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Genetic background of liver cirrhosis complications
Šenkeříková, Renáta ; Špičák, Julius (advisor) ; Brůha, Radan (referee) ; Husová, Libuše (referee)
Liver cirrhosis represents the end stage of most chronic liver diseases. The course of the disease and its complications can be significantly influenced by host genetic factors and the severity of portal hypertension (PH). The aim of the study was to describe the role of genetic factors influencing the progression and complications of liver disease and to determine the role of non-invasive assessment of the stage of liver fibrosis and severity of PH and their correlation with portosystemic gradient (HVPG) measurements. We first focused on the role of allelic variants in TLR4 signalling pathway genes in the risk of occurrence of severe bacterial infections in patients with advanced liver cirrhosis, liver transplant (LT) candidates. We found that the TNFA c.-238G/A promoter variant significantly reduced the risk of bacterial infections and was associated with a decreased mortality rate. We further investigated the role of the variant G allele in PNPLA3 gene in the progression of chronic liver failure and the need for LT in patients with liver cirrhosis due to HCV infection. As a result, we found that the carriage of the variant G allele led to a faster progression of chronic liver failure and the need for LT at a younger age. Third, we investigated whether the efficacy of triple combination treatment...
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Selected genetic factors modifying the natural course of viral infections in organ transplant settings
Chmelová, Klára ; Šperl, Jan (advisor) ; Husa, Petr (referee) ; Brůha, Radan (referee)
Solid organ transplantation (SOT) represents a life-saving procedure and a future perspective for patients suffering from organ failure. On the other hand, SOT recipients are burdened with numerous complications, including infections or lifelong administration of immunosuppressive medication. There are several well-known factors related to graft and patient survival, including general health status, age at the time of SOT, diagnosis leading to SOT, acute or antibody-mediated rejection, development of the metabolic syndrome and complications including viral diseases. Viral infections in SOT recipients may present with a very distinct natural history compared with the healthy population. Several can cause immune activation leading to graft rejection; others can be associated more likely with immune tolerance. We aimed to identify the impact of variants of selected genes on the natural history of various viral diseases in SOT recipients and thus their overall outcome, morbidity and graft survival. Cytomegalovirus (CMV) infection is the most common viral infection in SOT recipients. We focused on the role of the IL28B rs12979860 locus genotype in the risk of CMV disease occurrence. We proved the T allele is associated with a more frequent occurrence of CMV disease in liver transplant (LTx) recipients...
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Metabolic and genetic risks of development of non-alcoholic fatty liver disease in patients after liver transplantation and its impact on patient and graft survival
Míková, Irena ; Trunečka, Pavel (advisor) ; Červinková, Zuzana (referee) ; Brůha, Radan (referee)
Nonalcoholic fatty liver disease (NAFLD) occurs frequently not only in the general population, but also in liver transplant (LT) recipients. The data about prevalence, evolution, causes and significance of steatosis in patients after LT are limited. In a large retrospective study in LT recipients with histological evaluation of steatosis, we found high prevalence of steatosis (56,4 %) and steatohepatitis (10,4 %), the prevalence of steatosis increased after LT. Pretransplant predictors of steatosis included alcoholic cirrhosis and high BMI, whereas increased alkaline phosphatase and mycophenolate mofetil given initially were protective. Posttransplant predictors of steatosis included BMI, serum triglycerides, alcohol consumption and presence of type 2 diabetes mellitus, whereas increased serum creatinine was protective. Presence of significant steatosis/steatohepatitis was not associated with increased grade of fibrosis. There was no difference between the occurrence of steatosis in surviving and lost grafts. Survival of patients with/without significant steatosis was similar with a trend to higher long-term mortality of patients with significant steatosis. In the evaluation of the impact of TM6SF2 rs58542926 and PNPLA3 rs738409 genotypes of the donor and recipient on pathophysiology of steatosis...
