Dissertations / Theses: 'ALF(Acute Liver Failure)'

1

GADIPUDI, LAILA LAVANYA. "Macrophage Phenotype during Liver Injury and Repair." Doctoral thesis, Università del Piemonte Orientale, 2022. http://hdl.handle.net/11579/142900.

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2

Craig, Darren George Norman. "Studies in acute liver failure." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/29077.

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Acute liver failure (ALF) is a devastating condition with a high associated mortality rate. Paracetamol hepatotoxicity remains the leading cause of ALF in the developed world. The studies outlined in this thesis explore the current management of ALF, and systematically review the prognostic tests currently used in paracetamol-induced ALF. Using a database of over 900 acute liver injury patients, the impact of unintentional paracetamol overdose is retrospectively analysed, demonstrating a strong association between this mode of paracetamol overdose and adverse clinical outcomes, including the requirement for emergency orthotopic liver transplantation. Current prognostic tests for severe paracetamol-induced hepatotoxicity have been criticised for their relatively low sensitivity, with the result that not all patients who might benefit from tertiary level care are identified. This thesis demonstrates that the development of the Systemic Inflammatory Response Syndrome (SIRS) or extrahepatic organ failure is strongly associated with death following paracetamol overdose. Due to their very high sensitivity in this condition, both the SIRS and Sequential Organ Failure Assessment scores have potential as future gatekeepers to improve the triage of paracetamol overdose patients, thereby delivering tertiary level care to those most likely to require emergency transplantation. A greater understanding of the pathophysiological links between the initial hepatic injury and development of the SIRS could help to identify novel biomarkers for ALF, and help guide future therapeutic avenues. Using serum samples from a prospectively collected cohort of acute liver injury patients, this thesis identifies two novel biomarkers, serum ferritin and the long pentraxin PTX3, which show a strong association with outcome following paracetamol hepatotoxicity. These biomarkers illustrate the importance that the innate immune system plays in the pathogenesis of paracetamol-induced ALF, and identifies several exciting areas for future cellular and animal-based studies.

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3

Triantafyllou, Evangelos. "Mechanisms of immune-mediated liver injury in acute liver failure." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/mechanisms-of-immunemediated-liver-injury-in-acute-liver-failure(e3e4fdce-9d38-4bdf-b1b4-979f35aef0ae).html.

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Background: Acute liver failure (ALF) is characterized by overwhelming hepatocyte death and liver inflammation where the infiltration of myeloid cells in areas of necrosis is contrasted by immune cell depletion and dysregulation in the systemic circulation. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown to date. In this thesis, I used both human and murine experimental models in order to investigate the impact of Mer Tyrosine Kinase (MerTK) during ALF and examine how the micro-environmental mediator, Secretory Leukocyte Protease Inhibitor (SLPI), governs this immunological response. Methods: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotypic, functional and transcriptomic profile and tissue topography of MerTK+ monocytes and macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on hepatic resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. Furthermore, SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. Results: I demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in both circulatory and tissue compartments of ALF patients. Compared to WT mice, that show an increase of MerTK+MHCIIhigh hepatic macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterized by a decreased proportion of liver-resident Kupffer cells and increased number of hepatic neutrophils. Both in vitro and in APAPtreated mice, SLPI reprograms macrophages towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. Conclusions: The work presented in this thesis has identified a prorestorative, MerTK+, macrophage phenotype that evolves during the resolution phase of APAP-induced ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.

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4

Possamai, Lucia. "Susceptibility factors in paracetamol-induced acute liver failure." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/25269.

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Paracetamol is a popular antipyretic and analgesic medication. It is a known hepatotoxin in overdose and is the commonest cause of acute liver failure in the UK. There is significant variability in inter-individual susceptibility to the hepatotoxic effects of paracetamol, which is incompletely understood. This thesis describes work done in murine models of paracetamol-induced acute liver failure with the aim of identifying causes of variable susceptibility and understanding the immune response to liver injury. A quantitative trait locus (QTL) mapping approach was taken using a murine strain susceptible to paracetamol hepatotoxicity (C3H/HeH) crossed with a relatively resistant strain (C57BL/6). Novel QTLs on murine chromosome 17 and 18 were identified that associated with response to paracetamol. Within the loci a number of candidate genes were identified. A survey of 10 inbred mouse strains for their response to paracetamol was conducted and highlighted the large variability within each strain. It was hypothesised that this variability might be due to differences in intestinal microbiota. A study of the role of intestinal microbiota in paracetamol-induced liver failure was conducted, by comparing response in germ free (GF) mice and conventional (CV) controls. This demonstrated that the presence of intestinal microbiota influenced the sulphonation:glucuronidation ratio during paracetamol metabolism. Although the extent of liver injury as assessed by necrosis and liver enzyme elevation was the same in GF and CV mice, there was evidence of a protective effect of a sterile intestine. Finally a reverse genetics approach was taken to study the influence of the gene Slpi in the secondary immune response to liver injury. It was shown that absence of SLPI protected mice against peak liver injury. The work presented in this thesis highlights some potential sources of variability in response to paracetamol and a number of targets that with further research could have therapeutic potential.

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5

Bhanage, Chaitanya Devidas. "Review of current extracorporeal technologies for acute liver failure." Thesis, University of Strathclyde, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502314.

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The liver is the metabolic powerhouse of the body and plays an important role in metabolism. The function of the liver includes drug detoxification, plasma protein synthesis and glycogen storage. Chronic liver failure (CLF) takes months or years to develop, whereas acute liver failure (ALF) may develop within 1-2 weeks. In the USA, 1 in every 10 persons is affected with a liver, biliary or gall bladder disease. The estimated medical and work loss cost per year due to Hepatitis B & Hepatitis 0 is more than $700 million & $600 million respectively. The accepted treatment of end-stage CLF is transplantation. However, the ability of the liver to regenerate has pointed to the development of temporary liver assist devices for the treatment of ALF. The purpose of this project is to review the state-of-the-art in liver assist devices and exciting developments in the field.

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Balko, Jody. "Use of Procalcitonin as a Biomarker of Bacterial Infection in Acute Liver Failure and Acute Liver Injury." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2744.

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Infections in patients with acute liver failure (ALF) and acute liver injury (ALI) are a frequent occurrence. Because ALF and ALI patients share many of the same clinical features as patients with severe sepsis and septic shock, identifying an infection based upon clinical manifestations is extremely difficult. Bacterial culture and sensitivity reports require 24 to 72 hours to be finalized after the need for a culture is suspected and obtained. During this time period, ALF and ALI patients are either not receiving required antibiotic therapy, receiving antibiotic therapy that is not required or not appropriate for the infecting bacterial pathogen, or receiving the correct antibiotic prophylaxis. Receiving an antibiotic that is not needed or inappropriate adds another level of complexity to the ALF and ALI patients because antibiotics may exacerbate liver dysfunction. The purpose of this study was to determine the utility of serum procalcitonin concentrations (SPCTC) as a biomarker of bacterial infections in patients with acute liver failure (ALF) and acute liver injury (ALI). This three part study measured SPCTC retrospectively on samples from ALF and ALI patients who were prospectively enrolled in the United States Acute Liver Failure Study Group (USALFSG) ALF and ALI studies. In the first part of the study, subjects were categorized according to how many SIRS continuum components they had and whether there was a documented infection. In the second part, serial samples on subjects who developed infections were identified. And, in the third part, serial samples on subjects diagnosed with infection on day one of the study and categorized based upon transplant free survival (TFS) or death and/or liver transplant (DoT) were identified. Procalcitonin was not found to be useful in identifying infection in the ALF and ALI patient populations. A cut-off for indication of infection was calculated to be 1.62 ng/mL using receiver operator curve (ROC) analysis. Despite the fact that there was an overall increase in SPCTC as the severity of illness increased in patients with a documented infection, there were confounding variables including antibiotic use, missing data, and small sample size that may have contributed to the poor sensitivity and specificity (0.643 and 0.620 respectively) calculated as part of the ROC analysis. SPCTC values appeared to be increased in subject with acetaminophen (APAP) toxicity and may have affected the cut-off, sensitivity, and specificity results. Increased SPCTC values were seen in APAP subjects who did not have a documented infection. It is unknown at this time if the SPCTC were increase due to liver damage, an undiagnosed infection, or as a result of increase cytokine production due to the APAP toxicity. Serial PCT concentrations in patients who achieved TFS showed a greater decrease over time than those of patients who died or received a liver transplant, however, the TFS group contained a large portion of APAP subjects. Further prospective studies are needed to determine the extent of interference with SPCTC in patients with APAP toxicity and to better define the PCT concentration cut-off between infection and no infection in the ALF and ALI populations.

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7

Anwar, Khurshid. "Role of apoptosis (programmed cell death) in acute liver failure." Thesis, University of Surrey, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370058.

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8

Kyriakides, Michael. "Metabolic phenotyping applied to pre-clinical drug induced liver injury and acute liver failure." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/29110.

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Liver disease is a prevalent clinical challenge caused by a variety of factors including viral infections and xenobiotic overdose. Improving our mechanistic understanding of disease development will lead to an improved stratification of patients and ultimately a better prognosis. This thesis addresses the role of metabonomics in providing insight into a variety of preclinical models and a clinical study. The metabolic phenotype of preclinical models of paracetamol (APAP) and methotrexate (MTX) toxicity were characterised, together with the study of clinical samples from decompensated cirrhosis, acute on chronic liver failure (ACLF) and acute liver failure (ALF) patients. A comparative metabonomic approach was applied to study the metabolic consequences following administration of APAP and its non-hepatotoxic isomer; N-acetyl-m-aminophenol (AMAP), in mice. The analysis revealed an APAP-induced hepatotoxicity through mitochondrial dysfunction which was characterized by an upregulation of glycolysis as well as the inhibition of beta-oxidation and the Krebs cycle. The metabolic and toxic effects of MTX were investigated in healthy rats and in a model of non-alcoholic steatohepatitis (NASH; as modelled by the methionine choline deficient diet). MTX was shown to have an enhanced toxicity in the context of NASH, which was associated with unique metabolic changes. The clinical work revealed that the serum metabolic phenotypes of clinical decompensated cirrhosis, ACLF and ALF patients were also each characterized by unique metabolic perturbations. The ALF phenotype was associated with the most metabolic changes and consisted of markers of oxidative and energetic stress, as well as markers of amino acid metabolism dysfunction. Subsequently, the novel serum metabolic profiling of the hepatic vein, hepatic portal vein and peripheral artery of patients during liver transplantation aimed to characterize the hepatic disease microenvironment, which was discovered to mainly consist of a perturbed amino acid metabolism.

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9

Sakamoto, Seisuke. "Living donor liver transplantation for acute liver failure in infants: The impact of unknown etiology." Kyoto University, 2008. http://hdl.handle.net/2433/124328.

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10

Yang, Stephen Chen. "Polyketals a new drug delivery platform for treating acute liver failure /." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/31785.

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Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2009.
Committee Chair: Murthy, Niren; Committee Member: Bellamkonda, Ravi; Committee Member: Davis, Michael; Committee Member: May, Sheldon; Committee Member: Milam, Valeria. Part of the SMARTech Electronic Thesis and Dissertation Collection.

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11

Donati, Matthew Charles. "Analysis of a strain of hepatitis E virus associated with acute liver failure." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271544.

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12

Unger, Carly, and Layth S. Al-Jashaami. "Ciprofloxacin Exposure Leading to Fatal Hepatotoxicity: An Unusual Correlation." INT SCIENTIFIC LITERATURE, INC, 2016. http://hdl.handle.net/10150/624362.

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13

Thompson, Alexandra Inés. "Investigation of the role of hepatic stellate cells in acute liver failure and hepatocarcinogenesis." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28936.

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Introduction: Hepatic stellate cells (HSC) and myofibroblasts may be relevant stromal drivers of human hepatocellular carcinoma (HCC). It was hypothesised that targeted inhibition of αv integrin-mediated TGF-β activation, by HSC or hepatocytes, may result in reduced peri-tumoural and intra-tumoural extracellular matrix formation, and reduced hepatic carcinogenesis. The role of HSC in acute liver injury is less well characterised. It was anticipated that integrin signalling on HSC and hepatocytes might also be relevant in the acute setting. The emerging technique of intravital microscopy (IVM) allows detailed, real-time investigation of the cellular processes involved in hepatocyte injury, cell death and repair. It was hypothesised that this could be coupled with mouse models of HCC and acute liver injury, to perform sequential imaging under anaesthesia. Aims: (i) To determine the effect of targeted inhibition of αv integrins on HSC and hepatocytes, during hepatocarcinogenesis, in a mouse model of HCC. (ii) To investigate the effect of targeted inhibition of αv and other integrins on HSC, hepatocytes, and liver sinusoidal endothelial cells (LSEC), during acute liver injury, in the mouse model of paracetamol-induced liver injury. (iii) To develop IVM of the liver, via an abdominal imaging window, with optimisation of surgical and imaging techniques, to allow sequential imaging of the same animal. Methods: The diethylnitrosamine (DEN)-induced mouse model of hepatocarcinogenesis was used, and PDGFRβ-Cre;αvfl/fl and Alb-Cre;αvfl/fl mice were employed to deplete αv integrins on HSC and hepatocytes respectively. Tumours were harvested at 40 weeks post-DEN. Tumour size and number was evaluated in all animals. PDGFRβ-Cre;αvfl/fl and Alb-Cre;αvfl/fl mice were used in the paracetamol model, to investigate the role of αv integrins in acute liver injury. PDGFRβ-Cre;β8fl/fl and Alb-Cre;β 8fl/fl animals were also tested in this model. The role of integrins in liver sinusoidal endothelial cells (LSEC) during paracetamol-induced liver injury was evaluated using Cdh5-Cre mice. IVM of the liver was performed by surgical implantation of an abdominal imaging window, consisting of a titanium ring and coverslip, secured in place with a purse string suture. Fluorescent reporter mice were used to identify hepatic and vascular architecture, and other label-free microscope technologies were utilised to image collagen, lipid distribution, necrotic areas and blood flow within tissues. Results: In large cohorts of PDGFRβ-Cre;αvfl/fl, Alb-Cre;αvfl/fl, and control animals, there was no difference in mean tumour size or number, at 40 weeks. Targeted inhibition of α v integrins and β 8 integrin on hepatocytes, HSC or LSEC was not protective in paracetamol-induced liver injury. IVM of the liver can be performed on animals with HCC and throughout paracetamol-induced liver injury, to obtain high quality, real-time images of multiple cell lineages and the hepatic microenvironment. Conclusions: The role of TGF-β in HCC pathogenesis is complex and context-dependent. Targeted loss of αv integrin did not result in reduction in tumour burden in this non-cirrhotic model of HCC. IVM of the liver is a powerful tool to quantify inflammatory infiltrates and assessment of vascular remodelling throughout the course of acute liver injury and regeneration, providing insights into the biological processes determining recovery.

