Novel Biomarkers For Non-Alcoholic Fatty Liver Disease and Associated Symptoms

Abstract

Obesity is on the rise in populations across the world, and represents a major health concern. It is a component of Metabolic Syndrome, a collection of risk factors that predispose to diabetes and cardiovascular disease. Metabolic Syndrome is often accompanied by non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disease ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH) and liver fibrosis. Currently, the gold standard for NASH and liver fibrosis diagnostics is liver biopsy; thus, a non-invasive procedure for detecting and staging NAFLD is greatly needed. The research presented herein involves evaluating various kinds of soluble biomarkers and the development of a novel, serum-based biomarker panel for NASH and NASH-related fibrosis. The biomarker panel comprises proteins that reflect the disease process of NASH and NASH-related fibrosis, including hormones derived from adipose tissue (adipokines) and proteins involved in fibrogenesis and cell death. While the sample size in this study was small at 79 patients, it is anticipated that subsequent testing of the panel on larger populations of NAFLD patients will ultimately support its use in clinical settings. A second study was conducted with the goal of discovering novel, as-of-yet untested biomarkers of NASH and NASH-related fibrosis that may be tied to the deregulation of cell signaling pathways in adipose tissue. A previous study used a phosphoproteomic approach to discover that several kinase-driven pathways were deregulated in the adipose tissue of patients with NASH and NASH-related fibrosis; enrichment analysis showed that these pathways were linked to the regulation of cell functions by insulin, as well as signal transduction by AKT and PIP3. Subsequent pathway analyses were then conducted to identify a set of secreted, soluble proteins associated with these pathways. From this set two promising candidates were selected based on extensive literature searches; these were the chemokine CCL-2/MCP-1, and soluble Fas ligand. These candidates were then tested on a small cohort of patients with NASH and NASH-related fibrosis to determine if they had the potential to be diagnostically predictive, and it was discovered that both worked reasonably well as biomarkers of fibrosis. Consequently, these molecules may be released at abnormal levels by adipose tissue in patients with NAFLD and may in turn play a role in fibrogenesis associated with NASH; they would therefore be good candidates to test in future development of biomarker panels for NASH-related fibrosis. A third study was undertaken to evaluate the association between levels of various soluble molecules and fatigue in patients with NAFLD or hepatitis C. Specifically, I correlated self-reported assessments of fatigue dissecting this condition into fatigue associated with physical activity (peripheral fatigue) or more global lack of energy and motivation (central fatigue) with measures of inflammation, or with abnormalities of glucose and lipid metabolism. The study demonstrated that a substantial majority of patients with chronic liver disease report significant peripheral fatigue. This type of fatigue was linked to elevated serum levels of IL-6 and IL-8, linking it to an inflammatory component, which is not the case for central fatigue.