Development of Serum Markers for the Non-Invasive Assessment of Longitudinal Change and Adjacent Stage Differentiation in Hepatic Fibrosis

Abstract

Development of Serum Markers for the Non-Invasive Assessment of Longitudinal Change and Adjacent Stage Differentiation in Hepatic Fibrosis Fibrogenesis is a dynamic process involving extracellular matrix synthesis and degradation that is dependent upon disease specific liver injury. The accepted standard measurement of hepatic fibrosis is through liver biopsy. Non-invasive markers of fibrosis were mostly developed in cross-sectional chronic hepatitis C (CHC) study cohorts. There is a need to develop valid non-invasive biomarkers of fibrosis that can follow dynamic changes in fibrogenesis. Our hypothesis was that current serum fibrosis marker panels were likely to have poor diagnostic performance for following changes in CHC fibrosis, or for the diagnosis of early stage nonalcoholic steatohepatitis (NASH). For this thesis, we utilized well-characterized biorepository data and samples from tertiary referral centers and phase II-III CHC clinical studies. Sequential algorithms that include FibroTest (FT-AT) reduce the need for biopsy in CHC in most patients for a diagnosis of cirrhosis, but only one-third of patients were correctly classified in a prognostic fibrosis classification. FT-AT and Hepascore are associated with poor directional change on longitudinal fibrosis assessment. In CHC non-responders, FT-AT declined by 5% despite an increase in histologic collagen area of 30% over 12 months. Current serum markers had modest diagnostic accuracy for NASH, and were not able to differentiate bland steatosis from early NASH. Next generation serum fibrosis markers should incorporate specific targeted proteins that have been linked to fibrogenesis at various stages in the disease process. Our multiplex panel study of 37 candidate serum biomarkers in >800 CHC patients noted that varying combinations of markers had poor accuracy for adjacent fibrosis stage. Our quantitative differential proteomic expression profile study in CHC liver tissue identified > 1700 proteins and >260 functional protein classes associated with fibrosis stage, providing feasibility for new approaches to fibrogenesis biomarker discovery. Keywords: Fibrogenesis, biomarkers, liver biopsy, hepatitis C