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14

Henderson, Neil C. "Molecular mechanisms of hepatic injury and repair." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/1554.

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In this thesis I examined molecular mechanisms involved in acute and chronic liver injury, and also studied basic pathways mediating tumour promotion. Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen activated protein kinase family and is a key intracellular signaling molecule involved in the control of cell fate. Paracetamol induced hepatic JNK activation in both human and murine paracetamol hepatotoxicity, and in a murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in murine paracetamol hepatotoxicity. In addition, delayed administration of JNK inhibitor was more effective than N-acetylcysteine following paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride or anti-Fas antibody mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic TNF-alpha production following paracetamol poisoning. These data demonstrate a central role for JNK in the pathogenesis of paracetamol induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity. Liver fibrosis with loss of tissue architecture and subsequent hepatic failure represents a massive healthcare burden worldwide. Expression of Galectin-3 (a beta-galactoside binding animal lectin) is upregulated in established human fibrotic liver disease, during the development of experimental liver fibrosis and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the gene encoding Galectin-3 blocks transdifferentiation of precursors to myofibroblasts in vitro and in vivo, markedly attenuating hepatic scarring in a murine model of liver fibrosis. Inhibition of Galectin-3 expression by siRNA in primary murine and human hepatic stellate cells significantly reduced myofibroblast activation and procollagen(I) expression. The reduction in hepatic fibrosis observed in the Galectin-3-/- mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3-/- hepatic stellate cells, in contrast with wild type hepatic stellate cells. However TGF-beta stimulated signaling via Smad-2 and 3 was equivalent in both Galectin-3-/- and wild type hepatic stellate cells indicating that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. This supports a novel and important mechanistic role for Galectin-3 in the regulation of myofibroblast activation and consequent liver fibrosis. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation following hepatic injury and may therefore provide a novel therapeutic approach to the prevention and treatment of liver fibrosis. CD98hc (a ligand for Galectin-3) constitutively and specifically associates with beta1 integrins and is highly expressed on the surface of human tumour cells irrespective of the tissue of origin. CD98hc promotes both anchorage- and serum-independent growth. Using chimeras of CD98hc and the type II membrane protein CD69 demonstrated that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumour promotion by integrins.

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15

Kita, Sadahiko. "The protective effect of transplanted liver cells into the mesentery on the rescue of acute liver failure after massive hepatectomy." Kyoto University, 2016. http://hdl.handle.net/2433/216179.

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出版日2016/2/15を明示する必要あり。発行号・ページ数が決まっていればそれらも明示する必要あり。 Final publication is available at http://dx.doi.org/10.3727/096368916X690999
Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第19925号
医博第4145号
新制||医||1017(附属図書館)
33011
京都大学大学院医学研究科医学専攻
(主査)教授長船健二, 教授伊達洋至, 教授坂井義治
学位規則第4条第1項該当

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16

Salamone, Federico. "Therapeutic effect of adipose tissue-mesenchymal stem cells transplantation in rats with acute liver failure." Thesis, Universita' degli Studi di Catania, 2011. http://hdl.handle.net/10761/97.

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Background and aims. Acute liver failure (ALF) is a life-threatening condition in which a sudden and massive liver injury can determines encephalopathy, coagulopathy and eventually multiorgan failure leading to death. The main cause of ALF in industrialized countries is acetaminophen (APAP) intoxication. When pharmacological treatment fails, orthotopic liver transplantation (OLT) is the standard of choice; however, the shortage of donor organs for OLT makes the need of finding alternative therapeutic options. In this study, we aimed at identifying if the transplantion of ASCs may exert a therapeutic effect in APAP-ALF and if ASCs transplantation may affect oxidative stress and JNK activation, which are key events involved in the pathogenesis of APAP-ALF. Materials and methods. ASCs were isolated from abdominal subcutaneous tissue of a healthy donor undergoing ernioplasty and were transfected with a green fluorescent protein (GFP) before transplantation.Twelve Sprague-Dawley rats, weighting 200 gr, were administrated 300 mg/Kg of APAP i.p. Four rats served as healthy controls. After 2 hour from APAP dose, six rats were transplanted 200.000 ASCs, suspended in saline, via the caudal vein, whereas six animals received only the vehicle. After 24 hours from APAP administration, rats were sacrificed and blood, liver and brain samples were collected. Plasma AST, ALT, ammonia and prothrombin time were measured; brain water content was also determined. Histological damage was evaluated by using hematoxylin-eosine staining. Indirect immunofluorescence for the identification of GFP+ cells was performed on frozen liver samples. Monoclonal antibodies for human CK-8 and vimentin were used for immunohistochemistry. Liver isoprostanes and 8-hydroxyguanosine (8-OHG) was determined by ELISA. Hepatic nitrite/nitrate was measured colorimetrically. JNK expression was evaluated by western blot. Results. Rats with APAP intoxication presented a marked increase of AST (P<0.01), ALT (P<0.01), ammonia (P<0.05) and prothrombin time (P<0.01), and increased brain water content (P<0.05) as compared to healthy animals. Transplantation of ASCs decreased AST (P<0.01), ALT (P<0.01), ammonia (P<0.05) and prothrombin time (P<0.01) to the levels observed in control rats. Consistently, brain water content of transplanted rats was similar to healthy animals and these animals did not present clinical encephalopathy as well. Liver sections of rats with APAP-ALF showed diffuse vacuolar degeneration indicating mitochondrial damage and scattered necroinflammatory foci. In rats transplanted with ASCs, liver injury was almost absent. GFP-staining demonstrated that ASCs engrafted into the liver, where they localized in the parenchyma and around sinusoids. Most cells presented a shaped fibroblast-like morphology, but few cells had a round epithelial-like aspect. Consistently, most ASCs were vimentin-positive, whereas only few cells were CK-8 positive. Rats with APAP-ALF presented a marked increase of liver isoprostanes (P<0.01), 8-OHG (P<0.01) and nitrite/nitrates (P<0.01)as compared with control animals. Tranplantation of ASCs decreased liver isoprostanes (P<0.01), 8-OHG (P<0.01) and nitrite/nitrates (P<0.01) to the levels of control rats. Finally, the expression of phospho-JNK was markedly increased in rats with APAP-ALF (P<0.01) as compared to control rats, whereas ASCs transplantation restored pospho-JNK expression to levels of healthy animals. Conclusion. In this study we demonstrated for the first time that ASCs transplantation is effective in treating APAP-induced ALF and encephalopathy in rats. ASCs engraft in the injuried liver, where exerts potent antioxidant effects and inhibits JNK activation. Further studies are warranted in order to elucidate additional molecular pathways involved in the therapeutic effect of ASCs transplantation in ALF. In our opinion, our findings provide a strong rationale for the potential use of ASCs in the clinical management of patients with ALF.

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17

Koyama, Satoshi. "Dynamic changes of serum microRNA-122-5p through therapeutic courses indicates amelioration of acute liver injury accompanied by acute cardiac decompensation." Kyoto University, 2018. http://hdl.handle.net/2433/232103.

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18

Takemoto, Kenji. "Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure." Kyoto University, 2015. http://hdl.handle.net/2433/195964.

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Kenji Takemoto, Etsuro Hatano, Keiko Iwaisako, Masatoshi Takeiri, Naruto Noma, Saori Ohmae, Kan Toriguchi, Kazutaka Tanabe, Hirokazu Tanaka, Satoru Seo, Kojiro Taura, Keigo Machida, Norihiko Takeda, Shigehira Saji, Shinji Uemoto, Masataka Asagiri, Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure, FEBS Open Bio, Volume 4, 2014, Pages 777-787, ISSN 2211-5463
Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第18678号
医博第3950号
新制||医||1007(附属図書館)
31611
京都大学大学院医学研究科医学専攻
(主査)教授松原和夫, 教授渡邊直樹, 教授一山智
学位規則第4条第1項該当

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19

Zaccherini, Giacomo <1985&gt. "Clinical and pathophysiological characterization of patients with acutely decompensated cirrhosis and acute-on-chronic liver failure." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2022. http://amsdottorato.unibo.it/10083/1/Zaccherini%20-%20Tesi%20PhD.pdf.

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In the last decade, our understanding of the pathophysiological mechanisms underlying decompensated cirrhosis has greatly increased. Moreover, acute-on-chronic liver failure (ACLF) was defined as a distinct syndrome with specific features. Our research activities aimed to provide a contribution in characterizing patients with acutely decompensated cirrhosis and ACLF from a clinical and a pathophysiological perspective. As a first project, we addressed the clinical issue of predicting in-hospital development of ACLF in patients hospitalized for acute decompensation of cirrhosis. As a second contribution, we performed a reassessment of the whole metabolomic dataset obtained from 831 patients enrolled in the CANONIC study, focusing on amino acids, with the aim to uncover alterations in amino acids metabolic pathways. As a third perspective, we performed a GWAS on 270 patients with acute decompensation and ACLF included in the first clinical study. We categorized patients in 4 groups, according to their clinical presentation and their clinical course. We then performed two comparisons: group 1 vs group 4 (i.e., the most severe vs the mildest clinical courses), and group 1 vs group 2 (i.e., patients with different 1-year outcomes from a common clinical presentation with ACLF or bacterial infection). Three SNPs (rs9354118 on chromosome 6q16.1; rs1146878 on chromosome 13q22.2; rs6479397 on chromosome 9q22.31) were significantly associated with the selected phenotypes, but all of them were located in non-codifying DNA regions. However, their potential role as candidate Cis-Regulatory Elements (cCREs) opened interesting hypotheses on effects on the expression of neighboring genes. Indeed, four of them (FUT9 and UFL1 for SNP rs9354118, LMO7 and ACOD1 for rs1146878) are involved in the modulation of immune system activation and systemic inflammation. The results of the GWAS did not confirm previous findings reported in literature and presented some limitations. However, it provided the basis for further research in this still open issue.

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20

Cárdenas, Andrés. "Prognostic value and treatment of hyponatremia in patients with advanced cirrhosis and acute on chronic liver failure." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/396157.

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Patients with cirrhosis may develop significant complications of renal function manifested initially by increased sodium retention followed by impaired solute-free water excretion, and finally with renal vasoconstriction. These alterations are responsible for fluid accumulation in the form of ascites, hyponatremia and hepatorenal syndrome respectively. Patients with cirrhosis and hyponatremia have high levels of vasopressin. Patients with cirrhosis that develop acute complications such as ascites, hepatic encephalopathy, hyponatremia, gastrointestinal bleeding, and/or bacterial infections can be classified into those with mere decompensated cirrhosis and those in whom an acute event ifs followed with progressive liver and/or extrahepatic organ failure(s). These latter patients have a poor prognosis and have been defined as having acute on chronic liver failure (ACLF) ACLF defines a subgroup of cirrhotic patients who develop organ failure(s) following hospital admission with or without an identifiable precipitating event. Therapy for cirrhotic patients with hyponatremia with an antagonist of vasopressin (Tolvaptan) and the relationship of hyponatremia and ACLF remain unknown. The aim of this thesis was to evaluate the safety and efficacy of tolvaptan in raising serum sodium levels in patients with cirrhosis and ascites and determine the specific effects hyponatremia on the outcome of patients with ACLF. Patients with cirrhosis and hyponatremia that received tolvaptan for 1 month effectively increased serum sodium concentration in hyponatremic patients with cirrhosis. Compared to placebo tolvaptan also caused a significant increase in urine output and fluid intake and a negative fluid balance during first day after the initial dose. There also was a significant improvement in some components of health related quality of life (SF 12 health survey mental component scores) at the end of the study. Serum sodium levels reverted to baseline levels 1 week after stopping tolvaptan. In a sub-analysis of the CANONIC study ( a large study that re-defined ACLF in several European centers) patients with cirrhosis ACLF was more common in patients with hyponatremia (36%) compared to those without it (20%). On the other hand, the prevalence of hyponatremia in patients with ACLF was double than that in patients without ACLF (24% vs 12%, respectively). The most important finding of this analysis was the demonstration that hyponatremia influences the outcome of patients with ACLF. Moreover, both hyponatremia and ACLF independently affect this outcome. This means that hyponatremia in patients without ACLF significantly increases the risk of dying. However, even more interesting is the fact that if patients have both ACLF and hyponatremia (compared to those without either) then the risk of dying is almost 7 times higher. These findings indicate that hyponatremia influences the outcome of patients with ACLF.
Los pacientes con cirrosis pueden desarrollar complicaciones significativas de la función renal que se manifiesta inicialmente por el aumento de la retención de sodio seguido de alteración de la excreción de agua libre de solutos, y finalmente con la vasoconstricción renal. Estas alteraciones son responsables de la acumulación de líquido en forma de ascitis, hiponatremia y síndrome hepatorrenal, respectivamente. Los pacientes con cirrosis e hiponatremia tienen altos niveles de vasopresina. Los pacientes con cirrosis que desarrollan complicaciones agudas tales como ascitis, encefalopatía hepática, hiponatremia, sangrado gastrointestinal, y / o infecciones bacterianas pueden clasificarse en aquellos con mera cirrosis descompensada y aquellos en los que un evento agudo lleva a una insuficiencia hepática y fallo de organos extrahepáticos. Estos últimos pacientes tienen un mal pronóstico y se han definido como aquellos con insuficiencia hepática aguda sobre crónica o ACLF por sus siglas en ingles. ACLF define un subgrupo de pacientes cirróticos que desarrollan insuficiencia (s) de órganos después un ingreso en el hospital, con o sin un evento precipitante identificable. El manejo de los pacientes cirróticos con hiponatremia con un antagonista de la vasopresina (Tolvaptán) y la relación de la hiponatremia y ACLF siguen siendo desconocidos. El objetivo de esta tesis fue evaluar la seguridad y eficacia de tolvaptán en el aumento de los niveles de sodio sérico en pacientes con cirrosis y ascitis y determinar efectos específicos de la hiponatremia y su relación con el ACLF. Los pacientes con cirrosis e hiponatremia que recibieron tolvaptán por 1 mes aumentaron efectivamente la concentración de sodio sérico en comparación con el placebo. El tolvaptán también aumentó de forma significativa la producción de orina. También hubo una mejora significativa en algunos componentes de la calidad relacionada con la salud de la vida (encuesta de salud SF 12, en las puntuaciones de los componentes mentales) al final del estudio. Los niveles de sodio serico volvieron a los niveles basales 1 semana después de suspender tolvaptán. En un subanálisis del estudio CANONIC (un estudio de ACLF en varios centros europeos) en aquellos pacientes con cirrosis, el ACLF fue más común en pacientes con hiponatremia (36%) en comparación con aquellos sin ella (20%). Por otra parte, la prevalencia de la hiponatremia en pacientes con ACLF era el doble que en pacientes sin ACLF (24% vs 12%, respectivamente). El hallazgo más importante de este análisis fue la demostración de que la hiponatremia influye en el desenlace de los pacientes con ACLF. Por otra parte, tanto la hiponatremia y ACLF afectan de forma independiente este resultado. Esto significa que la hiponatremia en pacientes sin ACLF aumenta significativamente el riesgo de morir. Sin embargo, aún más interesante es el hecho de que si los pacientes tienen tanto ACLF e hiponatremia (en comparación con los que no tienen tampoco), entonces el riesgo de morir es casi 7 veces mayor. Estos hallazgos indican que la hiponatremia influye en el desenlace de los pacientes con ACLF.

