EFFECTS OF SAM IN PATIENTS WITH ALCOHOLIC LIVER DISEASE

描述(申请人提供)：来自对照动物研究的先前证据已经证实肝脏蛋氨酸代谢异常与酒精性肝病的发生有关，两项临床研究表明，S-腺苷蛋氨酸可能有效地促进中重度疾病患者的抗氧化防御和生存。肝脏SAM在ALD动物模型中缺乏，调节几个蛋氨酸循环途径，并上调谷胱甘肽的合成。这项研究的总体假设是ALD的严重程度与肝脏蛋氨酸代谢异常有关，并可通过SAM干预得到改善，总体目标是确定临床使用SAM治疗ALD的代谢基础和短期疗效。目的1比较40例缓解期酒精性肝病患者肝组织和血液中腺苷甲硫氨酸及其产物S同型半胱氨酸和其他蛋氨酸代谢产物的变化，并与40例非酒精性非肝病患者和20例健康人的血样进行对照。这些数据将用于确定 研究肝脏和血液中SAM、SAH和其他代谢物水平之间的关系，以及确定ALD及其严重程度对蛋氨酸代谢物的影响。具体目的二是在相同的40名ALD患者中展示SAM治疗的代谢和临床疗效，这些患者将随机接受SAM或安慰剂治疗，每天三次，持续6个月。每隔一段时间将采集血液样本，用于测量SAM、SAH和其他代谢物以及肝脏氧化损伤和功能的标志物。治疗前和治疗后的肝活检将通过计算机分级系统进行组织病理学评估。 这些数据将被用来确定SAM干预对蛋氨酸代谢的影响，并根据氧化损伤、肝功能和组织病理学的定量变化来建立其使用的理论基础。通过确认蛋氨酸代谢异常与临床、生化和病理疾病严重程度的关系，本研究将为确定SAM干预ALD的疗效奠定代谢基础。

DESCRIPTION (provided by applicant): Prior evidence from controlled animal studies has established the association of abnormal hepatic methionine metabolism and the development of alcoholic liver disease (ALD), and two clinical studies suggest that S-adenosylmethionine (SAM) may be efficacious in promoting anti-oxidant defense and survival in patients with moderately severe disease. Liver SAM is deficient in animal models of ALD, regulates several methionine cycle pathways, and up-regulates the synthesis of glutathione. The overall hypothesis of the proposed research is that the severity of ALD correlates with abnormal hepatic methionine metabolism and is improved by SAM intervention, and the overall objective is to define the metabolic rationale and short term efficacy of the clinical use of SAM in the treatment of ALD. Specific Aim I is to contrast the profiles of SAM, its product S-adenosylhomocysteine (SAH), and other methionine metabolites in liver biopsies and blood samples from 40 stable ALD patients contrasting with findings in 40 non-alcoholic non-liver disease patient controls and in blood samples from 20 healthy subjects. These data will be used to determine relationships between liver and blood SAM, SAH, and other metabolite levels and to define the effect of ALD and its severity on methionine metabolites. Specific Aim II is to demonstrate the metabolic and clinical efficacy of SAM treatment in the same 40 ALD patients who will be randomized to receive SAM or placebo in three daily doses over 6 mo. Blood samples at intervals will be used for measurements of SAM, SAH and other metabolites and markers of liver oxidative injury and function. Histopathology will be assessed by a computerized grading system in liver biopsies obtained before and after treatment. These data will be used to determine the effects of SAM intervention on methionine metabolism and to establish a rationale for its use according to quantitative changes in oxidative injury, liver function, and histopathology. By confirming the relationship of abnormal methionine metabolism to clinical, biochemical, and pathologic disease severity, the study will establish a metabolic basis for determining the efficacy of SAM intervention in ALD.