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Role of host-dependent factors in prediction of antiviral treatment response in chronic hepatitis C
Fraňková, Soňa ; Jirsa, Milan (advisor) ; Brůha, Radan (referee) ; Plíšek, Stanislav (referee)
Soňa Fraňková: Role of host-dependent factors in prediction of antiviral treatment response in chronic hepatitis C Abstract Hepatitis C virus infection represents a leading cause of liver disease in western countries. The primary goal of HCV therapy is elimination of the virus, i.e. sustained virological response (SVR) achievement. Genetic factors have long been suspected of playing a crucial role in determining response to IFN-α-based therapies, but pretreatment predictors of response were only poorly defined and did not allow personalization of therapy. The aim of the thesis is to describe the role of host-dependent factors in prediction of antiviral treatment response in chronic hepatitis C in specific groups of patients. First, we focused on the role of the IFNG -764G/C promoter variant in SVR achievement. We did not prove that this variant predicted SVR in Czech HCV-infected individuals. Next, we focused on the role of IL28B and IFNL4 in HCV-infected patients: we confirmed that the IL28B rs12979860 CC genotype slows down the progression of liver fibrosis in chronic HCV infection and that IFNL4 ss469415590 TT|ΔG genotyping does not bring a better prediction of treatment success than IL28B rs12979860 in the Czech population. Third, we assessed prediction of treatment response in HCV positive liver...
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Metabolism of estrogene in UGT1A1-deficient rats
Módos, Anna ; Muchová, Lucie (advisor) ; Brůha, Radan (referee)
Introduction Estrogen-induced cholestasis is a disease characterized by a failure of bile flow and bile production. It can develop in women after oral contraceptives use, hormone replacement therapy or during pregnancy. The estrogen metabolism is a complex process leading to formation of metabolites with different biological activities. It takes place primarily in the liver (Phase I and Phase II including hydroxylation, methylation, sulfation and glucuronidation). The enzymes from UDP-glucuronosyltransferases family , abbreviated UGT, are responsible for the glucuronidation of estrogens. Aims The objective of my work is to define estrogen metabolism and gene expression of UGT1A1, CYP1A2 and SULT1A1 and characterize cholestatic liver damage in the UGT1A1 deficient rat strain (Gunn rats) compared to rats with normal enzyme activity and try to define possible mechanisms responsible for the liver damage. Methods Adult female Gunn and corresponding heterozygous rats were treated with ethinylestradiol (EE, 5 mg/kg body weight SC) for 5 days, while control rats received propanediol (vehicle). Day six, the animals were sacrificed and plasma and liver tissue were collected for analysis. Markers of cholestasis and liver damage ALP, AST, ALT and bilirubin were determined using an automatic analyzer, total...
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Some aspects of molecular mechanisms of xenobiotics' hepatotoxicity and hepatoprotection : Modulatory roles of natural polyphenols
Lekic, Nataša ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Brůha, Radan (referee)
Background & Aims: Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. The aim of this work is to find early signal markers of drug-induced injury of the liver by focusing on select antioxidant/oxidant and apoptotic genes. As well, to address the relationship between conventional liver dysfunction markers and the measured mRNA and protein expressions in the D-galactosamine/lipopolysaccharide and tert-butylhydroperoxide hepatotoxicity models. Furthermore, potential hepatoprotective capabilities of antioxidant polyphenols quercetin and curcumin were evaluated in relation to its modulation of the oxidative stress and apoptotic parameters in the given xenobiotic hepatotoxicity models. Methods: Biochemical markers testing the hepatic function included aminotransferases (ALT, AST) and bilirubin. Measurements of TBARS and conjugated dienes were used to assess lipoperoxidation. Plasma levels of catalase and reduced glutathione were used as indicators of the oxidative status of the cell. Real time PCR was used to analyse the mRNA expressions of the inducible nitric oxide synthase (NOS-2), heme oxygenase-1 (HO-1), superoxide dismutase (SOD-1), glutathione peroxidase (Gpx-1), caspase 3 (Casp3), BH3 interacting domain death agonist (Bid) and Bcl-2...
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Effect of malnutrition on prognosis of patients with liver cirrhosis after bleeding from esophageal varices
Zagrebelná, Valérie ; Hrabák, Petr (advisor) ; Brůha, Radan (referee)
Liver cirrhosis is the final stage of chronic liver disease that arises from various causes (mainly chronic alcohol abusus, autoimmune and chronic viral hepatitis B and C, NAFLd - non-alcoholic fatty liver disease, bile duct disease or congenital metabolic disease - haemochromatosis and Wilson's disease). During development of liver cirrhosis, inflammatory liver cell damage, their necrosis and their conversion to fibrotic tissue occur. Most of the complications of hepatic cirrhosis are based in hepatic insufficiency and portal hypertension. Major complications of hepatic cirrhosis include bleeding from esophageal varices (the most serious complication that is fatal), hepatic encephalopathy, ascites, hepatorenal syndrome and hepatocelular cancer. The aim of the work was to determine how many patients suffered from protein-calorie malnutrition, and what effect malnutrition had on the survival and condition of patients. The work also dealt with bleeding from esophageal varices, reccurrence of varicose bleeding and complications associated with liver cirrhosis. One of the goal was to see if fit matched the predicted survival of patients, according to Child-Pugh's classification. The methodology of the work was retrospective research with the help of obtaining data from histories and findings obtained...