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21

Mlotha-Mitole, Rachel. "A retrospective review of acute liver failure in children admitted at Red Cross War Memorial Children's Hospital." Master's thesis, Faculty of Health Sciences, 2021. http://hdl.handle.net/11427/33863.

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Acute liver failure (ALF) describes a clinical syndrome resulting from severe liver damage and extensive loss of functional parenchymal liver mass triggered by various factors. Early recognition and initiation of specific therapy may improve outcomes and reduce the need for liver transplantation, a treatment modality not universally available in resource constraint areas. There is paucity of data describing this syndrome in Sub-Saharan Africa in children. Objective This study aims to retrospectively review and determine the clinical presentation, aetiology, complications & outcome of ALF in children admitted at the Red Cross War Memorial Children's Hospital (RCWMCH). Methods All records of children from 0 to 13 years admitted at the RCWMCH over the period from January 2005 to December 2016 with ALF were retrospectively reviewed, after obtaining ethical approval. Patients with pre-existing evidence of chronic liver disease were excluded. Demographic variables as well as clinical presentation and investigations were captured, with determination of outcomes at 3 weeks and 6 weeks of diagnosis. Results Study included 24 children., 16 females (66.7%) and 8 males (33.3%). Median Age was 15 months, with interquartile range from 5 to 28 months. Diarrhoea, jaundice, respiratory distress, hepatomegaly and encephalopathy were common clinical features. Aetiology was infection in 37.5 % of cases (n=9, 2 of whom had autoimmune hepatitis comorbidity) and hepatitis A was most common infectious cause (n=4, 44%). Causes were indeterminate in 29.2%. Two patients had autoimmune hepatitis without co-morbidity; Reye syndrome 12.5% and 17% had miscellaneous causes. Transaminases were raised to thousands in viral causes of hepatitis, with a low C reactive protein. INR >4 and Total Bilirubin>210umol/L were associated with death outcome (p=0.04 and p=0.03 respectively. Conclusion Viral hepatitis A is the leading infective cause of acute liver failure in this study cohort and 29.2% of cases were indeterminable. INR >4 and Bilirubin > 210umol/l were predictors of poor outcome. Follow up study is recommended to better understand clinical spectrum and outcomes of children with acute liver failure in this low resource setting.

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22

Lintern, K. B. "Immobilisation of lactate oxidase and deoxyribonuclease I for use within a bio-artificial liver assist device for the treatment of acute liver failure." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1411473/.

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Constraints of cell supply indicate that proliferating cell lines are likely to be essential components of Bio-Artificial Liver support devices (BAL) for the treatment of acute liver failure. The Liver Group BAL employs clones of cells derived from the HepG2 cell line, which in common with many tumour derived cells, are predominantly dependent on anaerobic glycolysis for energy supply, leading to production of lactate within the bioreactor. The BAL system requires prolonged culture of alginate encapsulated HepG2 cells, and lactate accumulation presents a potential hazard in this system: at ~15 mM, accumulated lactate becomes toxic to the cells in the bioreactor, and also compromises alginate bead integrity by chelating the calcium ions necessary for alginate polymerisation. Furthermore, the tumour lineage of the cells could prove a potential threat to patient safety should any HepG2 DNA enter the patient’s system. It was hypothesised that inclusion of immobilised Lactate oxidase (LOx) to catalyse degradation of lactate into pyruvate could offset these limitations whilst simultaneously providing a potential energy source utilisable by HepG2 cells. In a similar fashion, immobilised Deoxyribonuclease I (DNase I) could be utilised to remove non-patient DNA during the treatment phase of the BAL system. Here it is demonstrated that functionalised glass beads are a feasible method of immobilising LOx and DNase I. Enzymatic activity was retained even after prolonged incubation at 37°C in the presence of human plasma, offering a means of reducing lactate levels during HepG2 culture, and potentially removing circulating DNA below practically detectable levels, thus facilitating cellular performance and BAL efficiency as a safe and effective potential therapy for acute liver failure.

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23

Čičinskaitė, Ilona. "Ūminio ir lėtinio paūmėjusio kepenų funkcijos nepakankamumo priežastys, išeitys ir prognozės kriterijai." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2006. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2005~D_20060105_114953-62440.

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Acute liver failure (ALF) is a rather rare clinical syndrome developing due to an acute massive dysfunction of the liver cells in previously healthy persons (at least 8 weeks there was no diagnosis of any liver disease) resulting in rapidly progressing multiple organ dysfunction syndrome. Without liver transplantation 80-95 % of the patients die. Factors, influencing the outcome are etiology, the patient's age and the course of the disease. Spontaneous recovery, however, is possible in 5-60 % of ALF cases when regeneration of the liver starts, therefore the main goal of the treatment is to create the most favorable conditions for regeneration. Causes of ALF may be different. The most common cause of ALF is viral hepatitis, but the prevailing causative agent of hepatitis is different in different countries. Drug-induced (acetaminophen, halotane) liver dysfunction ranks second. The order of other etiological factors according to their frequency is: mushroom (Amanita) poisoning, carbon tetrachloride toxicity, heat stroke, synthetic amphetamine ("Ecstasy") and disorders of liver blood vessels. In cases of unfavorable prognosis for patients with ALF the only method of treatment with good prognosis is liver transplantation (LT). From 50 to 70 % of patients with lethal ALF prognosis survive after emergency LT. There is no unified ALF prognostic system or indications for LT in the world, therefore a precise individual prognosis for every patient and well-timed decision about LT are... [to full text]

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24

Clark, Sarah Jane. "The growth hormone, insulin-like growth factor, insulin-like growth factor binding proteins and insulin axis in acute liver failure." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397943.

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25

Shi, Baomin [Verfasser]. "Transplantation of Monocyte-derived Hepatocyte-like Cells (NeoHep cells) Improves Survival in A Model of Acute Liver Failure / Baomin Shi." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023233983/34.

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26

Silva, Pedro Eduardo Soares e. "Validação do clif-sofa e da definição de acute-on-chronic liver failure do consórcio easl-clif como preditores de mortalidade na cirrose." reponame:Repositório Institucional da UFSC, 2014. https://repositorio.ufsc.br/xmlui/handle/123456789/129683.

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Dissertação (mestrado profissional) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Cuidados Intensivos e Paliativos, Florianópolis, 2014.
Made available in DSpace on 2015-02-05T21:22:47Z (GMT). No. of bitstreams: 1 330259.pdf: 983576 bytes, checksum: 22ebb0c057d6c02096f4f218dddcf687 (MD5) Previous issue date: 2014
Introdução: O conceito de acute-on-chronic liver failure (ACLF) surgiu para identificar os pacientes com falência orgânica e com altas taxas de mortalidade. Entretanto, a ausência de uma definição precisa limita a aplicação clínica e a pesquisa relacionada a esta complicação.Objetivos: Validar a definição de ACLF e o escore CLIF-SOFA recentemente proposto pelo consórcio EASL-CLIF como preditores de mortalidade em pacientes admitidos por descompensação aguda da cirrose.Material e Métodos: Neste estudo de coorte prospectivo, os pacientes foram acompanhados durante sua internação hospitalar e, no caso de alta hospitalar, a avaliação da mortalidade foi realizada por contato telefônico no trigésimo e nonagésimo dias. Todos os pacientes realizaram avaliação laboratorial na admissão hospitalar.Resultados: Entre dezembro de 2010 e novembro de 2013, 192 pacientes cirróticos foram incluídos. Na admissão, 46 pacientes (24%) preencheram os critérios para ACLF ( Graus 1, 2 e 3 em 18%, 4% e 2%, respectivamente). A mortalidade em 30 dias foi de 65% no grupo ACLF e de 12% nos demais pacientes (P<0,001). Análise de regressão logística demonstrou que a mortalidade em 30 dias foi independentemente associada com a presença de ascite e ACLF na admissão. A estimativa da probabilidade de sobrevida de Kaplan-Meier no nonagésimo dia foi de 92% em pacientes sem ascite ou ACLF e de apenas 22% nos pacientes com ascite e ACLF. A AUROC do CLIF-SOFA em predizer a mortalidade em 30 dias foi de 0,847 ± 0.034, com sensibilidade de 64%, especificidade de 90% e razão de verossimilhança positiva de 6,61 para valores = 9.Conclusões: Nessa experiência de um único centro, o escore CLIF-SOFA e a definição do consórcio EASL-CLIF de ACLF provaram ser fortes preditores de mortalidade em curto prazo em pacientes admitidos por descompensação aguda da cirrose hepática.

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27

Seria, Elisa Libera. "Rigenerazione epatica mediante l'impiego di cellule staminali mesenchimali in un modello murino di danno epatico tetracloruro-indotto." Doctoral thesis, Università di Catania, 2012. http://hdl.handle.net/10761/1133.

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Bone marrow-derived mesenchymal stem cells (MSCs) have been investigated as marker of liver regeneration in an experimental model of acute liver failure (ALF). This model was created in Wistar rats through an intraperitoneal injection of carbon tetrachloride (CCl4). MSCs (3 million) were collected by long bones of 10 Wistar rats and then intravenously infused 24 hours after induction of ALF in 16 rats, Group A. In control Group B, 16 rats received a peritoneal injection of CCl4, and an intravenous infusion of normal saline. All rats were sacrificed at 2, 3, 4 and 7 days post-CCl4-injection. To assess the efficacy of the induction of the ALF, 4 rats Group (C) were sacrified 1 day after poisoning. Biochemical markers (BM) of liver function as platelets counts and pathology examination of the procured livers were staged on post-infusion-days 2, 3, 4 and 7. In Group A platelets count was higher than in the untreated control Group on post-CCl4-infusion day 2nd (p = 0.02) and 3rd (p=0.001). Also The trend of BM as transaminases was higher in the non-treated Group B, GOT (p=0.002), GPT (p<0.0001). Pathology examination showed greater grade of hepatocellular necrosis, and neutrophilic infiltration in Group B (p=0.02). MSCs infusion determined a less aggressive picture of hepatic damage.

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Santos, Felipe Miranda. "Potencial terapêutico da s-nitrosoglutationa (GSNO) na insuficiência hepática aguda experimental induzida por paracetamol." Centro de Pesquisas Gonçalo Moniz, 2012. https://www.arca.fiocruz.br/handle/icict/7221.

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Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Farmácia. Salvador, BA, Brasil
A intoxicação pelo paracetamol é a principal causa de insuficiência hepática aguda (IHA) em vários países do ocidente. A hepatotoxicidade é mediada por um metabólito intermediário reativo que depleta as reservas do antioxidante endógeno glutationa (GSH). O tratamento precoce com n-acetilcisteína (NAC) é recomendado para restabelecer a concentração fisiológica de GSH. A snitrosoglutationa (GSNO) é uma molécula antioxidante derivada do GSH capaz de reduzir o estresse oxidativo em diversos sistemas celulares e modelos experimentais. OBJETIVO: Avaliar se GSNO é capaz de reduzir a taxa de mortalidade, extensão da necrose hepática, manifestações bioquímicas e comparar sua eficácia com NAC e GSH no tratamento da IHA experimental induzida por paracetamol. METODOLOGIA: Camundongos isogênicos machos da linhagem C57Bl/6 foram tratados por três semanas com água suplementada com etanol a 10%. Os animais foram divididos em cinco grupos. O grupo 1 (controle negativo) recebeu solução salina 0,9%. Os demais grupos receberam 300 mg/Kg de paracetamol para indução de IHA. Após 3 horas, o grupo 2 (controle positivo) foi tratado com salina tamponada com fosfato (PBS) e os grupos 3, 4 e 5 foram tratados, respectivamente, com 600 Umol/kg de NAC, GSH e GSNO. A eutanásia foi feita 12 horas após a indução de IHA. A extensão da necrose hepática foi avaliada por morfometria através do software IMAGEPRO-PLUS. Os níveis séricos de transaminases e fosfatase alcalina foram avaliados como marcadores bioquímicos de lesão hepática. A taxa de mortalidade foi avaliada em um experimento independente, após uma dose de 350 mg/Kg de paracetamol. RESULTADOS: O tratamento com GSNO 600 Umol/kg aumentou a taxa de sobrevida em relação aos grupos tratados com NAC ou PBS. Entretanto, não houve diferença de mortalidade entre os grupos GSNO e GSH. A avaliação morfométrica revelou menor extensão de necrose hepática nos animais tratados com GSNO em comparação com NAC e PBS. Houve redução de atividade sérica de ALT, mas não de AST no grupo GSNO em comparação com PBS e NAC. Os níveis séricos de fosfatase alcalina, albumina, ureia e creatinina não apresentaram diferenças entre os diversos grupos. CONCLUSÃO: O tratamento com GSNO aumenta a taxa de sobrevida e reduz a extensão de necrose hepática na IHA experimental por paracetamol. O GSNO apresenta eficácia superior à NAC e idêntica ao GSH em dose equimolar. Estes achados sugerem que o efeito protetor do GSNO parece independer da porção nitroso da molécula. Possíveis mecanismos de proteção extra-hepáticos merecem ser investigados
Paracetamol overdose is the main cause of acute liver failure (ALF) in western countries. The hepatotoxicity is mediated by a reactive metabolite that depletes the pool of glutathione (GSH), an endogenous antioxidant molecule. Early treatment with n-acetylcysteine (NAC) is recommended to replenish the pool of GSH. S-nitrosoglutathione (GSNO) is a potent antioxidant molecule that reduces oxidative stress in several cellular systems and experimental models. OBJECTIVE: To evaluate if GSNO reduces the mortality rate, the hepatocelular necrosis extension and to compare its therapeutic efficacy with NAC and GSH in experimental ALF induced by paracetamol. METHODS: Male mice were treated for three weeks with alcohol 10% orally. The animals were divided in five groups. Group 1 (negative control) received saline 0.9%. All the other groups received 300 mg/Kg paracetamol for induction of ALF. After 3 hours, group 2 (positive control) received phosphate buffered saline (PBS) and groups 3, 4 and 5 were treated respectively with 600 Umol/kg of NAC, GSH and GSNO. The animals were sacrificed after 12 hours of induction of ALF. The area of liver necrosis was evaluated by morphometric analysis with the software IMAGEPRO. Transaminases and alkaline phosfatase were determined as markers of liver injury. Mortality rate was evaluated in an independent experiment after a dose of 350 mg/Kg of paracetamol. RESULTS: GSNO treatment (600 Umol/kg) significantly improved the survival rate compared to PBS and NAC treatments. There was no statistical difference in survival rate between GSNO and GSH groups. In addition, GSNO attenuated the area of liver necrosis in comparison to NAC and PBS, but not to GSH. GSNO reduced the serum ALT, but not AST activity in comparison to PBS and NAC. There was no statistical difference in alkaline phosphatase, urea, creatinine and albumin among the groups that received paracetamol. CONCLUSION: GSNO treatment augmented survival rate and reduced the area of liver necrosis in comparison to NAC, but was equally as effective as GSH. These findings suggest that the hepatoprotector effect of GSNO is independent of the nitroso moiety of the molecule. Potential extra-hepatic mechanisms remain to be evaluated.

