When fat cells invade the liver, they can cause inflammation that leaves disruptive scars—known as fibrosis—linked to cirrhosis and other liver diseases. Obesity is the most prevalent metabolic risk for liver fibrosis. The second major risk for liver scarring is alcohol abuse. Although obesity and alcohol abuse can have similar clinical outcomes, how they might interact and enhance disease progression has been unexplored.

Now, an investigator from the USC Keck School of Medicine will develop a model to understand possible synergies over time between the two major biological drivers of liver fibrosis.

“We hope that this model of understanding liver disease could help us direct more precise and effective interventions,” said Brian P. Lee, MD MAS, Assistant Professor of Medicine in the Division of Gastrointestinal and Liver Diseases. “We want to decipher how obesity and alcohol abuse may be linked. Our long-term goal is to understand who will develop liver scarring and cirrhosis in the future. If someone comes into the clinic, what is their future risk of liver cirrhosis? How can we act now to reduce that risk? Can we eventually identify genetic and other profiles of people most at risk and find treatments for liver disease?”

Lee has received a National Institutes of Health K23 Mentored Patient-Oriented Research Career Development Award to perform this multi-year study. The K23 grant provides institutional research training opportunities for individuals with a clinical doctoral degree who undertake an intensive, supervised, patient-oriented research experience.

Lee will continue to be supported by critical training opportunities and research guidance and mentoring by the Biostatistics, Epidemiology, and Research Design (BERD) group at the University of Southern California Clinical and Translational Science Institute (SC CTSI).

“The people at SC CTSI have been such an incredible resource, providing mentoring and guidance, and I only hope that that connection will grow,” Lee said.

The BERD group has supported Lee through every phase of this exciting project.

“Our BERD group worked extensively with Dr. Lee to provide biostatistical support for his K23 grant application, that included advice on study design, sample size and statistical power, and data analysis plans,” said Wendy Mack, PhD, Director of the BERD group at SC CTSI and professor of Biostatistics in the USC Department of Population and Public Health Sciences. “We will continue to provide significant statistical mentoring to Dr. Lee as he completes his K23 research. BERD is excited to not only participate in this important research, but more importantly to contribute to the development of Dr. Lee’s research career.”

This research will also address race- and sex disparity in liver fibrosis. Blacks, for instance, more frequently present obesity and harmful alcohol use than Whites, yet they have a lower incidence of liver disease. Women typically develop liver injury with lower quantities of alcohol than men, and they have greater damage at diagnosis.

Lee will collaborate with data scientists at the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which recruited 5,115 non-Hispanic Black and White adults, age 18-30, in the years 1985-86. CARDIA has more than 30 years of ongoing clinical, behavioral, diet and outcomes data, with alcohol questionnaires and blood samples from nine examinations over time.

CARDIA includes clinical genetic markers but not the one necessary to guide liver fibrosis diagnosis and monitoring: the Enhanced Liver Fibrosis (ELF). ELF is the only validated biomarker with FDA Breakthrough Device designation, and it is recommended by National Institute for Health and Care Excellence (NICE). For Dr. Lee’s research, CARDIA will supply blood samples and research data, and the global company Siemens will perform diagnostic tests of the presence of the ELF biomarker in those samples.

Another potential clue in an individual’s risk profile for a liver disease could be the presence of the genetic marker PCSK9, which is a cholesterol regulator associated with liver fat, inflammation, and fibrosis in humans.

“There are already FDA-approved medications that target and inhibit PCSK9 to decrease your risk of heart attacks and cardiovascular mortality,” said Lee. “We are looking for the presence of this marker in the CARDIA study and how it may contribute to liver disease. If those genetic results are promising, you could envision that someday you may be able to identify patients who could benefit from having a PCSK9 inhibitor to address potential risk from liver disease.”