leaching of cell contents into the blood. The level of radical sorption of ABTS by blood plasma briefly increased by 20% by the 5th minute of the reperfusion period; at the same period, an increase in glutathione peroxidase activity by 2.5 times was noted. The total antioxidant activity, determined by the iron-reducing method, was increased by 2 times within the period of 15-30 minutes after the restoration of blood flow. The main manifestations of reperfusion damage to the liver developed in 60 minutes after the restoration of blood flow and were characterized by a sharp decrease in total AOA by 1.5-2 times and the concentration of reduced glutathione by 20%. The system of antioxidant protection of blood plasma was the first to react to the spread of the pathological process at the systemic level and its changes persisted one day after liver ischemia. A 20-minute vascular exclusion of the liver was accompa- nied by changes in the antioxidant balance in the erythrocyte suspension, but these changes returned to normal a day after the restoration of blood flow. The data obtained make it possible to distinguish between the contribution of ischemic and reperfusion injuries to the development of oxidative disorders, which is important from the standpoint of assessing the possibilities of anti- oxidant therapy.

Анализ результатов противовирусной терапии хронического гепатита С на стадии цирроза печени у пациентов с ВИЧ-инфекцией

Objective. To analyze the features of the course of chronic hepatitis С virus (HCV) and effectiveness of its treatment in patients with HIV infection. Patients and methods. The study was conducted on the basis of the State Budgetary Health Institution “Samara Regional Clinical Center for AIDS Prevention and Control”. Twenty-two HIV-infected patients with HCV genotype 2 and 3 and HCV-related liver cirrhosis were observed. All patients had compensated cirrhosis (class A according to the Child-Pugh classification). Patients were aged between 33 and 65 years, with an average age of 46.5 years. There were 17 (77.3%) male and 5 (22.7%) female patients. Results. The effectiveness of antiviral therapy (AT) for HCV with progression to liver cirrhosis and the dynamics of clinical and laboratory parameters in 22 HIV-infected patients were assessed. HCV genotypes were distributed as follows: genotype 3 was detected in 20 patients (91%), genotype 2 – in 2 patients (9%). According to the results of elastometry, the stages of fibrosis were distributed as follows: F0–F2 – in 0 (0.0%) patients, F3 – in 3 (13.6%) patients, F4 – in 19 (86.4%) patients. Serum levels of HCV RNA prior to treatment averaged 310,335 copies/mL (1,020 to 795,000 copies/mL). After 8 and 12 weeks of antiviral therapy for HCV, all 22 patients had no HCV RNA in the blood. However, in one patient HCV RNA levels reached 53,856 copies/mL 24 weeks after the end of antiviral therapy (reinfection due to the injection of psychoactive substances). Conclusion. Thus, all 22 treated patients with HIV infection and HCV with progression to liver cirrhosis achieved sustained virologic response 12 (SVR12) after an 8-week course of antiviral therapy for HCV (glecaprevir/pibrentasvir). Hepatitis C virus eradication is likely to reduce the risk of fibrosis progression, decompensated cirrhosis, and hepatocellular carcinoma formation. In turn, laboratory manifestations in the form of hepatocyte cytolysis syndrome (AST/ALT) and intrahepatic cholestasis (GGT) ceased by the end of treatment. Against the background of antiviral therapy for HCV, CD4 cell count tended to increase in patients, which would subsequently reduce the risk of severe opportunistic infections and complications. There were no adverse events during treatment with glecaprevir/pibrentasvir (neither clinical symptoms nor change in clinical and biochemical blood tests), which confirms the safety of the chosen treatment regimen. The only problem remains the adherence to treatment of such a complex group of patients as HCV/HIV co-infected, as well as the possibility of HCV reinfection through sexual contact with HCV patients and/or through injecting psychoactive substances. Key words: antiretroviral therapy, HIV infection, direct-acting antivirals, chronic hepatitis C, liver cirrhosis

Synthesis of Silymarin-Gold Nanoparticle Conjugate and Analysis of its Liver-Protecting Activity.

The liver disease problem prompts investigators to search for new methods of liver treatment. Silymarin (Sil) protects the liver by reducing the concentration of free radicals and the extent of damage to the cell membranes. A particularly interesting method to increase the bioavailability of Sil is to use synthesized gold nanoparticles (AuNPs) as reagents. The study considered whether it was possible to use the silymarin-AuNP conjugate as a potential liver-protecting drug. AuNPs were conjugated to Sil and the liver-protecting activity of the conjugate was examined. Experimental hepatitis and hepatocyte cytolysis after carbon tetrachloride action were used as a model system, and the experiments were conducted with laboratory animals. For the first time, silymarin was conjugated to colloidal gold nanoparticles (AuNPs). Electron microscopy showed that the resultant preparations were monodisperse and that the mean conjugate diameter was 18-30 nm ± 0.5 nm (mean diameter of the native nanoparticles, 15 ± 0.5 nm). In experimental hepatitis in mice, conjugate administration interfered with glutathione depletion in hepatocytes in response to carbon tetrachloride. It also was conducive to an increase in energy metabolism and stimulated the monocyte-macrophage function of the liver. The results were confirmed by the high respiratory activity of the hepatocytes in cell culture. We conclude that the silymarin-AuNP conjugate holds promise as a liver-protecting agent in acute liver disease caused by carbon tetrachloride poisoning.

Changes in the blood coagulation system that determine postoperative complications in patients with non-tumor mechanical jaundice

The OBJECTIVE was to study the features of changes in the blood coagulation system that contribute to the development of postoperative complications in patients depending on the stage of non-tumor mechanical jaundice at admission.METHODS AND MATERIALS. A total of 537 patients with mechanical jaundice were examined and changes in the blood coagulation system were analyzed. Vascular-platelet hemostasis was characterized by the following tests: capillary resistance, the number of desquamated endothelial cells, the number of blood platelets. Plasma hemostasis was analyzed using activated partial thromboplastin time, plasma soluble fibrin level, thrombin time, prothrombin ratio, prothrombin index, and fibrinogen blood level. Then, XIIa-dependent fibrinolysis in the blood and the level of the fibrin D-dimer in the blood plasma were determined.RESULTS. It was found that in the first stage of mechanical jaundice, with cholestasis, there were no changes in blood coagulation system that go beyond the normal limits. In the second stage, during cytolysis of hepatocytes, hyperbilirubinemia and hypertransaminasemia contribute to the activation of platelet first, and then plasma hemostasis. In the third stage (cholangitis), the death of endotheliocytes increases and there is a deficiency of blood coagulation factors due to their consumption and increased fibrinolysis.CONCLUSION. In the stage of cholestasis in patients with non-tumors mechanical jaundice, the parameters of the coagulation system remain within the reference values. In the stage of cytolysis, as endotheliotoxicosis increases, platelet and plasma hemostasis begins to activate, which can lead to thrombosis and thromboembolism in vital organs. In the stage of cholangitis, further activation of plasma hemostasis causes hemorrhagic syndrome. The occurrence of the described disorders in blood coagulation system with the progression of MJ dictates the need to monitor the changes in the blood coagulation system and their correction for the prevention of intra-and postoperative complications.