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29

Júnior, Fernando Mendes Paschoal. "Autorregulação encefálica na insuficiência hepática fulminante antes e após transplante hepático." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-09082016-153844/.

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O presente estudo avaliou a autorregulação encefálica (ARE) em doentes com insuficiência hepática fulminante (IHF) antes e após transplante hepático. Foram avaliados 25 pacientes com diagnóstico de IHF, 17 foram avaliados antes e após o transplante hepático, sendo seis (24,0%) do sexo masculino e 19 (76,0%) feminino. A média de idade foi de 33,8 anos, que variou de 14 a 56 anos, com desvio padrão de 13,1 anos. A hemodinâmica encefálica foi avaliada pela velocidade de fluxo sanguíneo encefálico (VFSE) nas artérias cerebrais médias e artéria basilar (AB), que usou o ultrassom Doppler transcraniano (DTC), dispositivo de dois canais, com transdutores de 2 mega Hertz (MHz). A autorregulação encefálica foi mensurada pelo índice de autorregulação (IARE) estática que leva em conta os efeitos do aumento da pressão arterial média (PAM) sobre a VFSE. Para isso, promoveu-se o aumento da PAM (20 mmHg a 30 mmHg) com infusão de noradrenalina.. Ao se avaliar o IARE considerando a velocidade de fluxo sanguíneo em quatro momentos (pré-transplante, 1°, 2° e 3° dia após o transplante), observou-se que houve diferença estatística em artéria cerebral média (ACM) à direita (p=0,008), esquerda (p=0,007), máxima (p=0,005), e AB (p=0,006); assim como na análise em cada tempo do IARE, observou-se diferença estatística em ACM à direita (p=0,012), esquerda (p=0,009), máxima (p=0,006), e AB (p=0,011). A análise categórica do IARE na artéria cerebral média e basilar descreveu que a maioria dos doentes reestabeleceu a AR no 2° dia em ACM e 3° na AB (índice > 0,6), enquanto com o índice > 0,8 em ambas as artérias a ARE reestabeleceu no 2° dia. As variáveis sistêmicas como pressão parcial de CO2 e hemoglobina nos tempos da avaliação não apresentaram diferença estatística p=0,100 e p=0,093 respectivamente. Os resultados obtidos apontam para o comprometimento da ARE antes e após transplante hepático, tanto em circulação anterior como posterior, e que tende a ser reestabelecido entre 48 a 72 horas. Os achados deste estudo favorecem o manejo adequado de doentes nestas fases (antes e após transplante) e podem evitar a evolução para complicações neurológicas, como tumefação encefálica e hipertensão intracraniana, que indicam prognóstico ruim para a evolução clínica destes doentes. Estudos futuros necessitam ser realizados para que se consolide o uso da monitoração contínua com métodos não invasivos como o DTC para direcionar o manejo hemodinâmico encefálico na IHF
This study evaluated cerebral autoregulation in patients with fulminant hepatic failure (FHF) before and after liver transplantation. A total of 25 patients comprising six (24.0%) males and 19 (76.0%) females with FHF were evaluated. Seventeen patients were evaluated both before and after liver transplantation. Mean age of the patients was 33.8 years, with a range of 14-56 years and standard deviation of 13.1 years. Brain hemodynamics was assessed by cerebral blood flow velocity in the middle cerebral arteries (MCA) and basilar artery (BA) using transcranial Doppler ultrasound on a two-channel device with 2 MHz transducers. Cerebral autoregulation was measured by static cerebral autoregulation index (SCAI), which accounts for the effects of increase in mean arterial blood pressure (ABP) on cerebral blood flow velocity. An increase in ABP (20 mmHg to 30 mmHg) was induced with norepinephrine infusion. Evaluation of SCAI based on blood flow velocity (BVF) at four timepoints (pre-transplant and on 1st, 2nd and 3rd days post-transplant) revealed a statistical difference in the MCA right (p = 0.008) left (p = 0.007), maximum (p = 0.005) and the BA (p = 0.006). In addition, analysis by timepoint showed a statistical difference in MCA (p = 0.012), left (p = 0.009), maximum (p = 0.006) and in the BA (p = 0.011). Categorical analysis of autoregulation in the MCA and BA showed that most patients reestablished autoregulation in the MCA on the 2nd day post-transplant and in the BA (index > 0.6) on the 3rd day, while autoregulation was reestablished in both arteries (index > 0.8) on the 2nd day. On the assessment by timepoint, the systemic variables CO2 partial pressure and hemoglobin showed no statistically significant differences (p = 0.100 and p = 0.093, respectively). The results reveal impaired SCAI before and after liver transplantation, both in anterior and posterior circulation, with a tendency to reestablish at 48 to72 hours. The findings of this study can help improve management of patients at these stages (pre and post transplantation), preventing neurological complications such as brain swelling and intracranial hypertension, associated with poor prognosis for the clinical course. Future studies should be conducted to consolidate the use of continuous monitoring with noninvasive method (TCD), to provide more accurate information to guide brain hemodynamic management in FHF

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30

Pasqua, Mattia. "Preclinical studies on an extracorporeal bioartificial liver." Thesis, Compiègne, 2020. http://www.theses.fr/2020COMP2557.

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Pour tous les patients souffrant d'une insuffisance hépatique aigue, il existe un besoin urgent de solutions alternatives à la transplantation du foie. En raison de divers facteurs, ces patients n'ont pas toujours accès à un organe et meurent dans l’attente d’une greffe. Il est donc impératif de trouver des alternatives viables à la transplantation du foie. Parmi les différentes alternatives apparues ces dernières années, notre groupe a principalement étudié le concept de foie bioartificiel. Il s'agit d'un dispositif de circulation extracorporelle équipé d'éléments artificiels (charbon actif et résine ionique) et d'éléments biologiques (biomasse hépatique) capables de soutenir l'organe défaillant. Ce dispositif a pour rôle de fournir les fonctions hépatiques, perdues à cause de la maladie, afin d'aider le patient à rester en vie jusqu'à ce qu'un organe soit disponible ou de favoriser la régénération naturelle du foie. Cette thèse retrace l'évolution de ces dispositifs au cours du temps, en décrivant leur principe de fonctionnement et les principaux résultats proposés par la littérature. Un accent est ensuite mis sur le développement de notre dispositif de suppléance hépatique et sur la voie scientifique qui a permis d'optimiser au mieux la biomasse hépatique. Ce travail a conduit à la mise au point d'un dispositif BAL prêt à l'emploi sur des modèles de petits animaux en insuffisance hépatique aigue
For all patients suffering of acute liver failure, there is an urgent need of alternatives to liver transplantation. Due to a variety of factors, those patients do not always have easy access to an available organ and die waiting for a transplant. Therefore, it is imperative to find viable alternatives to liver transplantation. Among the various alternatives that emerged in recent years, our group has mainly investigated the concept of bioartificial liver. It is an extracorporeal circulation device equipped with artificial elements (activated charcoal and ionic resin) and a biological element (hepatic biomass) capable of supporting the failing organ. This device has the role of providing hepatic functions, lost due to the disease, helping the patient to remain alive until an organ is available or, otherwise, capable of promoting natural liver regeneration. This thesis retraces the evolution of these devices over time, describing their principle of operation and the main results proposed by the literature. The focus is then moved on the development of our liver supply device and the scientific path that allowed optimizing the hepatic biomass at best. This thesis work led to the development of a ready-to-use BAL device on animal models of acute liver failure

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Rosa, Edovando José Flores da. "AVALIAÇÃO DA CAPACIDADE DO DISSELENETO DE DIFENILA EM REDUZIR A FALÊNCIA HEPÁTICA AGUDA INDUZIDA POR PARACETAMOL EM CAMUNDONGOS." Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/11219.

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Paracetamol (APAP) is commonly used analgesic and antipyretic, however high doses can induce damage hepatic. The metabolic N-acetyl-p-benzoquinone imine (NAPQI) is responsible for the toxic effects. The accumulation of this metabolic causes oxidative stress, cellular death and tissue necrosis. Toxicity of APAP is also related to development of inflammation, accumulation of neutrophils and release of proinflammatory mediators. The treatment consists of the N-acetylcysteine administration, which it must be administered quickly. The diphenyl diselenide (PhSe)2 is an organoselenium compound that exhibit antioxidant activity and pharmacological proprieties. The aim of this study is evaluate the ability of (PhSe)2 in reducing acute liver failure induced by APAP in mice. The animals received APAP 600 mg/kg, and after 1h were treated with (PhSe)2 15.6 mg/kg. After 4h APAP administration was collected serum and hepatic tissue for analysis. APAP administration caused severe damage hepatic, oxidative stress induction and glutathione levels reduction. APAP also caused increase of myeloperoxidase activity. The treatment with (PhSe)2 was effective in reduction of alterations caused by APAP, suggesting a promising therapeutic option for the treatment of acute liver failure.
O paracetamol (APAP) é comumente usado como analgésico e antipirético, porém doses elevadas podem induzir dano hepático. O metabólito N-acetil-p-benzoquinina imina (NAPQI), é responsável pelos efeitos tóxicos. O acúmulo deste metabólito ocasiona estresse oxidativo, morte celular e necrose tecidual. A toxicidade do APAP também está relacionada com desenvolvimento de inflamação, acúmulo de neutrófilos e liberação de mediadores pró-inflamatórios. O tratamento consiste na administração de N-acetilcisteína, a qual deve ser administrada relativamente cedo. O disseleneto de difenila (PhSe)2 é um composto orgânico de selênio que apresenta atividade antioxidante e propriedades farmacológicas. O objetivo deste estudo é avaliar a capacidade do (PhSe)2 em reduzir a falência hepática aguda induzida pelo APAP em camundongos. Os animais receberam APAP 600 mg/kg, e 1h após foram tratados com (PhSe)2 15,6 mg/kg. Após 4 h da administração de APAP coletou-se amostras de soro e tecido hepático para as análises. O APAP ocasionou severo dano hepático, indução de estresse oxidativo e redução dos níveis de glutationa. O APAP também provocou aumento na atividade da mieloperoxidase. O tratamento com (PhSe)2 mostrou-se efetivo na redução das alterações geradas pelo APAP, sugerindo uma opção terapêutica promissora para o tratamento da falência hepática aguda.

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Angiolini, Virgínia Andrea. "Diferenciação de células tronco mesenquimais em células tipo-hepatócitos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/158682.

