Project Abstract Nonalcoholic steatohepatitis (NASH) is the aggressive form of nonalcoholic fatty liver disease, the most common liver disease in children in the United States. The disease affects almost 1/3 of all obese children, estimated to be approximately 7 million children. Treatment is based on lifestyle changes such as a low sugar diet and increasing exercise, but no therapeutics are approved for children or adults. Currently, diagnosis of NASH requires a liver biopsy, which is cumbersome, expensive and has inherent risk. The lack of 1) non-invasive biomarkers to diagnose NASH and 2) pharmacodynamic/response biomarkers of NASH to therapy are considered by many to be an important barrier in the field. These biomarkers are needed to advance clinical care, focusing resources on the children with the most progressive form of the disease. And they are needed to drive therapeutic development because children with NASH are prioritized for participation in clinical trials and response biomarkers for NASH are needed to become surrogate endpoint biomarkers for clinical trials to accelerate drug development. This proposal represents an exceptional multidisciplinary effort to address these important gaps in knowledge. The project will be led by Dr. Miriam Vos, expert in pediatric NAFLD and experienced in early biomarker development research. Co-investigators including Dr. Kristal Maner-Smith, expert in lipidomics and Dr. Ayman Akil, expert in machine learning and biomarker discovery. The team seeks to develop a panel of biomarkers to predict NASH and to reflect response of NASH to therapy through the 2 following aims. Aim 1 will define and validate a panel of metabolites and lipids diagnostic of NASH in children. Aim 2 will define and validate a panel of metabolites, lipids and clinical variables that are associated with treatment induced improvement in NASH. Aims 1 and 2 will both capitalize on the exceptionally high-quality samples available from the NASH clinical research network and deposited within the NIDDK Central Repository. Repository serum samples are available from two pediatric clinical studies including the NAFLD Database study and the TONIC randomized clinical trial and were collected near in time to a liver biopsy as well as with detailed clinical phenotyping. Validation cohort and control samples will be drawn from the Emory Liver Biopsy Biorepository study and an ongoing Healthy Control pediatric cohort at Emory. Preliminary data demonstrates strong associations between specific metabolites and pathologic features of NASH including hepatocyte ballooning, inflammation and steatosis supporting feasibility. These studies are designed to have a sustained, powerful impact on the pediatric NASH biomarker field and to directly improve the health of children through efficient diagnosis of NASH and successful therapeutic development for NASH.

Project Narrative This proposal seeks to improve child health through detecting and validating novel biomarkers for pediatric nonalcoholic steatohepatitis, the more progressive form of nonalcoholic fatty liver disease. Discovery of biomarkers specific for pediatric NASH will improve clinical care and accelerate drug development for NASH in children.