Nonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicity

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dc.contributor.advisorHall, Pauline de la Motteen_ZA
dc.contributor.advisorMarais, Daviden_ZA
dc.contributor.advisorShephard, Eniden_ZA
dc.contributor.authorClarkson, Vivianen_ZA
dc.date.accessioned2014-10-20T07:18:47Z
dc.date.available2014-10-20T07:18:47Z
dc.date.issued2004en_ZA
dc.descriptionIncludes bibliographical references (leaves 163-176).en_ZA
dc.description.abstractThe term "Nonalcoholic steatohepatitis" (NASH) describes a form of liver disease indistinguishable from alcoholic liver disease, but present in persons who consume insignificant amounts of alcohol. The spectrum of non-alcoholic liver disease ranges from non-progressive steatosis, through to NASH and sometimes to cirrhosis. Risk factors predisposing to NASH include obesity, diabetes mellitus, hypertriglyceridermia and procedures leading to rapid and profound weight loss such as gastric bypass and bulimia. Given the high incidence of type II diabetes, obesity and various types of hyperlipidaemia in the Western Cape, NASH has become one of the most commonly encountered liver diseases in the Liver Clinic, Groote Schuur Hospital. Statistics also suggest nonalcoholic fatty liver disease underlies most cases of elevated liver enzymes in many other parts of the world. The exact pathogenic mechanisms involved are not well understood, and no effective treatment options are currently available. However, animal models of NASH now provide unique opportunities for study of this disease in the laboratory setting. This thesis employs a dietary animal model, which restricts methionine and choline intake, to replicate aspects of the injurious process in human NASH. Two lines of inquiry are pursued. The first involves an assessment of the effect of alcohol consumption on fatty liver of non- alcoholic aetiology. Elevated liver enzymes, altered levels of lipid peroxides, and increased cytochrome P450 activity recorded in this study, suggest alcohol may exacerbate nonalcoholic fatty liver disease. The second line of inquiry is an exploration of the role of Tumor Necrosis Factor alpha (TNFα, a cytokine implicated in pathogenesis of alcoholic liver disease and thought to be pivotal in NASH pathogenesis. The role of TNFα in the dietary model of NASH is investigated using mice lacking functional TNFα genes, as well as wild type mice in which expression of this cytokine is induced by endotoxin challenge. Endotoxin challenge does elicit a marked inflammatory response and enhanced generation of lipid peroxides in the fatty liver, both of which may contribute to injury. However, as knockout mice still develop experimental NASH, TNFα cannot be considered the sole driving force required for the development of NASH. This strength of the project lies in the use of a variety of techniques (in the fields of Pathology, Immunology and Lipid Biochemistry) to investigate a range of aspects of NASH. The results of the alcohol study may provide the first empirical evidence supporting the need to restrict alcohol intake in patients with NASH, while the data on TNFα is vital for illuminating the complex, (potentially) counter-intuitive role of this cytokine in NASH. Where definitive conclusions cannot be drawn from the data, the questions posited may constitute the basis for future research.en_ZA
dc.identifier.apacitationClarkson, V. (2004). <i>Nonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicity</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Anatomical Pathology. Retrieved from http://hdl.handle.net/11427/8627en_ZA
dc.identifier.chicagocitationClarkson, Vivian. <i>"Nonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicity."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Anatomical Pathology, 2004. http://hdl.handle.net/11427/8627en_ZA
dc.identifier.citationClarkson, V. 2004. Nonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicity. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Clarkson, Vivian AB - The term "Nonalcoholic steatohepatitis" (NASH) describes a form of liver disease indistinguishable from alcoholic liver disease, but present in persons who consume insignificant amounts of alcohol. The spectrum of non-alcoholic liver disease ranges from non-progressive steatosis, through to NASH and sometimes to cirrhosis. Risk factors predisposing to NASH include obesity, diabetes mellitus, hypertriglyceridermia and procedures leading to rapid and profound weight loss such as gastric bypass and bulimia. Given the high incidence of type II diabetes, obesity and various types of hyperlipidaemia in the Western Cape, NASH has become one of the most commonly encountered liver diseases in the Liver Clinic, Groote Schuur Hospital. Statistics also suggest nonalcoholic fatty liver disease underlies most cases of elevated liver enzymes in many other parts of the world. The exact pathogenic mechanisms involved are not well understood, and no effective treatment options are currently available. However, animal models of NASH now provide unique opportunities for study of this disease in the laboratory setting. This thesis employs a dietary animal model, which restricts methionine and choline intake, to replicate aspects of the injurious process in human NASH. Two lines of inquiry are pursued. The first involves an assessment of the effect of alcohol consumption on fatty liver of non- alcoholic aetiology. Elevated liver enzymes, altered levels of lipid peroxides, and increased cytochrome P450 activity recorded in this study, suggest alcohol may exacerbate nonalcoholic fatty liver disease. The second line of inquiry is an exploration of the role of Tumor Necrosis Factor alpha (TNFα, a cytokine implicated in pathogenesis of alcoholic liver disease and thought to be pivotal in NASH pathogenesis. The role of TNFα in the dietary model of NASH is investigated using mice lacking functional TNFα genes, as well as wild type mice in which expression of this cytokine is induced by endotoxin challenge. Endotoxin challenge does elicit a marked inflammatory response and enhanced generation of lipid peroxides in the fatty liver, both of which may contribute to injury. However, as knockout mice still develop experimental NASH, TNFα cannot be considered the sole driving force required for the development of NASH. This strength of the project lies in the use of a variety of techniques (in the fields of Pathology, Immunology and Lipid Biochemistry) to investigate a range of aspects of NASH. The results of the alcohol study may provide the first empirical evidence supporting the need to restrict alcohol intake in patients with NASH, while the data on TNFα is vital for illuminating the complex, (potentially) counter-intuitive role of this cytokine in NASH. Where definitive conclusions cannot be drawn from the data, the questions posited may constitute the basis for future research. DA - 2004 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2004 T1 - Nonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicity TI - Nonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicity UR - http://hdl.handle.net/11427/8627 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/8627
dc.identifier.vancouvercitationClarkson V. Nonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicity. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Anatomical Pathology, 2004 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/8627en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Anatomical Pathologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherAnatomical Pathologyen_ZA
dc.titleNonalcoholic steatohepatitis (NASH) : animal studies of interactive hepatoxicityen_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMScen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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