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Introdução: O fígado é um órgão chave na manutenção da homeostasia corpórea e o transplante hepático ainda continua sendo o padrão-ouro no tratamento da insuficiência hepática aguda. A falta de doadores tem favorecido o desenvolvimento da terapia celular. Células derivadas de medula óssea podem se diferenciar em células tipo-hepatócitos em menos de 24 horas e a comunicação através de vesículas extracelulares (VEs) é um dos mecanismos propostos para explicar essa capacidade. Muitos estudos têm demonstrado que as células-tronco mesenquimais (CTMs) da medula tem alta plasticidade para se diferenciar em hepatócitos, mas os protocolos normalmente utilizados levam entre 7 e 28 dias. Objetivo: Analisar a capacidade de diferenciação das CTMs da medula em se tornar uma célula tipo-hepatócito através do mecanismo de comunicação celular por VEs em cultura (6 e 24 horas). Materiais e métodos: Para avaliar o efeito de hepatócitos primários isolados de ratos saudáveis e lesados com CCl4 na diferenciação das CTMs foi utilizado um sistema de co-cultivo com insertos que não permitem o contato entre as células colocando as CTMs na câmera superior e os hepatócitos na câmera inferior do sistema. Meio condicionado de hepatócitos com lesão foi utilizado para avaliar a capacidade das CTMs de capturar VEs e se diferenciar em célula-tipo hepatócito. Os marcadores de célula tipo-hepatócito avaliados foram expressão gênica (alfa fetoproteina, albumina e citoqueratina-18), armazenamento de glicogênio e liberação de ureia. Para rastrear VEs, hepatócitos de ratos lesados foram marcados com PKH-26. As VEs foram obtidas por ultracentrifugação do sobrenadante e analisadas por citometria de fluxo. Hepatócitos e CTMs também foram analisados por citometria de fluxo na busca de marcação positiva. Resultados: CTMs co-cultivadas durante 6 e 24 horas com hepatócitos não apresentaram expressão de genes hepáticos, mesmo quando expostas a um ambiente de lesão. Os ensaios funcionais confirmaram a falta de sinais de diferenciação, sendo que não foi observado armazenamento de glicogênio nem liberação de ureia nas CTMs. Um achado interessante foi que ao analisar o sobrenadante da câmera superior do sistema de co-cultivo, não foram achadas VEs marcadas com PKH-26 nem CTMs com rastros do marcador. Por outro lado, os experimentos utilizando meio condicionado mostraram que as CTMs têm capacidade de capturar VEs. A citometria de fluxo mostrou que às 6 horas e 24 horas respetivamente 2,28% e 3,97% das CTMs eram positivas para o marcador PKH-26. Quando analisadas no microscópio de fluorescência, foram vistos pontos vermelhos nas CTMs alguns dos quais parecem carregar a proteína albumina. Porém a expressão gênica e analise de ureia não se adequaram a um perfil de célula tipo-hepatócito. Conclusões: O sistema de co-cultivo não foi adequado para permitir a transferência e comunicação através de VEs entre hepatócitos e CTMs sendo que as VEs não conseguem atingir a câmara superior. Os experimentos com meio condicionado sugerem que as CTMs têm capacidade de capturar VEs derivadas de hepatócitos, porém a captação não conduz ao desenvolvimento de um perfil de célula tipo-hepatócito em 6 e 24 horas. São necessários mais estudos para esclarecer a dinâmica de transferência das VEs e suas consequências em longo prazo.
Introduction: Liver is a key organ for corporeal homeostasis maintenance and whole organ replacement still remains the gold standard procedure to treat acute liver failure. Shortage of liver donor has promoted the increase on cell-therapy research. Bone marrow (BM) derived cell have shown potential for differentiation into hepatocyte-like cells in a short time and extracellular vesicles communication (EVs) is one of the proposed mechanisms. Plasticity of bone marrow mesenchymal stem cells (BM-MSCs) is extensively supported by scientific literature but protocols applied to differentiation usually take from 7 to 28 days. Objective: To analyze in vitro differentiation potential of BM-MSCs into hepatocyte-like cells through EVs transfer mechanism in 6 and 24 hours. Materials and Methods: Co-culture system with cell-impermeable inserts and conditioned medium experiments were used to explore the effects of healthy and CCl4-injured hepatocytes, over BM-MSCs differentiation. Assessment of hepatocyte-like cell profile on BM-MSCs was revealed by gene expression (alpha fetoprotein, albumin and cytokeratin-18), glycogen storage and urea release. Hepatocytes from CCl4-injured rats were labeled by PKH-26 to track EVs. Ultracentrifugation was used to isolate EVs from supernatant medium of the two chamber of the co-culture system. PKH-26 positive EVs and PKH-26 positive cells were revealed by flow cytometry analysis and fluorescent microscopy. BM-MSCs cultured with conditioned medium were stained with ALB-FITC antibody. Results: Co-cultured BM-MSCs for 6 and 24 hours, showed no expression of hepatocyte-like genes, even after exposure to damaged microenvironment. Functional assays confirm the lack of differentiation signs there were no glycogen storage or urea release. Interestingly, EVs traffic analysis revealed no PKH-26 positive EVs at the upper chamber of co-culture system and no positive BM-MSCs were found either. On the other hand, conditioned medium experiment showed that BM-MSCs could uptake EVs. Flow cytometry analysis showed positive PKH-26 BM-MSCs at 6 (2.28%) and 24 (3.97%) hours. Flourescence microscopy revealed red points into BM-MSCs and immunofluorescence suggest that some EVs contain albumin. Gene expression and urea assay of BM-MSCs were not in accordance with a hepatocyte-like profile. Conclusions: Co-culture system, by using cell-impermeable membrane, was not adequate to promote EVs transfer between hepatocyte and BM-MSCs since EVs do not pass from the lower to the upper chamber. Conditioned medium experiments can suggest that BM-MSCs could uptake hepatocyte-derived EVs but this not drive to a hepatocyte-like profile in a short period of time. More studies will be necessary to clarify the dynamic of EVs transfer and their long time effects.

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Souza, Bruno Solano de Freitas. "Terapia com células da medula óssea em modelo experimental de insuficiência hepática aguda induzida por acetominofen." Centro de Pesquisas Gonçalo Moniz, 2012. https://www.arca.fiocruz.br/handle/icict/7642.

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Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil
Introdução e objetivos: A insuficiência hepática aguda (IHA), apesar de rara, permanece como uma condição rapidamente progressiva e frequentemente fatal. A intoxicação por acetaminofen (APAP) induz necrose hepática maciça e frequentemente leva à morte por edema cerebral. Terapias celulares são de grande interesse como potenciais tratamentos para IHA. Neste projeto foi avaliado o potencial terapêutico das células mononucleares da medula óssea (CMMO) em um modelo experimental de IHA induzida por APAP em camundongos. Métodos: A IHA foi induzida em camundongos C57Bl/6, previamente submetidos à dieta alcoólica por três semanas, através da administração de APAP na dose de 300 mg/kg por via intraperitoneal. Após a indução da IHA, os camundongos foram transplantados, por via endovenosa, com 107 CMMO obtidas de doadores transgênicos para a proteína verde fluorescente (GFP) ou injetados com salina. As curvas de sobrevivência, os níveis plasmáticos de aminotransferases, amônia, uréia e creatinina, a extensão da necrose hepática, o infiltrado inflamatório e a expressão de citocinas e metaloproteinases foram avaliados. A microscopia confocal foi utilizada para estudar a migração das células transplantadas para o fígado. A permeabilidade da barreira hemato-encefálica foi avaliada pela injeção do corante azul de Evans (AE) por via endovenosa. Resultados: Observou-se que os camundongos tratados com CMMO apresentaram uma redução significativa da mortalidade, com uma taxa de 60% de sobrevivência quando comparados a 20% de sobrevivência do grupo controle. As células transplantadas migraram para o fígado, mas não foi observada a diferenciação destas em células hepáticas ou fusão celular. Não foram encontradas diferenças estatisticamente significativas na extensão de necrose hepática no fígado, nos níveis plasmáticos de transaminases e amônia, na intensidade do infiltrado inflamatório no fígado entre os dois grupos com IHA, bem como nos níveis hepáticos das citocinas TNF-a e IL-10 e de transcritos para adrenomedula e endotelina 1 no cérebro, assim como na atividade da metaloproteinase 9 no soro. No entanto, observou-se uma redução dos níveis séricos de TNF-a no grupo tratado com CMMO quando comparado ao grupo injetado com salina. Esta redução está correlacionada ao aumento do mRNA para IL-10 na medula óssea e no baço dos animais tratados com CMMO. A avaliação do extravasamento do corante azul de Evans para o cérebro demonstrou que o grupo tratado com células mononucleares da medula óssea apresentou uma redução da permeabilidade da barreira hemato-encefálica quando comparado ao grupo injetado com salina. Conclusão: As CMMO exercem um efeito protetor em camundongos com IHA induzida por APAP, sem alterar o dano hepático, provavelmente através da modulação da resposta inflamatória sistêmica e da diminuição da permeabilidade da barreira hemato-encefálica.
Introduction and objectives: Acute liver failure (IHA), although rare, remains a rapidly progressive and often fatal condition. Poisoning by acetaminophen (APAP) induces a massive hepatic necrosis and often leads to death by cerebral edema. Cell therapies are of great interest as potential treatments for IHA. In this project we evaluated the therapeutic potential of bone marrow mononuclear cells (BMC) in an experimental model of IHA induced by APAP in mice. Methods: The IHA was induced in C57BL/6 mice previously submitted to the alcohol diet for three weeks by the administration of APAP at a dose of 300 mg / kg, intraperitoneally. After induction of IHA, the mice were transplanted intravenously with 107 BMC obtained from donors transgenic for green fluorescent protein (GFP) or injected with saline. The survival curves, plasma levels of aminotransferases, ammonia, urea and creatinine, the extent of hepatic necrosis, inflammatory infiltrate and the expression of cytokines and metalloproteinases were evaluated. Confocal microscopy was used to study the migration of transplanted cells to the liver. The permeability of the blood-brain barrier was assessed by injection of Evans blue dye (AE) intravenously. Results: We found that mice treated with BMC showed a significant reduction in mortality, with a rate of 60% survival compared to 20% survival in the control group. The transplanted cells migrated to the liver, but we did not observe the differentiation of these cells or fusion with liver cells. There were no statistically significant differences in the extent of hepatic necrosis in the liver, plasma levels of transaminases and ammonia, and in the intensity of the inflammatory infiltrate in the liver between the two groups with IHA, as well as in hepatic levels of TNF-α and IL-10, transcripts for endothelin 1 and adrenomedullin in the brain and serum metalloproteinase 9 activity. However, there was a reduction of serum TNF-α in BMC-treated group compared to the group injected with saline. This decrease correlated with the increase in IL-10 mRNA expression in the bone marrow and spleen of BMC-treated mice. The assessment of Evans blue extravasation into the brain showed that the group treated with BMC had a reduced permeability of the blood-brain barrier compared to the group injected with saline. Conclusion: Bone marrow mononuclear cells exert a protective effect in mice with APAPinduced IHA, without changing the liver injury, probably through modulation of systemic inflammatory response and decrease the permeability of the blood-brain barrier.

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Mouri, Sarah. "L’encéphalopathie hépatique au cours de la cirrhose, de la physiopathologie au traitement FOUR Score, a Reliable Score for Assessing Overt Hepatic Encephalopathy in Cirrhotic Patients Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis." Thesis, Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS250.pdf.

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L’encéphalopathie hépatique (EH) est une complication sévère de la cirrhose. La physiopathologie est mal élucidée. Le rôle de l’hyperammoniémie est connu. L’inflammation systémique pourrait participer (rôle sur la perméabilité de la barrière hémato-encéphalique (BHE)). Il existerait aussi des anomalies du cycle de Krebs (TCA) dans l’EH (étude pilote métabolomique de liquide céphalorachidien de patients). Les objectifs étaient de déterminer les parts respectives de l’hyperammoniémie, de l’inflammation et d’un éventuel déficit énergétique dans l’EH, au moyen de modèles animaux et étudier la prévention des anomalies par des médicaments. L’EH était évaluée par un test comportemental sur deux modèles de cirrhose (biliaire-BDL et toxique- CCl4 versus contrôles). Les traitements étaient hyperammoniémiant(NH3), hypoammoniémiant (benzoate de sodium-BNa), antibiotique(rifaximine-RFX) ou visant à restaurer le TCA (biotine). L’ammoniémie, les cytokines et la perméabilité de la BHE par fluorimétrie était mesurées. L’ammoniémie était élevée dans les 2 modèles ; les BDL avaient une EH et une augmentation de perméabilité de la BHE, anomalies non retrouvées chez les CCl4. Les BDL avaient des cytokines significativement plus élevées que les CCl4. Le régime NH3 ne majorait pas les anomalies. Les traitements par BNa, RFX et biotine prévenaient l’apparition de l’EH et la modification de la BHE. L’hyperammoniémie et l’inflammation seraient donc synergiques dans l’EH. L’efficacité de la biotine ouvre la voie à de nouvelles perspectives physiopathologiques et thérapeutiques
Hepatic encephalopathy (HE) is a severe complication of cirrhosis. Pathophysiology still debated. Hyperammonia involvement is well known. Systemic inflammation could participate, increasing blood brain barrier (BBB) permeability. Alterations of TCA cycle could exist too in HE (pilot study of metabolomic in cerebrospinal fluids of patients with HE). The objectives were : to define the different contributions of ammonia, systemic inflammation and suspected dysregulation of energetic metabolism using animal models of cirrhosis ; to study efficiency of differents drugs on the abnormalities. We used a behavioral test to evaluate HE on two models of cirrhosis (biliary-BDL and toxic-CCl4) versus controls. Treatments given were hyperammoniemic (NH3), hypoammoniemic (sodium benzoate-BNa), antibiotic (rifaximine-RFX) or aiming to restore TCA (biotine). Ammonemia, cytokins and BBB permeability measured by fluorimetry were evaluated. Ammonemia was higher in the two models BDL and CCl4 compared to controls ; BDL had HE and an increased permeability of BBB ; these modifications were not observed in CCl4. Cytokins were significantly higher in BDL than in CCl4. NH3 treatment did not potentiate HE nor BBB alteration. BNa, RFX and biotine prevent the development of HE and BBB abnormalities. Hyperammonia and inflammation could act synergistically in HE. Innovating efficiency of biotine in HE could open new perspectives of pathophysiology pathway and therapeutic tools

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Araújo, Thiago Ferreira de. "Importância da detecção de mutações do gene ATP7B para o diagnóstico da doença de Wilson." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5168/tde-14082014-091501/.

