A Proteomics Signature of NASH

Global prevalence of nonalcoholic fatty liver disease (NAFLD) is presently 30% and increasing. While the majority of afflicted individuals have a relatively non-progressive form i.e., nonalcoholic fatty liver (NAFL), a significant subset with nonalcoholic steatohepatitis (NASH) are more likely to progress to cirrhosis. No pharmacological therapies are currently approved for NALFD or NASH and liver histology is the reference standard for identification of those at increased risk of progression. Despite the requirement of liver histology improvement as an endpoint for regulatory approval, several factors limit applicability of biopsy in clinical development, including invasiveness and attendant risks, and sampling and observer variability and costs. As such, there is a high unmet need for non-invasive tests that can robustly and reliably assess NAFLD for diagnosis, prognosis, and monitoring purposes. Large-scale profiling of serum/plasma proteins (proteomics) increasingly demonstrates utility to identify changes that accurately reflect and predict disease states and outcomes, including the fibrosis component of NASH that is driven by disease activity and remains the most robust histological marker of prognosis. Recently, longitudinal assessment of over 5000 serum proteins in 636 individuals with histologically confirmed NAFLD was used to develop and validate models for all four key individual liver biopsy components (steatosis, hepatocellular ballooning, lobular inflammation, fibrosis) and at-risk NASH, and with sufficient sensitivity and precision to characterize drug intervention-related changes. Taken together, these results support continued validation of such proteomics-based models and their promise to enable a “liquid biopsy” assessment of NAFLD.

 

Learning Objectives