Candidate approaches will be taken to evaluate the performance of existing biomarkers of liver disease and a discovery approach will be taken to the identification of new biomarkers using nanotechnology, metabonomics and genomics.
Stratification by use of Non-invasive Tests to measure Liver Fibrosis in AH
AH prognosis is heavily influenced by the degree of fibrosis or cirrhosis which currently can only be determined by histology. In other hepatic disorders, non-invasive tests (NITs) such as ELF Score have replaced histological assessment of fibrosis, providing equivalent or improved prognostic information. Baseline ELF score (and other NITs) will be determined in the MICAH cohort of whom 20% will have histological assessment, and in ISAIAH trial and the MAFIA trial patients giving a total of 324 patients in whom the correlation of ELF with histology can be measured. Histological fibrosis will be measured using metavir, laenec stage and collagen proportionate area. Semiquantitative assessment of histological inflammation will be used to evaluate the impact of liver inflammation on the performance of NITs in assessing liver fibrosis.
Using all patients in the MICAH cohort and trials, we will investigate the prognostic performance of NITs measured at baseline, at discharge and at 90 days and changes in NITs from baseline to discharge, baseline to 90 days and discharge to 90 days with respect to liver related and all-cause morbidity and mortality.
NIT values will be evaluated alongside PNPLA3 genotype and transferrin level in the prognostic scoring system.
In all participants we will measure Carbohydrate deficient Transferrin levels and gamma glutamyl transferase (an established marker of abstinence) at 90 days post enrolment to determine abstinence.
ELF & Procalcitonin
In ISAIAH and MAFIA, we will investigate the diagnostic and prognostic performance of ELF at baseline and at the end of treatment. Absolute levels of ELF and change in ELF will be evaluated to determine the ability of ELF values and change in ELF to stratify patients into meaningful groups with respect to response to the CTIMP and overall prognosis.
Procalcitonin, a serum marker of infection and systemic inflammatory response (SIRS), will be measured at presentation and weekly during admission in all patients participating in the two CTIMPs. Predictive performance of procaltonin for infection or SIRS will be explored alongside 16S-DNA.
Nanoparticles: Diagnostic validation and development of Partner Diagnostics for Stratification
Reactive fluorescent polymers developed by Peveler and Rosenberg and gold particles coated with ammonium cations and conjugated with fluorophores will be used to determine profiles that recapitulate the performance of the best NIT in assessing fibrosis. The two classes of nanoparticles will be used to detect signal patterns that can be used to stratify groups of patients for prognosis in AH and for treatment response in the clinical trials of pharmacological agents investigated for the treatment of AH.
microRNA in AKI
A pilot study conducted with Prof Simpson’s group in Edinburgh revealed a potential signal for prediction of AKI based on microRNA profile. We will provide additional samples to the group to complete this study.
We will also use organ culture systems to assess the impact of alcohol and bacterial products on immune and parenchymal cell activation and survival, and consequences of cytokine administration on these responses.