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O diagnóstico da doença de Wilson (DW) é realizado por exames clínicos, laboratoriais, anatomopatológicos e de imagem. Mais de 500 mutações no gene ATP7B foram descritas como causadoras da DW. Para avaliar a importância da detecção de mutações no diagnóstico da DW em nosso meio, analisamos 35 pacientes com DW, 20 familiares de wilsonianos a partir de rastreamento familiar, 18 com hepatite crônica criptogênica e sete com insuficiência hepática aguda grave. Para o diagnóstico da DW foi utilizado o sistema de escore sugerido pela Sociedade Europeia para o Estudo do Fígado de 2012. Os dados demográficos, clínicos, laboratoriais e histológicos foram obtidos retrospectivamente. Obteve-se o DNA genômico de cada paciente a partir de sangue periférico e realizou-se o sequenciamento direto dos 21 éxons e suas bordas intrônicas do gene ATP7B. Todos os pacientes com DW apresentavam no mínimo quatro pontos. No grupo de rastreamento familiar o sequenciamento foi importante para o diagnóstico de DW em 14 familiares; no grupo de hepatite crônica criptogênica em oito pacientes e no grupo de insuficiência hepática aguda grave em três pacientes. Foi caracterizada uma família com cinco genótipos diferentes (dois homozigotos p.A1135Qfs/p.A1135Qfs e p.M645R/p.M645R), um heterozigoto composto (p.A1135Qfs/p.M645R) e dois heterozigotos simples (p.A1135Qfs/0 e p.M645R/0) com fenótipos variados. Foram detectadas duas mutações em heterozigose simples em pacientes com insuficiência hepática aguda grave. A mutação p.A1135Qfs e p.L708P foram as mais frequentes em todos os grupos. Foi identificada pela primeira vez a mutação p.M645R em homozigose. Concluímos que os resultados confirmaram que o sequenciamento do gene ATP7B foi útil: 1) para confirmar que as mutações p.A1135Qfs e p.L708P são as mais importantes na população brasileira; 2) para demonstrar que a mutação tida como a mais frequente na Europa, a p.H1069Q, tem bem menor importância em nosso meio, embora mais frequentemente do que o observado anteriormente; 3) para confirmar (ou excluir) precocemente o diagnóstico e evitar a realização de exames desnecessários e invasivos e iniciar (ou não realizar) o tratamento, com base mais sólida, em pacientes com hepatopatia crônica idiopática e em familiares de portadores de DW; 4) para definir o diagnóstico de DW em casos de insuficiência hepática aguda grave, diagnóstico ainda que tardio, mas de suma importância para realização de estudo familiar subsequente, 5) para identificação não esperada de heterozigotos simples e polimorfismos de significado ainda não esclarecido em pacientes com insuficiência hepática aguda grave; 6) para identificação de casos inusitados de três genótipos diferentes causadores da doença na mesma família (homozigose de duas mutações diferentes e heterozigose composta); 7) para melhor definir que a mutação p.M645R em homozigose tem potencial para desenvolver a DW, embora resultados de estudos em in vitro sugiram função normal da proteína defeituosa sintetizada; 8) para definir que há casos de doentes com a mutação p.M645R em heterozigose composta de evolução extremamente benigna, com diagnóstico após a quinta década de vida, com discretas alterações hepáticas. Porém há casos com evolução mais grave tanto do ponto de vista hepático quanto neurológico, possivelmente influenciados pelas mutações que a acompanham
Wilson\'s disease (WD) is an autosomal recessive disorder secondary to mutations in the ATP7B gene resulting in toxic accumulation of copper in various tissues. The diagnosis of WD is made by the analysis of clinical, laboratory, histological findings and imaging tests. More than 500 mutations have been described in the ATP7B gene as the cause of WD. In order to expand the knowledge of the importance of mutation detection in the diagnosis of WD, we analyzed 36 patients with WD, 20 individuals from family screening, 18 with cryptogenic chronic hepatitis and seven with severe acute liver failure. For the diagnosis of WD the International Scoring System suggested by the European Association for the Study of the Liver (EASL) in 2012 was used. Demographic, clinical, laboratory and histological data were obtained retrospectively. Direct sequencing of 21 exons and intron boundaries of ATP7B gene was performed in genomic DNA extracted from peripheral blood leucocytes of all subjects. All patients with WD have at least four points of the scoring system without considering the DPA challenge test. In the family screening group, sequencing was important for the diagnosis of DW in fourteen patients; eight patients in the group of cryptogenic chronic hepatitis, and three patients in the group of severe acute liver failure. Five different genotypes were identified in one family (two homozygous, p.A1135Qfs/p.A1135Qfs and p.M645R/p.M645R, one compound heterozygous p.A1135Qfs/p.M645R, and two simple heterozygous p.A1135Qfs/0 and p.M645R/0). Two patients with acute liver failure were detected as simple heterozygous. The p.A1135Qfs and p.L708P were the most frequent mutations in all groups. It is the first time p.M645R mutation was detected in homozygosity. The ATP7B gene sequencing was useful: 1) to confirm that p.A1135Qfs and p.L708P mutations are the most frequent in the Brazilian population; 2) to confirm that the most common mutation in Europe, p.H1069Q has lower frequency in our area; 3) to confirm (or exclude) an early diagnosis and to avoid unnecessary and invasive tests and to initiate (or not) the specific treatment with a stronger basis in patients with chronic liver disease and individuals from family screening of patients with Wilson disease; 4) to confirm the diagnosis, although late, of cases with severe acute liver failure, but very important to perform family screening; 5) to identify simple heterozygotes in patients with severe acute liver failure; 6) to describe unusual cases of three different genotypes of WD patients in a same family (two different homozygous mutations and one compound heterozygous); 7) to better define that p.M645R mutation in homozigosity develops WD, although the results from in vitro studies suggested a normal function for the defective synthesized protein; 8) to define that there are patients with p.M645R mutations in compound heretozigosity with a very benign clinical picture, with late diagnosis, after the fifth decade of life, with mild liver alterations. However, there are patients with a more severe clinical evaluation, hepatic or neurologic, probably secondary to the influence of the other mutation

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Huber, Adrian Thomas. "Multi-organ non-invasive tissue characterization of fibrosis, adipose tissue, edema and inflammation with magnetic resonance (MR) imaging : applications to myocardium, skeletal muscle and liver interactions Cardiac MR strain: a noninvasive biomarker of fibro-fatty remodeling of the left atrial myocardium Comparison of MR T1 and T2 mapping parameters to characterize myocardial and skeletal muscle involvement in systemic Idiopathic Inflammatory Myopathy (IIM) Non-invasive differentiation of acute viral myocarditis and idiopathic inflammatory myopathy with cardiac involvement using magnetic resonance imaging T1 and T2 mapping CT predicts liver fibrosis: Prospective evaluation of morphology- and attenuationbased quantitative scores in routine portal venous abdominal scans." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS135.

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Cette thèse réalise une preuve de concept pour quantifier la déformation de l’oreillette gauche (OG) en IRM, ainsi que la relaxométrie IRM dans le myocarde, dans les muscles squelettiques et dans le foie. Grâce à l’interaction entre radiologues et ingénieurs, deux logiciels différents ont été développés, appliqués et validés pour l'analyse de la déformation myocardique multi-chambre et pour la cartographie quantitative du T1 multi-organes. La première publication a montré une forte corrélation de la déformation de l’OG, avec le degré de remplacement fibro-graisseux en histologie. Ce biomarqueur d'imagerie fonctionnelle est prometteur, puisque le remodelage structurel du myocarde est un substrat morphologique connu du dysfonctionnement électro-physiologique et de la fibrillation atriale. La deuxième publication a démontré l'influence de la composition et de la vascularisation de différents tissus sur les paramètres cartographiques T1. ΔT1 (prise de contraste musculaire relative) et EHF (prise de contraste musculaire normalisée par la prise de contraste dans le sang) ont été introduits comme alternatives simples au volume extracellulaire (ECV). Dans la troisième publication, les paramètres de relaxométrie appliqués aux muscles squelettiques ont permis une discrimination entre patients avec myocardite aiguë et patients avec des myosites systémiques. La quatrième publication a introduit le T1 du foie pour quantifier l’insuffisance cardiaque chez des patients avec des cardiomyopathies idiopathiques dilatées, montrant de meilleures performances que les paramètres fonctionnels établis tels que les volumes, la fraction d'éjection ou la déformation myocardique
This thesis provides a proof of concept for MR atrial strain, as well as MR relaxometry in the myocardium, in skeletal muscles and in the liver. Thanks to a close interaction between radiologist and software engineers, two different softwares were developed, applied and validated: one for multiorgan T1 mapping in the myocardium, skeletal muscle and liver, another one for cardiac four-chamber strain analysis and volumetry. The first publication showed a strong correlation of LA strain with the degree of fibro-fatty replacement in histology. Such functional imaging biomarker in combination with LA volumetry could help to guide clinical decisions, since myocardial structural remodeling is a known morphologic substrate of LA dysfunction, atrial fibrillation and adverse outcome. In the second publication, MR relaxometry parameters applied to the myocardium and skeletal muscles in IIM patients and healthy volunteers were used as a model to demonstrate influences of different tissue composition and vascularization on T1 mapping parameters. ΔT1 and EHF were introduced as simple alternatives to ECV in highly vascularized tissues such as the myocardium. In the third publication, MR relaxometry parameters applied to the skeletal muscls allowed for an accurate discrimination of AVM and IIM with cardiac involvement. However, when applied to the myocardium, parametric mapping did not separate between the two groups. The fourth publication introduced native T1 of the liver an easily accessible and accurate non-invasive imaging associate of congestive HF in IDCM patients with better performance than established functional parameters such as LV volumes, ejection fraction or strain

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Monteiro, Aurora Moura de Pinho. "Acute-on-chronic liver failure." Master's thesis, 2018. http://hdl.handle.net/10451/41890.

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Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2018
A acute-on-chronic liver failure (ACLF) é uma entidade clínica que pode ser definida como uma deterioração aguda da função hepática em doentes com doença hepática crónica, geralmente associada a um evento precipitante, associada a falência de um ou mais órgãos e com uma elevada taxa de mortalidade a curto prazo. É hoje considerada uma entidade nova distinta da clássica descompensação aguda, não só devido à presença de falência orgânica e elevada mortalidade, mas também por ocorrer em idades mais jovens, estar mais associada à cirrose hepática de etiologia alcoólica, a maior prevalência de determinados eventos precipitantes e à intensa resposta inflamatória a que está associada. O transplante hepático é uma opção de tratamento potencialmente curativa e tem demonstrado bons resultados, em casos seleccionados. Os sistemas de suporte hepático extracorporal, a terapia com G-CSF (Granulocyte colony stimulating factor) e o transplante de células estaminais são alternativas que se encontram na vanguarda da abordagem terapêutica da ACLF. A presente revisão centra-se na compreensão da ACLF a nível clínico, do seu prognóstico e fisiopatologia bem como da abordagem terapêutica actual e potenciais alvos terapêuticos futuros.
Acute-on-chronic liver failure (ACLF) is a clinical entity encompassing an acute deterioration of liver function in patients with chronic liver disease, which is usually associated with a precipitating event and results in the failure of one or more organs and high short term mortality. ACLF is now considered as a new entity that is distinct from classic acute decompensation not only because of the presence of organ failure(s) and high short-term mortality but also because it occurs in younger patients, it associates with a higher prevalence of alcoholic etiology of cirrhosis, higher prevalence of some precipitants and more intense systemic inflammatory response. Liver transplantation is a potentially curative treatment option that has showed to have good outcomes in a subset of patients. Bioartificial liver support systems, granulocyte-colony stimulating factors or stem cell transplantation are in the horizon of medical care of this patient population. This review focuses upon the current understanding of ACLF from the clinical, prognostic and pathophysiologic perspectives and indicates potential therapeutic targets for intervention.

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Ho, Cheng-Maw, and 何承懋. "Acute liver failure & hepatocyte transplantation." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/60703296526846228581.

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博士
國立臺灣大學
臨床醫學研究所
104
Background and objective Acute liver failure (ALF) is uncommon but fatal. Current management is based mostly on clinical experience. Hepatocyte transplantation is a promising alternative to liver transplantation in patients with acute liver failure. The study is to investigate ALF from longitudinal population-scale epidemiological analysis, through individual cross-sectional histopathophysiological observation, ex vivo functional evaluation of hepatocytes, to preclinical animal experiment of hepatocyte transplantation. To this end, we investigated 1) the incidence, etiology, outcomes, and prognostic factors of ALF in Taiwan. 2) pathophysiological expression of regeneration and differentiation in acute failure liver. 3) whether the uptake and release of indocyanine green (ICG) by hepatocytes could be used as a rapid in vitro assay for hepatocyte functional assessment. 4) the impact of the rate of intraportal hepatocyte transplantation on early engraftment and repopulation and to improve the engraftment and repopulation efficiencies of hepatocyte transplantation for treatment of a rat model of acute liver failure in a clinically useful way without preconditioning. Materials and methods 1) For population study, patients with the admission diagnosis of ALF between January 2005 and September 2007 were identified from the Longitudinal Health Insurance Database of Taiwan. ALF was further confirmed by disease severity based on laboratory orders, prescriptions, and duration of hospital stay, and acute onset without prior liver disease. Prognostic factors were identified using Cox regression analysis. 2) For microscopic cross-sectional observational study, a human explant liver from acute HBV infection was examined for immunohistochemical expression of progenitors [marker: CK19, epithelial cell adhesion molecule (EpCAM)], differentiation [NUMB (an inhibitor of the Notch pathway), carbamoyl phosphate synthetase 1 (CPS-1, urea cycle enzyme), HNF4α, and HNF1β], and proliferation (Ki-67). 3) For in vitro study, human hepatocytes (1 x 106 cells) isolated from unused donor livers were incubated at 37°C for 30 min with ICG (0-2 mg/ml) in both cell suspension and on collagen-coated culture plates. Cells were then incubated in medium without ICG for 3 h with supernatants collected at 1, 2, and 3 h for measurement of ICG release. Viability of cells was determined by trypan blue exclusion, MTT (mitochondrial dehydrogenase activity) and SRB (cell attachment) assays. HepG2 cells were also used as comparison. 4) For animal study, acute hepatic injury was induced in Sprague-Dawley rats with D-galactosamine. Hepatocytes (1 x 107/ml) were infused intraportally over 30, 70, or 100 seconds to study early engraftment (2 days) and repopulation (7 days). Results 1) For population study, during the study period, 218 eligible cases were identified from 28,078 potential eligible ALF patients. The incidence was 80.2 per million person-years in average and increased with age. The mean age was 57.9±17.1 years and median survival was 171 days. The most common etiologies were viral (45.4%, mainly hepatitis B virus) and alcohol/toxin (33.0%). Independent prognostic factors included alcohol consumption (HR 1.67 [1.01-2.77]), malignancy (HR 2.90 [1.92-4.37]), frequency of check-ups per week for total bilirubin (HR 1.57 [1.40-1.76]), sepsis (HR 1.85 [1.20-2.85]), and use of hemodialysis/hemofiltration (HR 2.12 [1.15-3.9]) and proton pump inhibitor (HR 0.94 [0.90-0.98]). Among the 130 patients who survived ≥90 days, 66 (50.8%) were complicated by liver cirrhosis. Eight (3.7%) were referred for liver transplantation evaluation, but only one received transplantation and survived. 2) For cross-sectional study, histological examination of the explant liver showed submassive necrosis and prominent ductular reaction. The road of hepatocyte differentiation was nicely shown from the bipotential progenitor cells (thick stained, small cell size, high nuclear-cytoplasm ratio) and gradually spirally spreading outward to form daughter intermediate hepatocytes (light stained, larger cell size, lower nuclear-cytoplasm ratio). These differentiating cells did not proliferate actively, and express EpCAM and transition of NUMB and CPS-1. 3) For in vitro study, ICG was taken up and secreted by hepatocytes with the release reaching a plateau level soon after 1 hour. Concentrations of ICG above 1.0 mg/ml, had toxic effects on hepatocytes. Hepatocytes incubated with 1.0 mg/ml ICG had higher mitochondrial dehydrogenase activity compared to 0.5 mg/ml ICG or control (0.025 ± 0.0004 v.s 0.019 ± 0.0008 or 0.020 ± 0.002, P < 0.05). Incubation of HepG2 cells with ICG reduced albumin production (98.9 ± 0.02, 66.6 ± 0.05, 39.1 ± 0.4 ng/ml for control, 0.5 mg/ml, and 1.0 mg/ml ICG respectively) and also decreased [3H]-thymidine incorporation in a dose-response manner. 4) For animal study, three groups had significant difference in hepatocyte engraftment (P = 0.018) and repopulation efficiencies (P = 0.037) and infusion over 70 seconds produced superior outcomes. After the 70-second infusion, the transplanted cells immediately transmigrated the sinusoidal endothelial layer and rarely accumulated in the portal venules, with improved liver function significantly. The mean first peak pressures, without significant difference, were 14.8 ± 6.5, 17.7 ± 3.7, and 13.6 ± 3.0 mmHg in the 30, 70, and 100-second groups, respectively. Conclusion ALF in Taiwan is mainly due to viral infection. Patients with malignancy and alcohol exposure have worst prognosis. The use of proton pump inhibitor is associated with improved survival. Half of the ALF survivors have liver cirrhosis. Prominent ductular reaction with at-least partially functional hepatocyte differentiation did not guarantee successful regeneration in acute liver failure and there is demand left for hepatocyte transplantation. With further refinement of ICG could be used to develop a rapid assay for assessment of the function of isolated human hepatocytes. Differential hepatocyte transfusion rate contribute to accelerated early engraftment and repopulation in rats with acute liver injury. These proof-of-concept findings are of clinical significance because they are easy to translate into practice. Further studies are needed for improvement of hepatocyte transplantation for ALF in Taiwan, albeit some problems solved.