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Effects of n-3 polyunsaturated fatty acids on development of non-alcoholic fatty liver disease in experiment, prevalence in patients with type 2 diabetes mellitus and metabolic syndrome, non-invasive diagnostics
Dvořák, Karel ; Brůha, Radan (advisor) ; Ehrmann, Jiří (referee) ; Lotková, Halka (referee)
This thesis focuses on the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) on development of non-alcoholic fatty liver disease (NAFLD) in experiment, on prevalence of this condition in patients with type 2 diabetes mellitus and metabolic syndrome and also on non-invasive diagnostics. The aim was to study the effect of n-3 PUFA on NAFLD development in an experimental model and based on analysis of a group of patients with type 2 diabetes and metabolic syndrome to assess the prevalence of this condition. Lastly we aimed to evaluate non-invasive diagnostic methods of liver fibrosis and NASH. We demonstrated beneficial effects of n-3 PUFA administration on NAFLD development in a C57/Bl6 mice high fat methionin-cholin defficient dietary model of NAFLD. n-3 PUFA administration led to biochemical improvement, decrease of lipid accumulation in the liver as well as improvement of histology. These effects are determined by complex modulation of lipid metabolism, mainly due to decrease in availability of fatty acids for triglyceride synthesis in the liver, changes of adipokine levels and amelioration of proinflammatory status in the liver. In a group of type 2 diabetics we found NAFLD prevalence of almost 80%, 14% of these patients had also signs of liver fibrosis or cirrhosis. Non-invasive methods...
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Heme catabolic pathway in pathogenesis of liver diseases
Váňová, Kateřina ; Muchová, Lucie (advisor) ; Brůha, Radan (referee) ; Neužil, Jiří (referee)
This thesis focuses on the role of heme catabolic pathway in the pathogenesis of selected liver diseases. The aim was to clarify if the modulation of heme oxygenase (Hmox) and its catabolic products - especially carbon monoxide (CO) and bilirubin - affected the development and progression of liver diseases, focusing on inflammatory and cholestatic pathways. Firstly, we discovered that the induction of hmox1 prevented hepatocellular damage in endotoxin-induced inflammation. Furthermore, administration of CO in vivo in early-phase of endotoxin-induced cholestasis decreased the inflammatory cytokine production in the liver and simultaneously prevented downregulatory effect of cytokines on hepatocyte transporters resulting in hepatoprotection. For the first time, we characterized in vivo tissue distribution and elimination of inhaled CO in rats. In vitro experiments and the model of extrahepatic cholestasis revealed the significant role of intracellular bilirubin in hepatocellular protection against oxidative damage which accompanies cholestatic disorders. Last but not least, hmox1 induction by heme increased hepatocyte transporters expression and subsequently stimulated bile flow participating in conferring protection against estrogen-induced cholestasis. Presented results demonstrate that the heme...
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Sarcopenia as a Predictive Factor for Survival after Transjugular Intrahepatic Portosystemic Shunt Insertion (TIPS)
Šembera, Štěpán ; Hůlek, Petr (advisor) ; Brůha, Radan (referee) ; Urban, Ondřej (referee)
Sarcopenia as a Predictive Factor for Survival after Transjugular Intrahepatic Portosystemic Shunt insertion (TIPS) Introduction: Prediction in medicine most often represents an estimate of the outcome of a particular disease and is one of the basic tools of a physician. In the field of hepatology, the prognosis of a patient with liver cirrhosis is extraordinarily important. As in other cases, it helps to make a better decision about the right patient management. In cases where liver transplantation is indicated, it helps to place the patient correctly on the waiting list according to the urgency of the disease. Assessing the survival of patients after the transjugular intrahepatic portosystemic shunt (TIPS) using the MELD score (Model for End stage Liver Disease) has given to hepatology the universal and most reliable tool to assess the progression of chronic liver disease, not limited TIPS circumstances. The importance of sarcopenia for patients with liver cirrhosis has been widely discussed in the current decade. This work aims to evaluate the effect of sarcopenia on the survival of patients after TIPS. Methodology: This is a retrospective analysis of the survival of all patients with liver cirrhosis who underwent TIPS in one institution during the years 2006 - 2019. Sarcopenia was determined...
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