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

描述（由申请人提供）：肝细胞癌（HCC）诊断的中位生存期仅为8个月;因此，有效的预防策略是高度优先的。由于20世纪60 -70年代丙型肝炎的流行，发病率增加;约320万人慢性感染，其HCC的年发病率为3- 4%。幸运的是，高危人群很容易识别-几乎所有首先发展为HCC的人都有肝硬化或慢性肝炎，通常持续多年。慢性炎症引起的氧化应激是慢性肝病（CLD）和随后的HCC进展的主导力量。因此，饮食中的抗氧化剂，如类维生素A和类胡萝卜素，以前已报告在CLD的不足，可能构成一个主要的可改变的风险因素。这一假设得到了许多动物模型和流行病学研究的支持。然而，在设计安全有效的临床试验以补充高危患者的维生素A和类胡萝卜素储备之前，我们需要探索性研究：a）确定在美国常见的特征良好的患者亚组中类维生素A-类胡萝卜素耗竭的患病率和决定因素，B）鉴定可在早期试验中用作替代终点的氧化应激的最佳生物标志物，和c）确定血清和尿液中的生物标志物如何与肝脏本身中的抗氧化剂水平和肿瘤前变化的组织标志物相关。我们建议在UIC和芝加哥大学接受肝活检的CLD患者中进行横断面研究，以解决这些具体目标：1。确定CLD患者血清抗氧化剂水平的关键预测因子，2。量化CLD中氧化应激（血液，尿液）和低类维生素A/类胡萝卜素状态的系统测量之间的关联，和3。定量肝脏与血清中类维生素A/类胡萝卜素水平之间的关系，并确定肝脏中的浓度是否与同一组织中的肿瘤前变化相关。为了实现前两个目标，我们将招募140名患者（100名患有丙型肝炎的CLD患者和40名正常对照），并获得医疗，生活方式和饮食数据，以及血液和尿液样本。正常对照将包括10名受试者，通过部分肝切除术提供组织用于良性疾病。对于目标1，我们将测试多个因素（不良饮食，CLD阶段，吸烟，胰岛素抵抗，年龄和种族）作为血清抗氧化剂水平的独立预测因子的重要性。对于目标2，我们将通过尿液中的8 OHdG（氧化的排泄DNA碱基）和彗星试验（淋巴细胞中的DNA链断裂）测量DNA的氧化损伤，以检测这些标志物与血清抗氧化剂水平的相关性。对于目标3，我们将测量肝组织中的类维生素A/类胡萝卜素水平，并将其与肝组织中的氧化应激和肿瘤前变化（过度增殖、DNA损伤、核畸变）的生物标志物相关联。拟议工作的完成将直接导致CLD患者II期试验的全面建议，组织终点以及饮食或补充剂干预。公共卫生相关性：拟议的项目是努力寻找安全有效的方法来预防肝癌的一部分，通过纠正两类重要的饮食抗氧化剂的缺乏：类维生素A（维生素A）和类胡萝卜素（2-胡萝卜素，番茄红素）。患有慢性肝病的人患肝癌的风险非常高，并且已经观察到他们由于各种可能的原因而具有类维生素A/类胡萝卜素耗竭。在我们能够用正确的干预措施、正确的目标人群和正确的终点来正确地设计预防试验之前，我们需要进行初步研究来提供指导，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.