A Multidisciplinary Study of Biological Disparities in NASH Progression and Response to Statins to Inform Personalized Liver Cancer Chemoprevention in NAFLD
Abstract
This proposal addresses the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Liver Cancer, focusing on the prevention of liver cancer in patients with nonalcoholic fatty liver disease (NAFLD). NAFLD is a disease caused by excess lipid accumulation in the liver and is strongly associated with obesity. Once NAFLD is complicated by chronic liver injury and tissue scarring (i.e., nonalcoholic steatohepatitis or NASH), it could lead to cirrhosis, end-stage liver disease, and the development of liver cancer. Significant weight loss and regular exercise can reverse NAFLD. However, achieving therapeutic weight reduction by modifying dietary behavior and exercise habits is a substantial challenge in patients with NAFLD. No US Food and Drug Administration (FDA)-approved therapy for the treatment of NAFLD/NASH currently exists. Statin, a cholesterol-lowering medication, has been associated with a protective effect from disease progression and liver cancer development in chronic liver diseases in epidemiological studies. However, underlying mechanisms of the statin’s protective effects remain unknown in humans. No randomized controlled trials to test the statin’s efficacy on liver injury, scarring, and liver cancer have been reported in patients with NAFLD. Further, we don’t know which patients would benefit the most or the least from statin in the setting of NAFLD/NASH. Our recent clinical study demonstrated that statin’s protective effect on scarring may differ based on age and sex. In this study, we propose to investigate mechanisms underlying statin’s effects on liver injury, scarring, and liver cancer development using hepatic gene expression data from patients with NAFLD/NASH. We also propose to evaluate (1) the effect of atorvastatin on NASH and/or fibrosis in a randomized double-blind placebo-controlled clinical trial in patients with biopsy-proven NASH and fibrosis and (2) the association between statin use and incident diagnosis of cirrhosis and liver cancer and the incidence of drug adverse events related to statins in an epidemiological study using a large Veterans Health Administration (VHA) cohort of patients with NAFLD while considering possible age and sex differences in response to statins. NAFLD is a rapidly growing health concern among Veterans and in the United States (US) general population. Approximately 2.7 million Veterans are estimated to have NAFLD under VHA care. The prevalence of NAFLD has tripled in VHA between 2003 and 2011. NAFLD-related end-stage liver disease and liver cancer are now rapidly approaching to be the leading cause of liver transplant in the US. Thus, the significance of the health impact and financial burden from NAFLD-related cirrhosis and liver cancer, both in the VA healthcare system, as well as for our country at large, is enormous. The discovery of safe, cheap, and effective agents for the treatment of NASH and liver cancer prevention is an urgent unmet need for defraying the future impact of this epidemic. NAFLD affects both men and women and young and old; during reproductive age, it affects men more than women, but women following menopause suffer an increased risk of NAFLD and liver scarring. Thus, a better understanding of differences by age and sex in statin’s efficacy and the safety profile is essential for personalized prevention of NASH progression and liver cancer. This proposal addresses the FY19 PRCRP Military Health Focus Area of Gaps in Cancer Prevention. Upon successful completion of this proposal, investigators can lend further guidance regarding the role of statins in liver cancer prevention with insights as to possible differences by age and sex in the efficacy, tolerability, and safety of statins. This study is highly innovative as it bridges early basic science data to a clinical trial and further to evaluating the health-outcomes of statin therapy in US Veterans. The proposed research is of high impact and fills an existi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010512
Entities
People
- Ayako Suzuki
Organizations
- Duke University
- United States Army