Gut-Related Markers and Hepatocellular Cancer in a Multi-Ethnic Cirrhotic Cohort

项目摘要/摘要 在美国，肝细胞癌的发病率和死亡率正在上升 在所有癌症中速度最快的。以长期炎症为特征的肝硬变是一种明确的癌前病变。 病变，尽管从肝硬变到肝细胞癌的转变知之甚少。目前，唯一的临床 对于不断增加的肝硬变高危人群来说，选择是观察和等待肝细胞癌 发展。因此，迫切需要确定肝硬变进展为肝细胞癌的途径。 实验数据表明，肠道-肝脏轴的扰动对肝脏具有致癌作用。胆汁酸， 在肝脏中产生并由肠道细菌代谢的是小鼠的肝癌，以及内毒素 (细菌膜的一种成分)从肠道泄漏会导致小鼠患上肝癌。我们的预赛 数据显示，脱氧胆酸(DCA，一种次级胆汁酸和肠道代谢物)和肠道脂肪酸 结合蛋白(i-FABP，肠细胞损伤和肠道通透性的标志)升高，而几个 与肝硬变相比，肝硬变患者血浆中的其他胆汁酸和免疫标志物减少。 没有肝细胞癌。在先前的前瞻性队列研究中，我们已经证明了与脂多糖暴露相关的标志物 (例如CD14)和慢性免疫激活/炎症(例如白介素6和干扰素γ诱导的蛋白10)是 在感染艾滋病毒的高危人群中，在发生淋巴瘤之前几年就升高了。在 在拟议的研究中，我们将检查胆汁酸、脂多糖暴露的标志物和免疫的作用 前瞻性随访370例肝硬变高危临床队列患者对肝细胞癌内毒素的反应 用于肝细胞癌的发展。我们将从等待治疗的大量患者中招募为期两年的研究参与者 在洛杉矶的两个大型移植中心进行肝脏移植。我们预计我们研究的大约40% 人口将是西班牙裔，这将使我们能够研究人口群体中肝癌的路径，即 肝癌的风险最高，并将从拟议的研究中获益最多。研究参与者将 提供十二指肠吸出液、外周血样本、流行病学数据、营养数据、 并同意查阅他们的病历。到了第四年年中，我们预计56名成员将 在随访期内均发展为肝细胞癌。我们将设计一项嵌套病例对照研究，纳入56例肝细胞癌 2例和112例肝硬变对照(2：1配对)，并检测7种候选胆汁酸和14种免疫标志物 在这些参与者的配对血液(血清)和十二指肠抽吸液样本中。我们将对每一个人进行测试 单独的标志物，以及其他临床和流行病学特征，用于与肝细胞癌的关联 混合效应Logistic回归分析。从这项研究中获得的信息可能会打开治疗的前景 可延缓或避免肝硬变患者肝细胞癌的移植优先顺序的干预措施或新参数 有耐心的。

PROJECT SUMMARY/ABSTRACT In the United States, hepatocellular carcinoma (HCC) incidence and mortality rates are increasing among the most rapidly of all cancers. Cirrhosis, characterized by long-standing inflammation, is a well-defined pre-cancer lesion, although the transformation from cirrhosis to HCC is poorly understood. Currently, the only clinical option for the increasing, high-risk population of patients with liver cirrhosis is to watch and wait for HCC to develop. Thus, there is an urgent need to identify pathways for the progression of liver cirrhosis to HCC. Experimental data show that perturbations in the gut-liver axis are carcinogenic to the liver. Bile acids, produced in the liver and metabolized by gut bacteria are hepatocarcinogenic in mice, and lipopolysaccharide (LPS, a component of bacterial membranes) leaking from the gut causes liver cancer in mice. Our preliminary data show that deoxycholic acid (DCA, a secondary bile acid and gut metabolite) and intestinal fatty acid binding protein (I-FABP, a marker of enterocyte damage and gut permeability) are elevated, while several other bile acids and immune markers are reduced, in the plasma of cirrhotics with HCC compared to cirrhotics without HCC. In prior prospective cohort studies, we have demonstrated that markers related to LPS exposure (e.g. sCD14) and chronic immune activation/inflammation (e.g. interleukin 6 & IFNγ-induced protein 10) are elevated prior to the development of lymphoma in high risk HIV-infected populations by several years. In the proposed study, we will examine the contributions of bile acids, markers of LPS exposure, and immune response to LPS to HCC in a high-risk clinical cohort of 370 cirrhotic patients who are followed prospectively for HCC development. We will recruit study participants for two years from the large pool of patients awaiting a liver transplant at two large transplant centers in Los Angeles. We expect that approximately 40% of our study population will be Hispanic, which will allow us to examine pathways for HCC in the demographic group that is at the highest risk for HCC and stands to gain the most from the proposed research. Study participants will provide baseline duodenal aspirate fluid, peripheral blood specimens, epidemiological data, nutritional data, and consent to access their medical charts. Mid-way through year four, we expect that 56 cohort members will have developed HCC over the follow-up period. We will design a nested case-control study to include 56 HCC cases and 112 cirrhotic controls (matched 2:1), and measure 7 candidate bile acids and 14 immune markers in in paired blood (serum) and duodenal aspirate fluid specimens from these participants. We will test each marker individually, and with other clinical and epidemiological characteristics, for association with HCC using mixed effects logistic regression. The information gained from this study may open prospects for therapeutic interventions or new parameters for transplant prioritization that could delay or avert HCC in the cirrhotic patient.