Tanwar, Sudeep; (2018) Stratified medicine: an exploration of the utility of non-invasive serum markers for the management of chronic liver diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chronic liver disease (CLD), the 3rd commonest cause of premature death in the UK, is detected late when interventions are often ineffective. Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) account for a significant proportion of CLD in the UK. Numerous direct (molecules involved in matrix biology) and indirect biomarkers (standard laboratory tests) have been successfully developed to detect advanced liver fibrosis. Less success, however, has been achieved in the detection of alternative diagnostic targets such as early stage fibrosis, non-alcoholic steatohepatitis (NASH) and fibrosis evolution. In a study of 17 candidate biomarkers amongst patients with NAFLD, terminal peptide of procollagen 3 was identified as the only biomarker demonstrating good performance for the detection of NASH in both a derivation and validation cohort. Thereafter, these results were further validated in another NAFLD cohort. In a study of 9 biomarkers (indirect and direct) in the detection of fibrosis in NAFLD, direct biomarkers demonstrated better diagnostic performance overall and for early stage fibrosis although some indirect biomarkers identified advanced fibrosis and cirrhosis with good effect. Thereafter, parallel and serial combinations of 3 biomarkers of advanced fibrosis were proposed and successfully employed in a cohort of patients with NAFLD to improve diagnostic performance. In a study of 10 biomarkers in CHC, fibrosis detection was enhanced using complex biomarker panels that incorporated direct tests. Of note, the use an alternative assay for a constituent component significantly affected biomarker panel performance both overall and at diagnostic thresholds. The ability of the biomarkers to monitor fibrosis evolution arising due to putative antifibrotic was then studied in CHC. In the first study, changes in direct biomarker, ELF, could predict fibrosis evolution. In the second study, an improvement of indirect biomarker scores in patients with CHC cirrhosis during treatment was found to denote an improved prognosis.

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