PhD ThesisBackground 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.EPoS (Elucidating Pathways of Steatohepatitis)
consortium, funded by the Horizon 2020 Framework Program of the European Union, Rosetrees Trust and Abbvie