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"Therapeutic strategies in liver failure (role of artificial liver and implications of renin-angiotensin system)." Thesis, 2006. http://library.cuhk.edu.hk/record=b6074337.

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Concerning potential immunological reaction in patients receiving multiple bioartificial liver treatments (with porcine hepatocytes bioreactor), the beneficial effect of sequential plasmapheresis-hemoadsorption-bio-liver treatment protocol was studied. The hypothesis was tested in a trichosanthin-induced anaphylaxis rat model. Fatal anaphylactic response upon antigen challenge was reduced in a previously trichosanthin sensitized rat prior with cross circulation. It was suggested that circulating antibodies responsible for immunological response were removed by the non cell-based treatment. The potential risk of hypersensitivity reaction of subsequent cell-based treatment was reduced. In the design of HBLSS, the sequential plasmapheresis-hemofiltration-bio-liver treatment was suggested to alleviate potential immunological consequences and allow multiple uses in single patient.
In addition to artificial liver research, pharmacological therapies are sought to treat ALF. Recent studies suggested that the local renin-angiotensin system (RAS) in the liver regulate the fibrogenic response. The possible involvement of RAS in acute liver injury was investigated in the present study. In the D-galactosamine induced rat liver failure model, angiotensin II type 1 receptors (AT1R) were detected by immunohistochemical staining in the centrilobular region after induction of acute liver injury which was not evident in normal liver. There were associated elevation of total bilirubin, alanine aminotransferase and tissue inhibitor of metalloproteinase type 1 (TIMP-1). Losartan treatment was able to reduce all these parameters. TIMP-1 protein was reduced by 1.5 fold (p<0.05) on day 1 and 1.56 fold (p<0.05) on day 3 in the losartan treatment group relative to the GalN group. The survival rate of the losartan treatment group was significantly higher than that without treatment (5-day survival, 85% vs 42.5%, p<0.05). This finding suggested the local renin-angiotensin system plays a role in the pathophysiological mechanism of acute liver injury.
In summary, the presence study addressed two approaches in treating liver failure. The HBLSS treatment protocol improved survival of acute-on-chronic liver failure patients. The protective effect of losartan in liver injury suggests AT1R blockade is a potential therapeutic strategy in acute liver injury.
The mainstay treatment of acute liver failure (ALF) is conservative medical therapy. In patients having acute liver insufficiency, the only proven life-saving procedure is liver transplantation. The concept of supportive care in liver failure is to optimize patient's clinical condition by replacing some of the essential functions of liver and allowing liver regeneration in order to compensate the loss of hepatocellular functions.
There was increasing evidence suggesting a role of artificial liver (extracorporeal system) in the treatment of liver failure. A retrospective study was performed in a group of acute-on-chronic liver failure (AoCLF) patients treated with hybrid bioartificial liver support system (HBLSS). From 2001-2004, there were 40 chronic liver disease patients presented with acute deterioration. Patients were treated either with conventional medical therapy (n=21) or integrated with HBLSS treatment (n=19). The 60-day survival rate was 30% and 68.5% respectively (P<0.05 log-rank test). Integration of hybrid bioartificial liver support system (HBLSS) in treating acute-on-chronic liver failure (AoCLF) patients improved the survival outcome. Univariate analysis of admission blood parameters revealed creatinine appeared to predict mortality in AoCLF patients with HBLSS treatment.
Chan Hoi Ming Herman.
"June 2006."
Adviser: Siu-cheung Michael Tam.
Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1547.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (p. 104-116).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.
School code: 1307.

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Jiang, Wenlei. "Cerebral edema and acute liver failure : pathophysiological mechanisms and new therapeutic approaches." Thèse, 2010. http://hdl.handle.net/1866/3765.

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L’encéphalopathie hépatique (EH) se développe chez les patients atteints d’une maladie du foie et se caractérise par de nombreuses anomalies neuropsychiatriques. L’insuffisance hépatique aiguë (IHA) se caractérise par une perte progressive de l’état de conscience, par une augmentation rapide de l’œdème cérébral et une augmentation de la pression intracrânienne entraînant une herniation cérébrale et la mort. Plusieurs facteurs sont responsables du développement de l’EH mais depuis une centaine d’années, l’hyperammonémie qui peut atteindre des concentrations de l’ordre de plusieurs millimolaires chez les patients atteints d’IHA aux stades de coma est considérée comme un facteur crucial dans la pathogenèse de l’EH. La présente thèse comprend 4 articles suggérant l’implication de nouveaux mécanismes pathogéniques dans le développement de l’EH et de l’œdème cérébral associés à l’IHA et tente d’expliquer l’effet thérapeutique de l’hypothermie et de la minocycline dans la prévention de l’EH et de l’œdème cérébral: 1. L’IHA induite par dévascularisation hépatique chez le rat se caractérise par une augmentation de la production de cytokines pro-inflammatoires cérébrales (IL-6, IL-1, TNF-). Cette observation constitue la première évidence directe que des mécanismes neuro-inflammatoires jouent une rôle dans la pathogenèse de l’EH et de l’œdème cérébral associés à l’IHA (Chapitre 2.1, articles 1 et 2). 2. L’activation de la microglie telle que mesurée par l’expression de marqueurs spécifiques (OX42, OX-6) coïncide avec le développement de l’encéphalopathie (stade coma) et de l’œdème cérébral et s’accompagne d’une production accrue de cytokines pro-inflammatoires cérébrales (Chapitre 2.1, article 1 et 2). 3. Un stress oxydatif/nitrosatif causé par une augmentation de l’expression de l’oxyde nitrique synthétase et une augmentation de la synthèse d’oxyde nitrique cérébral participe à la pathogénèse des complications neurologiques de l’IHA (Chapitre 2.3, articles 3 et 4). 4. Des traitements anti-inflammatoires tels que l’hypothermie et la minocycline peuvent constituer de nouvelles approches thérapeutiques chez les patients atteints d’IHA (Chapitre 2.1, article 1; Chapitre 2.2, article 2). 5. Les effets bénéfiques de l’hypothermie et de la minocycline sur les complications neurologiques de l’IHA expérimentale s’expliquent, en partie, par une diminution du stress oxydatif/nitrosatif (Chapitre 2.3, article 3; Chapitre 2.4, article 4).
Hepatic encephalopathy (HE) contains a spectrum of neuropsychiatric abnormalities observed in patients with liver disease. A quick worsening of consciousness and increasingly growing cerebral edema, high intracranial pressure, which leads to cerebral herniation and death, are characteristics of acute liver failure (ALF). Multiple factors are found responsible for the development of HE, whereas, over 100 years, hyperammonia is considered the most crucial factor in defining the pathogenesis of HE in ALF, which can increase to millimolar concentrations in the brain at the coma stages of HE. The present thesis comprises 4 articles, which demonstrates new pathogenic mechanisms involved in the development of HE and cerebral edema in ALF, and elucidates part of the therapeutic mechanism of hypothermia and minocycline in the prevention of HE and cerebral edema during ALF. The major findings are listed below: (1) Experimental ALF leads to the increase in brain production of proinflammatory cytokines (IL-6, IL-1, TNF-α), and provides the first direct evidence that central inflammatory mechanisms play a role in the pathogenesis of the encephalopathy and brain edema in ALF (chapter 2.1 - article 1; chapter 2.1 - article 2). (2) Activation of cerebral microglia, measured by OX-42, OX-6, predicts the presence of severe encephalopathy (coma) and brain edema in rats with ischemic ALF, which accompanies the increased production of brain proinflammatory cytokines (chapter 2.1 - article 1; chapter 2.2 - article 2). (3) Oxidative/nitrosative stress participates in the pathogenesis of brain edema and its complications in experimental ALF animals with ischemic liver failure. The increases in cerebral NOS isoform expression caused by ALF were sufficient to cause increased NO production in the brain (chapter 2.3 - article 3; chapter 2.4 - article 4). (4) Anti-inflammatory treatment, such as hypothermia or antibiotics, may be beneficial in patients with ALF (chapter 2.1 - article 1; chapter 2.2 - article 2). (5) The beneficial effect of both hypothermia and minocycline on the neurological complications of experimental ALF is mediated, at least in part, by reduction of brain-derived oxidative/nitrosative stress (chapter 2.3 - article 3; chapter 2.4 - article 4).

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Quadros, Joana Maria Reboredo. "Auxiliary liver transplant for acute liver failure in children – a systematic review of case reports and case series." Master's thesis, 2021. http://hdl.handle.net/10316/98537.

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Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
A insuficiência hepática aguda pediátrica é uma patologia rara, mas está associada a uma elevada morbilidade e mortalidade. A sua abordagem terapêutica baseia-se na manutenção das funções vitais da criança, enquanto se gerem as múltiplas complicações que lhe estão associadas. O transplante hepático ortotópico é o único tratamento que melhora a sobrevivência, mas traz associada a necessidade de imunossupressão para toda a vida. Tendo isto em conta, o transplante hepático auxiliar surgiu como uma alternativa promissora. Através desta técnica é transplantado um enxerto que irá suportar a função do fígado nativo lesado, até que este regenere. Esta revisão pretende reunir informação sobre as complicações e resultados dos transplantes hepáticos auxiliares que já foram realizados. Para atingir este objetivo, fizemos uma revisão da literatura usando as bases de dados Medline, Embase, Scopus e Web of Science, e encontrámos 502 artigos. Após uma seleção inicial baseada nos títulos e resumos, aplicámos os seguintes critérios de exclusão: “tempo de seguimento < 6 meses”, “não referir complicações” e “não referir o esquema de imunossupressão (duplo ou triplo)”. 14 artigos foram analisados, incluindo 45 casos de insuficiência hepática aguda em idade pediátrica, tratados com transplante hepático auxiliar. Dos 45 casos, 26,7% eram do sexo feminino e 73,3% do sexo masculino. A idade média era 8,7 anos, e o tempo médio de seguimento de 5,5 anos. 75,6% fizeram um esquema de imunossupressão duplo e 24,4% um esquema triplo. As complicações mais frequentes foram infeções, pancitopenia, problemas vasculares, problemas biliares e rejeição. A taxa de mortalidade foi de 22,2%. A causa de morte mais frequente foi sépsis (70,0%). A cessação da imunossupressão foi possível em 68,6% dos sobreviventes.O transplante hepático auxiliar é uma opção segura, tendo uma taxa de complicações e mortalidade aceitável, enquanto assegura a grande vantagem de permitir a paragem da imunossupressão na maioria dos doentes.
Pediatric acute liver failure is a rare pathology, but it is associated with high morbidity and mortality. Its therapeutic approach is based on supporting the child’s vital functions, while managing the many complications that come with it. Orthotopic transplant is the only treatment that improves survival, but it does so with the consequence of immunosuppression for life. Considering this, auxiliary liver transplant emerged as an improved approach. This technique aims to provide a graft that supports the function of the damaged native liver until its regeneration. This review intends to provide insight about complications and outcomes of the auxiliary liver transplants that have already been performed. To reach this goal, we did a literature research using Medline, Embase, Scopus and Web of Science databases, and found 502 articles. After an initial selection based on titles and abstracts, we applied the following exclusion criteria: “follow-up time < 6 months”, “not referring complications”, and “not referring the immunosuppression scheme (double vs triple)”. 14 articles were analyzed, which comprise 45 cases of pediatric acute liver failure treated with auxiliary liver transplant. Among the 45 cases, there were 26.7% females and 73.3% males. Mean age was 8.7 years and mean follow-up time was 5.5 years. 75.6% had a double immunosuppression scheme and 24.4% a triple one. The main complications registered were infections, pancytopenia, vascular problems, biliary problems, and rejection. Mortality rate was 22.2%. The main cause of death was sepsis (70.0%). Immunosuppression withdrawal was possible in 68.6% of the survivors. Auxiliary liver transplant is a safe option, with an acceptable rate of complications and mortality, whilst having the great advantage of allowing the discontinuation of immunosuppressors in the majority of the survivors.

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Ronne, Luke John Thomas. "Design considerations and analysis of a bioreactor for application in a bio-artificial liver support system." Diss., 2007. http://hdl.handle.net/2263/24107.

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Acute Liver Failure (ALF) is a devastating ailment with a high mortality rate and limited treatment alternatives. This study presents a methodology for the design and development of a bio-artificial bioreactor to be used in a Bio-Artificial Liver Support System. The system will ultimately be used either to bridge a patient to orthotopic liver transplant (OLT), the only current cure for end stage ALF, or spontaneous recovery. Methods to optimize and visualize the flow and related mass transfer in the BR are presented. The use of magnetic resonance imaging (MRI), scanning electron microscopy (SEM) and simple testing methodology is applied with emphasis on modeling the flow conditions in the BR. The bioreactor (BR) used in the Bio-Artificial Liver Support System (BALSS), currently under-going animal trials at the University of Pretoria, was modeled and simulated for the flow conditions in the device. Two different perfusion steps were modeled including the seeding of hepatocyte cells and later the clinical perfusion step. It was found that the BR geometry was not optimal with “dead spots” and regions of retarded flow. This would restrict the effective transport of nutrients and oxygen to the cells. The different perfusion rates for the seeding and clinical perfusion steps allowed for different velocity contours with cells seeing inconsistent flow patterns and mass transfer gradients. An optimized BR design is suggested and simulated, that effectively reduces the areas of retarded flow (dead spots) and increases the flow speed uniformly through the BR to an order of magnitude similar to that found in the sinusoidal range. The scaffolding volume was also decreased to allow a larger local cell density promoting cell-cell interaction. Finally a summarized design table for the design of a hepatic BR is presented.
Dissertation (MEng (Mechanical))--University of Pretoria, 2008.
Mechanical and Aeronautical Engineering
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Blanchon, Daphné Stéphanie Victoria. "Effects of paracetamol-induced acute liver failure on the expression of connexin 43 and Pannexin 1 in primary rat hepatocytes." Master's thesis, 2014. http://hdl.handle.net/10451/39278.

