Novel non-invasive markers, imaging and interventions for the diagnosis, characterisation and treatment of non-alcoholic fatty liver disease

This DPhil thesis outlines research undertaken in non-alcoholic fatty liver disease (NAFLD).
Chapter 1 contains a literature review summarising current concepts in NAFLD including the burden of disease, clinical management including diagnosis and staging, and emerging therapeutic options to treat NAFLD. The first research chapter (Chapter 2) is an analysis of how patients with NAFLD are currently managed in clinical practice, the effectiveness of health interventions and of clinical outcomes measured by using currently available biomarkers. The outcomes and changes in liver and cardio-metabolic health markers of 165 patients with NAFLD who attended a secondary and tertiary metabolic hepatology (NAFLD) clinic at Oxford University NHS Foundation Trust over a median follow-up period of 13 months are presented. The analysis describes the burden of fatty liver disease in its various stages (steatosis, steatohepatitis (NASH), fibrosis, cirrhosis) across the Oxfordshire region. It outlines the use of non-invasive diagnostic and risk stratification tools including hepatic elastography, and how these change longitudinally at follow-up. Finally, as the quest for novel, specifically licenced therapies for NAFLD continues, this study outlines the interventions and approach used in the clinic including an analysis of changes to medical therapy including weight loss promoting agents such as glucagon-like peptide 1 (GLP-1) receptor agonists in patients with NAFLD.
The two subsequent research chapters explore two important themes arising from the clinic analysis. Chapter 3 outlines novel research which aims to help meet the need for improved diagnostic and staging tools for NAFLD, and in particular the need for novel non-invasive markers to allow for better risk stratification at diagnosis and for subsequent monitoring of the disease after therapy has been instigated. Drawing on previous work which implicates dysregulated glucocorticoid metabolism as a feature of NAFLD, with specific dysregulation varying across the spectrum of NAFLD, it investigates if the wider steroid metabolome can be used as a novel non-invasive biomarker tool to diagnose and stage NAFLD. This pilot study is conducted in 275 individuals with biopsy proven disease across the spectrum of NAFLD, and explores both specific glucocorticoid metabolic pathways in these individuals as well as use of the ‘global urinary steroid metabolome’ coupled with machine learning techniques to determine NAFLD stage. The results show excellent promise and suggest that if validated, this technique could have future high utility in clinical practice.
Following on from Chapter 1 which revealed that around 20 % of patients with type 2 diabetes attending the NAFLD clinic were commenced on GLP-1 therapy, and that the GLP1 agonist Liraglutide has been previously shown in research studies to be useful in patients with NASH, Chapter 4 investigates GLP-1 agonists as a novel therapy for NAFLD. What hitherto remains unclear is whether the benefit of GLP-1 therapy is solely due to its weight loss actions alone or whether there exist any direct GLP-1 effects on the liver. To seek to answer this question of any weight independent effects of Liraglutide in NASH, this chapter presents data from the ‘Lifestyle and Liraglutide in NASH’ (LiLi) clinical trial which contributes to the evidence base that may in due course inform medicines licensing agencies to licence GLP-1 agonist therapy as one the first treatments for NAFLD. 29 subjects with NASH were randomised to either Liraglutide or lifestyle intervention to induce weight loss and were followed for a minimum of 12 weeks. Both groups lost equal amounts of weight of approximately 5 % which allowed direct assessment of weight independent benefits. Data arising from metabolic tracer studies (deuterated water and 13C-glucose to detail lipid and glucose handling within the liver), biochemical and body composition data are presented. Data on liver fat and inflammation measured using magnetic resonance spectroscopy and using novel multiparametric magnetic resonance imaging (LiverMultiScanTM, Perspectum Diagnostics) pre and post weight loss intervention are also presented. This study finds that weight loss induced by Liraglutide is of equal efficacy and provides equivalent health benefits to losing weight via dietary lifestyle measures though this is only maintained whilst taking therapy. When considering that clinicians urgently require a range of tools at their disposal to tackle NAFLD and that weight loss and maintenance thereafter is difficult to achieve, this study concludes that GLP-1 agonists could play an important role as a future licenced therapy for NAFLD.

Keywords: NASH
biomarkers
NAFLD
Advisor: Tomlinson, J
Neubauer, S