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

描述(由申请人提供)：被诊断为肝细胞癌的中位生存期仅为8个月；因此，有效的预防策略是高度优先的。由于1960年S-70年S期间丙型肝炎的流行，发病率有所上升，约有320万人慢性感染，他们每年的肝癌发病率为3-4%。幸运的是，高危人群很容易被识别--几乎所有首先发展为肝癌的人都患有肝硬变或慢性肝炎，通常会持续数年。慢性炎症引起的氧化应激是慢性肝病(CLD)和随后的肝细胞癌进展的主要力量。因此，饮食中缺乏抗氧化剂，如维甲酸和类胡萝卜素，以前在CLD中已被报道，可能构成一个主要的可修改的危险因素。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，在设计针对高危患者补充维生素A和类胡萝卜素的安全有效的临床试验之前，我们需要进行探索性研究，以：a)确定典型的美国典型患者亚组中类维甲酸-胡萝卜素耗竭的患病率和决定因素，b)确定氧化应激的最佳生物标记物，作为早期试验的替代终点，以及c)确定血清和尿液中的生物标记物如何与肝脏自身的抗氧化剂水平和肿瘤前病变的组织标记物相关。我们建议对在UIC和芝加哥大学接受肝脏活检的CLD患者进行横断面研究，以解决这些特定的目标：1.确定CLD患者血清抗氧化剂水平的关键预测因素；2.量化系统性氧化应激指标(血液、尿液)与CLD患者低维甲酸/类胡萝卜素状态之间的关联；3.量化肝脏和血清中维甲酸/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肿瘤前的变化有关。为了达到前两个目标，我们将招募140名患者(100名丙型肝炎引起的慢性肝病患者和40名正常对照)，并获得医疗、生活方式和饮食数据，以及血液和尿样。正常对照组将包括10名良性情况下通过肝部分切除提供组织的受试者。对于目标1，我们将测试多种因素(不良饮食、慢性阻塞性肺病的分期、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素的重要性。对于目标2，我们将通过尿中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)来检测DNA的氧化损伤，以测试这些标志物与血清抗氧化剂水平的关系。对于目标3，我们将测量肝组织中的类维A酸/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(过度增殖、DNA损伤、核异常)的生物标记物联系起来。拟议工作的完成将直接导致CLD患者第二阶段试验的全面建议，包括组织终点和饮食或补充剂干预。与公共健康相关：拟议的项目是通过纠正两种重要的饮食抗氧化剂：维甲酸(维生素A)和类胡萝卜素(2-胡萝卜素，番茄红素)的不足，找到安全有效的预防肝癌方法的一部分。患有慢性肝病的人患肝癌的风险非常高，而且人们已经观察到，由于各种可能的原因，他们有类维A酸/类胡萝卜素耗竭。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，我们需要像我们所提议的那样，进行指导的初步研究。

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.