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

描述（由申请人提供）：诊断为肝细胞癌（HCC）的中位生存期仅为8个月；因此，有效的预防战略是重中之重。由于六七十年代丙型肝炎的流行，发病率有所增加；大约有320万人慢性感染，其HCC的年发病率为3-4%。幸运的是，高危人群很容易被识别——几乎所有HCC患者首先都有肝硬化或慢性肝炎，通常持续数年。慢性炎症引起的氧化应激是慢性肝病（CLD）和随后的HCC进展的主要力量。因此，饮食中缺乏抗氧化剂，如类维生素a和类胡萝卜素，可能是一个主要的可改变的危险因素。这一假设得到了大量动物模型和流行病学研究的支持。然而，在设计旨在补充高危患者维生素A和类胡萝卜素储备的安全有效的临床试验之前，我们需要探索性研究：a)确定在美国典型的特征明确的患者亚组中类维甲酸-类胡萝卜素消耗的患病率和决定因素，b)确定氧化应激的最佳生物标志物，可以作为早期试验的替代终点，c)确定血清和尿液中的生物标志物与肝脏本身的抗氧化水平和肿瘤前变化的组织标志物之间的关系。我们建议对在UIC和芝加哥大学接受肝活检的CLD患者进行横断面研究，以解决这些具体目标：确定CLD患者血清抗氧化水平的关键预测因素，2。2 .量化CLD中氧化应激（血液、尿液）与低类维生素a /类胡萝卜素状态之间的关系；量化肝脏中类维甲酸/类胡萝卜素水平与血清之间的关系，并确定肝脏中的浓度是否与同一组织的肿瘤前变化有关。为了实现前两个目标，我们将招募140名患者（100名因丙型肝炎而患有CLD的患者和40名正常对照者），并获得医疗、生活方式和饮食数据，以及血液和尿液样本。正常对照包括10名受试者，为良性情况提供部分肝切除组织。在目标1中，我们将测试多种因素（不良饮食、CLD分期、吸烟、胰岛素抵抗、年龄和种族）作为血清抗氧化水平独立预测因子的重要性。在Aim 2中，我们将通过尿液中的8OHdG（氧化的，排出的DNA碱基）和彗星试验（淋巴细胞中的DNA链断裂）来测量DNA的氧化损伤，以测试这些标记物与血清抗氧化水平的关联。在Aim 3中，我们将测量肝组织中的类维生素a /类胡萝卜素水平，并将其与肝组织中氧化应激和肿瘤前变化（增生、DNA损伤、核畸变）的生物标志物联系起来。这项工作的完成将直接导致CLD患者II期临床试验的全面提案，包括组织终点和饮食或补充剂干预。公共卫生相关性：拟议的项目是一项努力的一部分，目的是通过纠正两类重要的膳食抗氧化剂：类维生素A（维生素A）和类胡萝卜素（2-胡萝卜素、番茄红素）的缺乏，找到安全有效的预防肝癌的方法。患有慢性肝病的人患肝癌的风险非常高，据观察，由于各种可能的原因，他们的类维生素a /类胡萝卜素消耗殆尽。在我们能够正确设计具有正确干预措施、正确目标人群和正确终点的预防试验之前，我们需要初步研究作为指导，就像我们所建议的那样。

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.