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Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2014
Connexin and pannexin proteins provide communication between cells and the extracellular space as part of gap junctions and hemichannels. Through paracrine signaling or direct intercellular coupling these proteins ensure tissue homeostasis, which requires a dynamic balance between cell proliferation, differentiation and cell death. The liver was among the first organs in which connexin proteins were identified and Pannexin 1 hemichannels are held as key players in the regulation of hepatic inflammatory processes. In order to assess the link between Cx43 and Panx1 and hepatocellular inflammation and death, primary rat hepatocytes were isolated, cultivated and then exposed to various concentrations of paracetamol. The morphology of the hepatocytes was studied microscopically and hepatocyte viability was estimated. The expression of Cx43 and Panx1 was ultimately evaluated by Western blot and their cellular localization was examined via immunocytochemistry. Hepatocellular death occurred in a paracetamol concentration-dependent manner and upon exposure to paracetamol Cx43 appeared to be down-regulated whereas Panx1 appeared to be up-regulated. Although the immunocytochemistry findings require confirmation with confocal microscopy, Cx43 exhibited a strong nuclear localization, which decreased with the increment of paracetamol concentration, and Panx1 shifted to a likely dominant membrane localization. This suggests Panx1 plays indeed a major role in hepatic inflammation and could be used as a biomarker of hepatocellular damage.

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Ryska, Ondřej. "Využitelnost chirurgických modelů akutního selhání jater v experimentu." Doctoral thesis, 2013. http://www.nusl.cz/ntk/nusl-329273.

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Introduction The development of an appropriate animal model of ALF is paramount for the understanding of the disease pathogenesis and evaluation of potential therapeutic approaches. Acute liver failure (ALF) is a severe, usually rapidly progressive disease characterized by high mortality (60 - 90 %). Besides acute liver transplantation which faces a shortage of donors, the only possible therapeutic alternative is applying biological or non-biological liver support systems. To confirm the effectiveness of these methods, clinically relevant model of ALF on a large laboratory animal is essential. Surgically induced ALF models seem to be more reliable than models based on chemical intoxication. Ideal model of ALF has not yet been published. Surgical models are usually performed with devascularisation, large liver resection or hepatectomy. The aim of this work was to introduce three surgical models of ALF and evaluate their usefulness for testing biological and non-biological liver support systems. Materials and Methods Female laboratory pig weighing 35 - 45 kg was used for the experimental study. After induction of general anesthesia the thermodilution catheter was introduced via jugular vein. Femoral artery and vein were cannulated for invasive blood pressure monitoring and for infusions and...

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Nieuwoudt, Martin J. "Bio-artificial liver support system : an evaluation of models used in demonstrating or improving metabolic and clinical efficacy." Thesis, 2010. http://hdl.handle.net/2263/25455.

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Acute liver failure (ALF) is a rare but devastating clinical syndrome with multiple causes and a variable course. The mortality rate is high. Orthotopic liver transplantation is the only therapy of proven survival benefit but the limited supply of donor organs, the rapidity of progression and the variable course of ALF limit its use. A need therefore exists for a method to ‘bridge’ patients, that is, provide temporary support, to either the spontaneous regeneration of the innate liver or transplantation. One possibility includes bio-artificial liver support systems (BALSS). This technology is composed of an extracorporeal circulation system incorporating a bioreactor that contains parenchymal liver cells (hepatocytes) to perform the detoxifying, transforming and synthetic properties of a liver. However, the development of a BALSS holds particular challenges. Despite approximately four decades of research, bio-artificial liver (BAL) technology globally remains in a pre-commercial stage. The University of Pretoria (UP) and the Council for Scientific and Industrial Research (CSIR) have developed a BALSS with novel characteristics. These include a computationally optimized radial-flow primary porcine hepatocyte bioreactor perfused with blood plasma, and a perfluorocarbon oxygen carrier which replaces hemoglobin. There are also novel design properties in the circulation system itself. Demonstrating the metabolic and clinical efficacy of a BAL device requires implementing, in vitro (cell biology), in vivo (animal) and mathematical modeling studies. These studies are a formal necessity but are inherently ‘models’ of the in vivo human clinical circumstance. That is, they are limited by their experimentally controlled configuration/s. In investigating these, this thesis firstly provides a foundation by reviewing the clinical and biological context of ALF and BAL technology, then presents and evaluates particular studies/models that have been implemented over several years in the course of the UP-CSIR BAL project. For each section, thoughts and recommendations regarding future work that will facilitate the development of BAL technology are discussed in detail. The thesis is concluded with an evaluation of success and the consensus-agreed requirement of continued research and innovation in the field.
Thesis (PhD)--University of Pretoria, 2010.
Chemical Engineering
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46

Schneider, Christoph. "Inflammation bei chronischen Lebererkrankungen – neue Biomarker zur Mortalitätsabschätzung." 2020. https://ul.qucosa.de/id/qucosa%3A73882.

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47

Villiard, Roselyne. "Score PELOD : indice précoce de mortalité pédiatrique des transplantations hépatiques pour hépatite fulminante." Thèse, 2009. http://hdl.handle.net/1866/3636.

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Abstract:

La transplantation hépatique est le seul traitement définitif des enfants ayant une hépatite fulminante sans résolution spontanée. L’évolution de cette maladie dans la population pédiatrique diffère de celle adulte, particulièrement en regard de l’encéphalopathie. Pour définir les indications de transplantation hépatique, plusieurs indicateurs précoces de pronostic furent étudiés chez les adultes. Ces indicateurs n’ont pu être transposés à la population pédiatrique. Objectif primaire : Déterminer les marqueurs de risque de mortalité des enfants recevant une transplantation hépatique pour une hépatite fulminante, se définissant par une insuffisance hépatique sévère sans antécédent au cours des huit semaines précédentes. Méthode : Il s’agit d’une étude rétrospective incluant tous les enfants ayant reçu une transplantation hépatique pour une hépatite fulminante à l’hôpital Sainte-Justine entre 1985 et 2005. Le score PELOD (Pediatric Logistic Organ Dysfunction) est une mesure de sévérité clinique d’un enfant aux soins intensifs. Il fut calculé à l’admission et avant la transplantation hépatique. Résultats : Quatorze enfants (cinq mois à seize ans) reçurent une transplantation hépatique pour une hépatite fulminante. Neuf enfants (64%) survécurent et cinq (36%) décédèrent. L’utilisation de la ventilation mécanique fut associée à un mauvais pronostic (p = 0,027). Entre l’admission et la transplantation hépatique, 88% des enfants ayant eu une variation du score PELOD inférieure à cinq survécurent. Tous ceux ayant eu une variation supérieure à cinq décédèrent. (p = 0,027) Conclusion : La variation du score PELOD pourrait aider à définir un indicateur précoce de l’évolution d’un enfant après une transplantation hépatique pour une hépatite fulminante.
Hepatic transplantation is the only definitive treatment for acute liver failure for those children who do not recover spontaneously. Early indicators of prognosis in acute liver failure have been studied in adults in order to define the indication for liver transplantation. The course of the disease in the pediatric population, particularly with respect to hepatic encephalopathy, differs from that in adults. Consequently, these criteria are not applicable to the pediatric population. Primary objective: To determine the risk markers for mortality in children receiving liver transplantation for acute liver failure. Liver failure is defined as being severe failure without prior liver disease within the last eight weeks. Method: A retrospective study was conducted with children who had received a liver transplantation for acute liver failure at Sainte-Justine’s Hospital between 1985 and 2005. Data including the PELOD (Pediatric Logistic Organ Dysfunction) Score, a clinical score (0-71) of illness severity in children in intensive care, were recorded from patients’ charts. Results: 14 children, aged from five months to sixteen years old, were transplanted for fulminant liver failure. Nine (64%) survived and five (36%) died. The need for mechanical ventilation was associated with a poorer survival (p= 0,027). Of all of the children who had a PELOD Score variation inferior to five, between admission and transplantation, 88% survived. None of those with a score variation superior to five survived (p=0,027). Conclusion: In our single centre study, the PELOD Score variation was a pre-transplant marker of mortality after liver transplantation for pediatric acute liver failure.

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48

Chastre, Anne. "Le rôle de l’inflammation dans le développement des complications neurologiques associées à l’insuffisance hépatique aiguë chez la souris." Thèse, 2012. http://hdl.handle.net/1866/9886.

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L’insuffisance hépatique aiguë (IHA) se caractérise par la perte soudaine de la fonction hépatique résultant de la nécrose massive des hépatocytes en l’absence de pathologie hépatique préexistante. L’IHA s’accompagne de perturbations métaboliques et immunologiques qui peuvent entraîner l’apparition de complications périphériques et cérébrales telles qu’un syndrome de réponse inflammatoire systémique (SIRS), une encéphalopathie hépatique (EH), un œdème cérébral, une augmentation de la pression intracrânienne, et la mort par herniation du tronc cérébral. Les infections sont une complication fréquente de l’IHA et elles sont associées à un risque accru de développer un SIRS et une aggravation subséquente de l’EH avec un taux de mortalité augmenté. L’ammoniaque joue un rôle majeur dans les mécanismes physiopathologiques qui mènent au développement de l’EH et de l’œdème cérébral, et des études récentes suggèrent que les cytokines pro-inflammatoires sont également impliquées. Le but de cette thèse est d’étudier le rôle des cytokines pro-inflammatoires circulantes et cérébrales dans le développement de l’EH et de l’œdème cérébral lors d’IHA. Dans l’article 1, nous démontrons que l’inhibition périphérique du facteur de nécrose tumorale-α (TNF-α) par l’etanercept retarde la progression de l’EH en diminuant le dommage hépatocellulaire, réduisant l’inflammation périphérique et centrale ainsi que le stress oxydatif/nitrosatif hépatique et cérébral associé chez la souris avec une IHA induite par l’azoxyméthane (AOM). Ces résultats démontrent un rôle important du TNF-α dans la physiopathologie de l’EH lors d’IHA d’origine toxique et suggèrent que l’etanercept pourrait constituer une approche thérapeutique dans la prise en charge des patients en attente de transplantation hépatique. Dans l’article 2, nous simulons la présence d’une infection chez la souris avec une IHA induite par l’AOM pour mettre en évidence une éventuelle augmentation de la réponse inflammatoire. Nous démontrons que l’endotoxémie induite par le lipopolysaccharide (LPS) précipite la survenue du coma et aggrave la pathologie hépatique. Les cytokines pro-inflammatoires systémiques et cérébrales sont augmentées de façon synergique par le LPS lors d’IHA et résultent en une activation accrue de la métalloprotéinase matricielle-9 cérébrale qui s’accompagne d’une extravasation d’immunoglobulines G (IgG) dans le parenchyme cérébral. Ces résultats démontrent une augmentation majeure de la perméabilité de la barrière hémato-encéphalique (BHE) qui contribue à la pathogenèse de l’EH lors d’IHA en condition infectieuse. Les résultats de l’article 3 démontrent que l’augmentation de la perméabilité de la BHE lors d’IHA induite par l’AOM en condition non infectieuse ne résulte pas de l’altération de l’expression des protéines constitutives de la BHE. Dans l’article 4, nous démontrons que l’exposition d’astrocytes en culture à des concentrations physiopathologiques d’ammoniaque ou d’interleukine-1β résulte en l’altération de gènes astrocytaires impliqués dans la régulation du volume cellulaire et dans le stress oxydatif/nitrosatif. Un effet additif est observé dans le cas d’un traitement combiné au niveau des gènes astrocytaires impliqués dans le stress oxydatif/nitrosatif. L’ensemble des résultats de cette thèse démontre un rôle important de l’inflammation périphérique et cérébrale dans la survenue des complications neurologiques lors d’IHA et une meilleure compréhension des mécanismes physiopathologiques impliqués pourrait contribuer à la mise en place de stratégies thérapeutiques chez les patients atteints d’IHA en attente de transplantation.
Acute liver failure (ALF) is the clinical manifestation of an abrupt loss of hepatic function resuting from a massive hepatocyte necrosis in a patient with no preexisting liver disease. ALF is associated with metabolic and immunological disturbances that may lead to peripheral and cerebral complications such as systemic inflammatory response syndrome (SIRS), hepatic encephalopathy (HE), brain edema, increased intracranial pressure (ICP) and ultimately death by cerebral herniation. ALF is frequently complicated by infections, which are known to increase the risk of developing a SIRS with a subsequent worsening of HE and higher mortality rates. Ammonia plays a pivotal role in the pathophysiological mechanisms leading to HE and brain edema, and recent studies suggest that pro-inflammatory cytokines may also be involved. The aim of this thesis is therefore to investigate the role of circulating and cerebral pro-inflammatory cytokines in the setting of HE and brain edema during ALF. In article No. 1, we demonstrated that peripheral inhibition of tumor necrosis factor-alpha (TNF-α) by etanercept delays the progression of HE by reducing hepatocellular damage, decreasing peripheral and cerebral inflammation as well as associated oxidative/nitrosatif stress in mice with ALF induced by azoxymethane (AOM). These findings demonstrate an important role of TNF-α in the pathophysiology of HE during toxic liver injury and suggest that etanercept may provide a therapeutic approach in the management of patient awaiting liver transplantation. In article No. 2, we mimicked infection in mice with AOM-induced ALF in order to better understand the effects of an increased inflammatory response. We demonstrated that endotoxemia induced by lipopolysaccharide (LPS) precipitates the onset of coma and worsens the liver pathology. Peripheral and brain pro-inflammatory cytokines are synergistically raised by LPS during ALF and result in a large increase in cerebral matrix metalloprotease-9 (MMP-9) activity that was associated with immunoglobulin G (IgG) extravasation in the brain parenchyma. These results demonstrate a major increase of blood-brain barrier (BBB) permeability that contributes to the pathogenesis of HE during ALF with superimposed infection. Results from article No. 3 demonstrate that increase of BBB permeability during AOM-induced ALF without superimposed infection is not due to alteration of BBB constitutive proteins. In article No. 4, we demonstrated that exposure of cultured astrocytes to pathophysiological concentrations of ammonia or interleukin-1β results in an alteration of the expression of astrocytic genes implicated in cell volume regulation and oxidative/nitrosative stress. An additive effect on astrocytic genes implicated in oxidative/nitrosative was made evident in case of co-treatment. Taken together, results of the present thesis demonstrate a major role of peripheral and cerebral inflammation in the onset of neurological complications during ALF and a better understanding of the pathophysiological mechanisms implicated may contribute to new therapeutic strategies for ALF patients awaiting transplantation.

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Dissertations / Theses on the topic 'ALF(Acute Liver Failure)'

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