Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide. Given that NAFLD can progress from steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and potentially hepatocellular carcinoma, early diagnosis and accurate disease staging are primary clinical concerns. Hypothesizing that a subset of liver proteins will exhibit differential expression in NAFLD and that these proteins may represent candidate disease biomarkers; the aims of this project were to use proteomics to identify differentially expressed proteins both in an in vitro and an in vivo model of NASH. Preliminary studies developed and characterised both models used here; experiments utilized a relative quantitative proteomic approach with isobaric tags for relative and absolute quantitation labelling combined with nano-liquid chromatography and tandem mass spectrometry.

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Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis to the more progressive form non-alcoholic steatohepatitis. Genetic factors may be important risk determinants for disease progression. This study aimed to assess association of polymorphisms in candidate genes with NAFLD severity and to investigate functional significance of selected polymorphisms Two approaches were used for association studies, case-control analysis on adults (n=351) with biopsy-proven NAFLD and transmission disequilibrium on family trios (n=71) with an index child with NAFLD. A total of 37 polymorphisms in 14 candidate genes selected on the basis of either biological relevance or previous data suggesting a role in NAFLD were genotyped. Significant differences were seen for polymorphisms in 4 genes between stages of NAFLD or in transmission within families. For SOD2, which encodes manganese-dependent superoxide dismutase, the homozygous T genotype for rs4880 was more common in severe fibrosis (OR 2.23 (95% CI 1.19-4.17); p=0.01) and the T-allele was preferentially transmitted in the family trios (p=0.038). For the adiponutrin gene (PNPLA3), carriage of the variant G-allele (rs738409) was associated with severe steatosis (OR 1.87 (95% CI 1.15-3.04); p=0.01) and severe fibrosis (OR 2.02 (95% CI 1.29-3.1); p=0.002) in adults and preferentially transmitted in the family trios (p=0.001). For the claudin-10 gene (CLDN10), carriage of rs4143093 was associated with severe steatosis (OR 2.82 (95% CI 1.5-5.3); p=0.0009). To further assess the relevance of claudin-10 to NAFLD, immunohistochemistry was performed. Expression in liver sections was confirmed. The effect of rs4143093 genotype on expression was investigated but insufficient samples were available to reach a firm conclusion. For the gamma-glutamyl cysteine ligase catalytic subunit gene (GCLC), rs17883901 was preferentially transmitted in the family trios (p= 0.046), but did not affect disease severity in adults. Studies on functional significance of this polymorphism showed that no significant difference in promoter activity between allelic variants.

Introduction: Chronic liver disease (CLD) is a real and ever growing problem which has significant morbidity and mortality. It is one of the most prevalent diseases in the world and its rate is rising. CLD remains the only one of the top 5 UK killers to be on the increase; and it is the only one of these diseases to be without official guidelines or good practice documentation in the UK. A dearth of literature is available to inform clinicians of the functional ability and empirical experience of people with CLD, or of those having undergone a liver transplant. This study aims to address this much needed shortfall in the literature. Methods: This is a mixed methods study. The quantitative study explores the functional difficulty and symptom burden experienced by people with CLD. Here standardised functional assessment and symptom burden measurement tools were completed by people with CLD (n=468). Specifically those with alcoholic liver disease (n=107), non-alcoholic fatty liver disease (n=224), primary biliary cirrhosis (n=90), Primary sclerosing cholangitis (n=47).The scores were analysed using Prism 0.3 and SPSS version 19. A nested qualitative study (n=12) was used to add narrative depth to the quantitative results giving insight of the empirical issues of CLD. The qualitative study took the form of semi structured interviews’ of participants, specifically those with ALD (n=8) and NAFLD (n=4). The interviews used an occupational therapy model [Canadian Occupational Performance Model (COPM)] as their topic guide. Results: Functional difficulty is great in people with CLD and significantly more people with CLD are experiencing worse functional difficulty than comparator groups. In particular, people with CLD experience high levels of functional difficulty in the areas of hygiene and arising. This is an incredibly important finding for this patient group and for the profession of Occupational therapy. Here CLD is placed within the context of its impact rather than its physical/medical presentation. Furthermore, functional difficulty does not associate with liver disease severity but does associate with symptom burden. This again reiterates the importance of assessing the person rather than their condition. In particular, orthostatic and autonomic problems and cognitive difficulty have independent associations with worsening function. These are areas of disease management where occupational therapists are well placed to deliver expert intervention. Functional difficulty increases over time but not significantly so; although this increase in functional difficulty may have clinical implications. This reinforces the need for an occupational therapy strong CLD service that delivers intervention promoting symptom management and functional independence. People living with ALD and NAFLD are at most risk of functional difficulty and symptom burden and are disengaging with daily activity due to the constellation of functional difficulty, symptom burden, and impact of lifestyle. Functional difficulty is significant in people having undergone a liver transplant, and the number of those experiencing functional difficulty is significantly greater, than participants in comparator groups. Those having undergone a liver transplant were experiencing functional difficulty to the same degree as those with CLD. Symptom burden is important in the worsening of function for those in the LT cohort, with increased fatigue independently associating with increased functional difficulty. These findings are of great importance as for the first time, the notion of ‘cure’ for liver disease realises that functional difficulty and symptom burden remain significant for those transplanted. Occupational therapy could lead a major change in the service delivery currently given to those pre and post transplantation to address this shortfall. Conclusion: People with CLD, and those following liver transplant, are experiencing significant functional difficulty which to date has not been recognised, and as a consequence, not treated. The increasing number of people with CLD combined with the significant functional difficulty they experience is set to impact heavily on health resources both globally and in the UK. The development of an occupational therapy strong CLD service, which addresses specifically the holistic impact of the functional difficulty and symptom burden experienced by this patient group, is needed urgently to address the rising demand. An occupational therapy strong service is necessary to complement established liver services. This will address specifically of the under recognised and under treated management of daily activity and symptom burden for people with CLD; areas currently lacking in liver service provision and in which Occupational Therapists are expert.