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

多种族肝硬化队列中的肠道相关标志物和肝细胞癌

• 批准号: 9318169
• 负责人: Shehnaz Khursheed Hussain
• 金额: $ 42.12万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-22 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318169
• 关键词: Acids; Address; Aspirate substance; Automobile Driving; B-Cell Activation; B-Lymphocytes; Bacteria; Bile Acids; Biological Markers; Blood Circulation; Blood specimen; CD14 gene; CXCL13 gene; Cell membrane; Characteristics; Chronic; Cirrhosis; Clinical; Cohort Studies; Consent; Data; Deoxycholic Acid; Development; Diabetes Mellitus; Duodenum; Enterocytes; Epidemiology; Etiology; FABP2 gene; Functional disorder; HIV; Hepatic; Hepatocarcinogenesis; Hispanics; Human; Immune; Immune response; Immunologic Markers; Incidence; Individual; Inflammation; Interferon Type II; Interleukin-1 beta; Interleukin-18; Interleukin-2; Interleukin-6; Interleukins; Investigation; Knowledge; Lesion; Lipopolysaccharides; Liquid substance; Liver; Liver Cirrhosis; Liver diseases; Logistic Regressions; Los Angeles; Lymphoma; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Medical; Membrane; Molecular; Mus; Nested Case-Control Study; Nutritional; Obesity; Organ Donor; Participant; Pathway interactions; Patients; Permeability; Plasma; Population; Population Attributable Risks; Primary carcinoma of the liver cells; Prospective cohort study; Proteins; Public Health; Recruitment Activity; Recurrence; Research; Risk; Risk Factors; Sampling; Serum; Soil; Specimen; System; TNF gene; Taurocholic Acid; Testing; Therapeutic Intervention; Time; Transplant Recipients; Transplantation; United States; carcinogenicity; clinical risk; cohort; design; epidemiologic data; follow-up; high risk; high risk population; immune activation; immunogenic; improved outcome; individual patient; inflammatory milieu; insight; intestinal fatty acid binding protein; liver transplantation; member; mortality; neoplastic; nonalcoholic steatohepatitis; pandemic disease; patient population; peripheral blood; prevent; prospective; response biomarker; study population; zonulin

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.

项目总结/摘要 在美国，肝细胞癌（HCC）的发病率和死亡率在美国的大部分地区都在增加。 最快的癌症。肝硬化以长期炎症为特征，是一种明确的癌前病变 病变，虽然从肝硬化到HCC的转化知之甚少。目前，唯一的临床 对于越来越多的肝硬化高危人群， 开发.因此，迫切需要确定肝硬化发展为HCC的途径。 实验数据表明，肠-肝轴的扰动对肝脏是致癌的。胆汁酸， 在肝脏中产生并由肠道细菌代谢的脂多糖在小鼠中是肝癌， (LPS细菌膜的一种成分）从肠道泄漏导致小鼠肝癌。我们的初步 数据显示脱氧胆酸（DCA，二级胆汁酸和肠道代谢物）和肠脂肪酸 结合蛋白（I-FABP，肠上皮细胞损伤和肠道通透性的标志物）升高，而一些 与原发性肝癌患者相比， 没有HCC。在先前的前瞻性队列研究中，我们已经证明与LPS暴露相关的标志物 (e.g. sCD 14）和慢性免疫激活/炎症（例如白细胞介素6和IFNγ诱导的蛋白10）是 在高风险HIV感染人群中，在淋巴瘤发展之前升高数年。在 建议的研究，我们将检查胆汁酸，LPS暴露的标志物，和免疫的贡献， 在前瞻性随访的370例肝细胞癌患者的高危临床队列中， HCC的发展。我们将从大量等待治疗的患者中招募研究参与者，为期两年。 在洛杉矶的两个大型移植中心进行肝脏移植。我们预计大约40%的研究 人口将是西班牙裔，这将使我们能够检查HCC在人口统计学组中的途径， 患肝癌的风险最高，并且从拟议的研究中获益最多。研究参与者将 提供基线十二指肠穿刺液、外周血标本、流行病学数据、营养数据， 并同意查看他们的病历在第四年的中期，我们预计56名队列成员将 在随访期间发生HCC。我们将设计一项巢式病例对照研究，纳入56例HCC 112例正常对照组（2：1配对），测定了112例正常对照组的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）和十二指肠抽吸液标本中。我们将测试每个 单独标记，并与其他临床和流行病学特征，用于与HCC的关联，使用 混合效应logistic回归从这项研究中获得的信息可能会开辟治疗的前景。 干预措施或移植优先级的新参数，可能会延迟或避免HCC的发生。 病人