EPoS Project Description and Objectives
Elucidating Pathways of Steatohepatitis (EPoS)
Non-alcoholic fatty liver disease (NAFLD) represents a spectrum from isolated hepatic triglyceride accumulation (steatosis); through hepatic triglyceride accumulation plus inflammation (non-alcoholic steatohepatitis, NASH); and ultimately progressing to fibrosis/cirrhosis and potentially hepatocellular carcinoma in the absence of excessive alcohol consumption.
NAFLD is strongly associated with obesity and type 2 diabetes mellitus (T2DM). With the advent of increasingly sedentary lifestyles and changing dietary patterns, NAFLD prevalence has increased dramatically in concert with the rapidly progressing epidemics of both adult and childhood obesity and T2DM. NAFLD has therefore become one of the major health concerns due to its potential to progress to advanced liver disease and metabolic complications.
The overall objective of the EPoS project is to develop a global understanding of how host and environmental factors interact at the cellular, organ and organism level to promote the development of NAFLD and, importantly, the progression to fibrosing steatohepatitis (NASH) and end-stage liver disease; and so provide a clear path for integrating these datasets to inform cost effective diagnosis, prevention and treatment strategies in Europe.
The specific aims and objectives of the EPoS project are to:-
- Generate high quality data defining the pathophysiology of NAFLD using a multi-‘omics’ approach: Using samples and data from established histologically characterised patient cohorts, we will select individuals across the spectrum of NAFLD severity to form the ‘core’ EPoS Cohort. Large scale genetic, epigenetic, transcriptomic, metagenomic and metabolomic profiles will be analysed from members of this cohort.
- Develop a multi-dimensional pathophysiological profile across the spectrum of NAFLD using a systems medicine platform: The complex ‘omic’ datasets will be integrated across the spectrum of NAFLD and factors that associate with and/or predict disease progression identified.
- Validate these findings and identify translatable mechanisms: Specifically, we will study the effects of diet and environment on liver tissue, hepatocyte fat content, glucose/insulin tolerance, lipid homeostasis, proteomic/lipidomic signatures and the microbiome using in vitro systems and in vivo models of NAFLD. Expected outcomes include improved understanding of pathogenesis and first-stage validation of potential clinical biomarkers.
- Validate findings against clinical outcomes: Findings will be subsequently validated against clinically relevant outcome measures through the longitudinal follow-up of recruited patients (and assessment of samples from additional prospectively recruited cases) to determine utility as biomarkers.
- Measure health trends & clinical practice determinants: To inform future care pathway development so that new diagnostics/biomarkers and treatments from EPoS may be exploited and effectively delivered in the clinic we will assess the impact of NAFLD in European hepatological hospital medicine (including patterns of practice, clinical investigation strategies and determinants of disease severity) in cases presenting to outpatients with subsequent modelling of healthcare costs.