Retinoid and Carotenoid Depletion in Patients at High-Risk for Liver Cancer

Summary

Principal Investigator: Peter H Gann
Abstract: DESCRIPTION (provided by applicant): Median survival from a hepatocellular cancer (HCC) diagnosis is only 8 months;therefore, effective prevention strategies are a high priority. Due to the epidemic of hepatitis C in the 1960's-70's, incidence has increased;approximately 3.2 million people are chronically infected and their annual incidence of HCC is 3-4%. Fortuitously, persons at high-risk can easily be identified - virtually all who develop HCC first have cirrhosis or chronic hepatitis, often for years. Oxidative stress due to chronic inflammation is a dominant force in the progression of chronic liver disease (CLD) and subsequent HCC. Therefore, deficiencies in dietary antioxidants such as retinoids and carotenoids, which previously have been reported in CLD, may constitute a major modifiable risk factor. This hypothesis is supported by numerous animal model and epidemiological studies. However, before safe and effective clinical trials aimed at repleting vitamin A and carotenoid stores in high-risk patients can be designed, we need exploratory studies to: a) determine the prevalence and determinants of retinoid-carotenoid depletion in well-characterized subgroups of patients typically seen in the U.S., b ) identify optimal biomarkers of oxidative stress that can serve as surrogate endpoints in early trials, and c) determine how biomarkers in serum and urine relate to antioxidant levels in the liver itself and to tissue markers of pre-neoplastic change. We propose cross-sectional studies among CLD patients undergoing liver biopsy at UIC and the University of Chicago, to address these Specific Aims: 1. Identify key predictors of serum antioxidant levels in patients with CLD, 2. Quantify the association between systemic measures of oxidative stress (blood, urine) and low retinoid/carotenoid status in CLD, and 3. Quantify the relationship between retinoid/carotenoid levels in liver vs. serum, and determine whether concentrations in liver are associated with pre-neoplastic changes in the same tissue. To address the first 2 aims we will enroll 140 patients (100 with CLD due to hepatitis C and 40 normal controls) and obtain medical, lifestyle and diet data, as well as blood and urine samples. Normal controls will include 10 subjects providing tissue by partial hepatectomy for benign conditions. For Aim 1 we will test the importance of multiple factors (poor diet, stage of CLD, smoking, insulin resistance, age and race) as independent predictors of serum antioxidant levels. For Aim 2, we will measure oxidative damage to DNA via 8OHdG in urine (oxidized, excreted DNA bases) and the comet assay (DNA strand breaks in lymphocytes) to test the association of these markers with serum antioxidant levels. For Aim 3, we will measure retinoid/carotenoid levels in liver tissue and relate that to biomarkers of oxidative stress and pre-neoplastic change (hyperproliferation, DNA damage, nuclear aberration) in liver tissue. Completion of the proposed work will lead directly to full-scale proposals for Phase II trials in CLD patients, with tissue endpoints and either dietary or supplement interventions. PUBLIC HEALTH RELEVANCE: The proposed project is part of an effort to find safe and effective ways to prevent liver cancer, through correcting deficiencies in two important classes of dietary antioxidants: retinoids (vitamin A) and carotenoids (2-carotene, lycopene). Persons with chronic liver disease are at very high risk for liver cancer, and it has been observed that they have retinoid/carotenoid depletion, for a variety of possible reasons. Before we can properly design prevention trials with the right intervention, the right target population and the right endpoints, we need preliminary studies for guidance, such as we have proposed.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT