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Non-Alcoholic Fatty Liver Disease: Disease Burden and Development

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Non-Alcoholic Fatty Liver Disease: Disease Burden and Development Non-Alcoholic Fatty Liver Disease: Disease burden and development of novel fibrosis diagnostic and prognostic signatures Marie Patricia Boyle A thesis submitted for the degree of Doctor of Philosophy Institute of Cellular Medicine Newcastle University January 2020 I ABSTRACT .................................................................................................................................. I TABLE OF CONTENTS ................................................................................................................ II INDEX OF FIGURES .................................................................................................................... V TABLE OF TABLES ................................................................................................................... VII ABBREVIATIONS ..................................................................................................................... XII CO-AUTHOR CONTRIBUTIONS ............................................................................................... XIX ACKNOWLEDGMENTS .......................................................................................................... XXII DECLARATION ....................................................................................................................... XXII PUBLICATIONS AND PRESENTATIONS ASSOCIATED WITH THIS THESIS .............................. XXIII I ABSTRACT Background This thesis investigates novel diagnostic and prognostic disease biomarkers in NAFLD and explores both the quality of life (QoL) and economic burden associated with NAFLD. Methods To estimate HRQL burden, 147 patients completed validated QoL assessments within 6 months of diagnostic liver biopsy. NAFLD out-patient service utilisation was evaluated and micro-costed over a 12-month period. The clinical utility of serum collagen neo-epitope biomarkers to identify advanced fibrosis was established. DNA methylation was evaluated in circulating cell free DNA as a diagnostic biomarker in NAFLD using pyrosequencing and evaluated by whole genome bisulfide sequencing (WGBS) from paired liver biopsy tissue to characterise NAFLD prognostic signatures. Results HRQL Burden: Grade of lobular inflammation influenced CLDQ scores and FIS scores. One way ANCOVA analyses showed that CLDQ scores were influenced by fibrosis stage (F=1.910, p=0.014, effect size 0.814) Economic Burden: Multivariate regression analysis established the main cost drivers to be the number of clinic appointments (p=0.042) and the presence of advanced disease (p=0.001). Collagen Neo-epitope biomarkers the novel “FIBC3” diagnostic panel including PROC3 exhibited improved accuracy and outperformed other fibrosis indices for the detection of advanced fibrosis DNA methylation fibrosis biomarkers PPARγ CpG methylation displayed uniform hypermethylation at each CpG site between the liver fibrosis cohorts relative to uniform hypomethylation irrespective of liver disease aetiology DNA methylation prognostic signature; > 657 novel methylation signatures to distinguish low and high risk disease were identified. Conclusion Multiple factors negatively impact on reported HRQL, notably fatigue and lobular inflammation. The direct medical costs associated with NAFLD are substantial and increase with the presence of advanced disease. The ‘FIBC3’ panel is an accurate tool with a single threshold value that maintains both sensitivity and specificity for the identification of advanced fibrosis (F≥3). The first methylome map of low versus high risk disease in NAFLD suggest that high and low risk NAFLD while interrelated, may be biologically distinct from disease onset. Extending this towards clinical utility, uniform hypermethylation at the PPARγ gene promoter confirms this as a potential methylation signature for fibrosis progression in chronic liver disease. I TABLE OF CONTENTS ABSTRACT ........................................................................................................................................ I CHAPTER 1. .................................................................................................................................... 1 Introduction and Background ........................................................................................................ 1 CHAPTER 2. .................................................................................................................................. 35 NAFLD Disease Burden: Exploring emotional, mental, physical and social functioning in NAFLD: Data from the European NAFLD Registry; an analysis of Patient reported outcomes (PROs) in NAFLD ........................................................................................................................................... 35 2.1 INTRODUCTION .......................................................................................................................... 37 2.2. MATERIALS AND METHODS ....................................................................................................... 41 2.3. RESULTS ..................................................................................................................................... 46 2.4. DISCUSSION ............................................................................................................................... 70 2.5. CONCLUSION .............................................................................................................................. 81 CHAPTER 3. .................................................................................................................................. 82 Cost of Illness study associated with the prevalence, severity and patterns of clinical practice in outpatient visits for NAFLD– the United Kingdom CONSTANS STUDY ........................................ 82 3.1. INTRODUCTION .......................................................................................................................... 84 3.2. MATERIALS AND METHODS ....................................................................................................... 90 3.3. RESULTS ..................................................................................................................................... 94 3.4. DISCUSSION ............................................................................................................................. 117 3.5. CONCLUSION ............................................................................................................................ 129 CHAPTER 4. ................................................................................................................................ 130 An initial exploration of proteomic biomarkers in NASH ........................................................... 130 4.1. INTRODUCTION ........................................................................................................................ 132 4.2. MATERIALS AND METHODS ..................................................................................................... 137 II 4.3. RESULTS ................................................................................................................................... 140 4.4. DISCUSSION ............................................................................................................................. 166 4.5. CONCLUSION ............................................................................................................................ 172 CHAPTER 5. ................................................................................................................................ 173 Performance of the PROC3 Collagen Neo-Epitope Biomarker in NAFLD ................................... 173 5.1. INTRODUCTION ....................................................................................................................... 175 5.2. MATERIALS AND METHODS ................................................................................................... 179 5.3. RESULTS ................................................................................................................................... 182 5.4. DISCUSSION ............................................................................................................................. 208 5.5. CONCLUSION ............................................................................................................................ 216 CHAPTER 6. ................................................................................................................................ 217 Plasma DNA methylation as a biomarker for stratification of mild and severe liver fibrosis in non- alcoholic fatty liver disease ........................................................................................................ 217 6.1. INTRODUCTION ....................................................................................................................... 219 6.2. MATERIALS AND METHODS ..................................................................................................... 222 6.3. RESULTS ................................................................................................................................... 229 6.4. DISCUSSION ............................................................................................................................. 237 6.5. CONCLUSION ...........................................................................................................................
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