Liver Fibrosis, Inflammation & Oxidative Stress Markers

描述（由申请人提供）： 肝硬化是酗酒者死亡的主要原因。最近的实验性病理生理学研究提出了几种治疗方法，但其临床验证受到肝活检的要求，以确定疾病的阶段，治疗适应症和记录结果的阻碍。已经提出了各种循环标志物作为活检的替代品。本研究的具体目的是验证这些标志物，利用VA合作研究391中长达6年的789名酗酒者中收集的2，000多个连续肝活检和相应的血液样本，包括每月测量碳水化合物缺乏转铁蛋白以证实自我报告的酒精消费量。这项最近进行的试验评估了多不饱和磷脂酰胆碱（PPC），一种大豆提取物，对酒精性肝病的影响，其中1/3的患者合并丙型肝炎。肝脏病理学变化从脂肪肝到小静脉周围和间隔纤维化和肝硬化，伴有不同程度的炎症。将确定这些病变与以下提出的纤维化循环标志物的相关性：层粘连蛋白、腱生蛋白、tll型前胶原和胶原IV和VI。还将测量降解纤维化组织的酶的活性，例如金属蛋白酶及其抑制剂。此外，还将评估可能加速肝脏疾病进展的肝脏参数，如细胞角蛋白。还将评价影响纤维形成以及炎症的细胞因子，例如TNF α和TGF-β。一个主要的致病因素是由酒精诱导的细胞色素P450（CYP 2 E1）产生的自由基引起的氧化应激。因此，将评价氧化应激标志物（4-羟基壬烯醛、F2-异前列烷和丙二醛）与肝脏中CYP 2 E1诱导程度的相关性。一旦得到验证，这些标记物可以在未来的研究中用于检测易受CYP 2 E1毒素激活药物影响的受试者。作为特定病变（如肝硬化）标志物的对照，我们将使用无特定肝病患者的相同标志物值。 总之，一个可用的连续肝活检和每月血液样本库，收集与详细的临床信息，提供了一个独特的机会，以确定哪些循环标志物可以作为肝活检的部分替代品，从而优化诊断，预防和治疗酒精性肝损伤。

DESCRIPTION (provided by applicant): Liver cirrhosis is a major cause of mortality in alcoholics. Recent experimental pathophysiotogic studies suggest several therapeutic approaches but their clinical verification is hampered by the requirement of liver biopsies to establish the stage of the disease, the therapeutic indications and documentation of outcome. Various circulating markers have been proposed as substitute for biopsies. The specific aim of the present study is to validate these markers, taking advantage of over 2,000 sequential liver biopsies and corresponding blood samples collected in 789 alcoholics studied for up to 6 years in VA Cooperative Study 391, including monthly measurements of carbohydrate deficient transferrin to substantiate the self-reported alcohol consumption. This recently conducted trial assessed the effects of polyunsaturated phosphatidylcholine (PPC), a soybean extract, on alcoholic liver disease, with superimposed hepatitis C in 1/3 of the patients. The liver pathology varied from fatty liver to perivenular and septal fibrosis and cirrhosis, with variable degrees of inflammation. Correlation of these lesions with the following proposed circulating markers of fibrosis will be determined: laminin, tenascin, procollagen type tll and collagen IV and VI. The activity of enzymes that degrade fibrotic tissue, such as metalloproteinases and their inhibitors, will also be measured. In addition, hepatic parameters with the potential to prognosticate progression of liver disorders, such as cytokeratins, will be assessed. Cytokines that affect fibrogenesis as well as inflammation, e.g. TNFalpha and TGF-beta will also be evaluated. One major pathogenic factor is oxidative stress resulting from free radicals generated by alcohol-induced cytochrome P450 (CYP2E1). Accordingly, the correlation of markers of oxidative stress (4-hydroxynonenal, F2-isoprostanes and malondialdehyde) with the degree of CYP2E1 induction in the liver will be evaluated. Once validated, these markers could serve in future studies to detect subjects vulnerable to drugs activated to toxins by CYP2E1. As controls for the markers of a specific lesion (such as cirrhosis), we will use the values of the same markers in patients without the specific liver disease. In conclusion, an available bank of sequential liver biopsies and monthly blood samples, collected in association with detailed clinical information, offers a unique opportunity to establish which circulating markers can serve as partial substitute for liver biopsies, thereby optimizing the diagnosis, prevention and treatment of alcoholic liver injury.