Investigating the prognostic performance of non-invasive tests in alcohol related liver disease

Alcohol-related Liver Disease (ArLD) often presents late, when opportunities to improve prognosis are limited. In the last 18 months, the SARS-CoV-2 pandemic has exacerbated already climbing mortality rates from ArLD, with a 20% increase in ArLD-related deaths between 2019 and 2020, on the background of a 43% increase between 2001 and 2019. Non-invasive-tests for liver fibrosis are increasingly advocated for use in ArLD but are not yet established in routine practice. In this thesis I aimed to investigate current alcohol referral practice from primary-care to specialist hepatology services, and the performance of commonly used non- invasive tests to detect fibrosis severity and predict mortality in ArLD. A systematic review and meta-analysis on four non-invasive tests in ArLD revealed a paucity of studies on alcohol compared to other liver aetiologies, but found good performance (AUROC >0.7) of all four tests (FIB4/FibroTest/ELF/FibroScan) in detecting F2/F3/F4 fibrosis-stages. A 3-year retrospective evaluation of alcohol- referrals to secondary-care found two-thirds of referrals were ‘unnecessary’, in that they had no evidence of advanced fibrosis or cirrhosis. Only 16% had a non-invasive fibrosis test performed prior to referral, and I applied modelling of simple fibrosis scores (FIB4 and APRI) to demonstrate that the proportion of unnecessary referrals could be reduced by 50% if simple non-invasive fibrosis tests were used in primary- care before referral. I report the design and set-up of a pathway involving use of non-invasive tests in primary-care (specifically, the Enhanced Liver Fibrosis (ELF) test in people with alcohol-use-disorder (AUD), based in Camden and Islington practices). A prospective 1-year study in 99 inpatients diagnosed with AUD found a third of 3 patients had elevated ELF scores indicative of advanced fibrosis that had not been detected previously, despite multiple previous hospital attendances. ELF was not associated with recent alcohol intake or AST/ALT values, differentiating it from FibroScan. A second systematic review on prognostic-performance of non-invasive fibrosis tests found FIB4/ELF/FibroScan/FibroTest performed well (AUROCs all >0.7) in predicting mortality, and ELF/FibroTest performed equally well or better than liver histology. Finally, in a cohort of 162 serum samples from patients with Alcoholic Hepatitis (AH) from the ‘STOPAH’ cohort (a published Randomised Controlled Trial of steroids and pentoxifylline conducted in over 1,000 patients with AH), I provide the first evidence that the Enhanced Liver Fibrosis (ELF) test can be used to predict outcomes in alcoholic hepatitis (AH), and discovered a new prognostic biomarker combining ELF and ABIC, which outperformed traditional prognostic biomarkers in predicting 90-day mortality in AH