S-adenosylmethionine treatment in alcoholic cirrhosis

项目摘要 酒精性肝硬化是美国发病率和死亡率的主要原因。其中一个关键的驱动因素， 发病机制是肝甲硫氨酸腺苷转移酶1A（MAT1A）表达减少，导致 肝S-腺苷甲硫氨酸（SAMe）水平降低。SAMe水平的降低导致几个 不利的细胞内后果，包括促进免疫细胞中的炎症级联反应， 脂多糖（LPS）、氧化应激和内质网（ER）应激。那里 是广泛的临床前证据，支持使用SAMe在酒精性肝病，但人体试验使用 SAMe在酒精性肝硬化中没有提供明确的疗效证据。在西班牙进行的一项大型试验， 其中一名合作研究者（José Mato博士）显示SAMe治疗（1200 mg，分次给药，持续两年） 降低了晚期酒精中毒患者的死亡率，但这是一项事后分析， 机制进行了研究。在美国进行的一项较短（6个月）的试验结果是阴性的，但脱落率 非常高，并且需要禁欲才能留在试验中，这可能掩盖了SAMe效应 因为安慰剂组有明显改善，可能是由于禁欲。该应用程序涉及两个 美国的学术中心（洛杉矶的雪松-西奈医学中心和印第安纳州大学 医院），西班牙的一家研究机构（CIC bioGUNE），以及NIAAA内部肝脏研究科学家（Bin博士 Gao）检测酒精性肝硬化患者的SAMe。我们提出了一个随机双盲安慰剂 确定SAMe治疗酒精性肝硬化患者的疗效及其机制作用的对照试验 在真实的世界中，鼓励但不要求禁欲。此外，我们的目标是调查 SAMe的潜在机制，并使用新的代谢组学来跟踪对治疗的反应， 基线代谢组学谱与对SAMe的响应相关。提出了两个具体目标：目标1：我们 将在SAMe（1，200 mg/天，分两次给药）之间进行随机双盲安慰剂对照研究 分次给药）和安慰剂治疗酒精性肝硬化患者（Child A级和B级）24个月。的 主要终点将是组间任何原因的死亡率。关键次要终点为 肠通透性、血清内毒素、免疫细胞活化标志物和肝脏特异性 mortality.使用液相色谱-质谱法（LC-MS）和NMR的互补代谢组学 基线时的光谱和试验结束时的NMR将评估对治疗的反应， 谱预测对SAMe的响应。目的2：我们将确定SAMe处理对氧化应激的影响， 和ER应激诱导的线粒体DNA和细胞色素P450 2E1富集的微粒。我们的应用程序 是新颖的，并且与未满足需要的研究领域相关，在该领域中没有被证明有效的治疗方法。 此外，我们的建议可能揭示SAMe在酒精性肝硬化中作用的新机制， 代谢组学在这些患者的个性化治疗中的应用。

Project Summary Alcoholic cirrhosis is a leading cause of morbidity and mortality in the US. One of the key drivers in its pathogenesis is the reduction in hepatic methionine adenosyltransferase 1A (MAT1A) expression resulting in the reduction in hepatic S-adenosylmethionine (SAMe) levels. The reduction in SAMe level leads to several adverse intracellular consequences, which include promoting the inflammatory cascades in immune cells such as macrophages by lipopolysaccharides (LPS), oxidative stress and endoplasmic reticulum (ER) stress. There is extensive preclinical evidence that support the use of SAMe in alcoholic liver disease but human trials using SAMe in alcoholic cirrhosis have not provided clear evidence of efficacy. One large trial conducted in Spain by one of the co-investigators (Dr. José Mato) showed SAMe treatment (1200 mg in divided doses for two years) reduced the mortality of less advanced alcoholic cirrhotics but this was done as a post-hoc analysis and no mechanism was investigated. A shorter (six months) trial done in the U.S. was negative but the dropout rate was very high and abstinence was required to stay in the trial, which may have obscured the SAMe effect since placebo group had marked improvement likely due to abstinence. This application involves two academic centers in the United States (Cedars-Sinai Medical Center in Los Angeles and Indiana University Hospital), a research institute in Spain (CIC bioGUNE), and NIAAA intramural liver research scientist (Dr. Bin Gao) to examine SAMe in humans with alcoholic cirrhosis. We propose a randomized double-blind placebo controlled trial to determine the efficacy of SAMe and its mechanistic effects in patients with alcoholic cirrhosis in the real world setting by encouraging but not requiring abstinence. In addition, we aim to investigate the underlying mechanism(s) of SAMe and use novel metabolomics to follow response to treatment and examine if baseline metabolomics profiles correlate with response to SAMe. Two specific aims are proposed: Aim 1: we will perform a randomized double-blind placebo controlled study between SAMe (1,200 mg/day given in two divided dose) and placebo, in patients with alcoholic cirrhosis (Child class A and B) for 24 months. The primary endpoint will be the mortality of any causes between groups. The key secondary endpoints are the changes in intestinal permeability, serum endotoxin, markers of immune cell activations, and liver-specific mortality. Complementary metabolomics using liquid-chromatography-mass spectrometry (LC-MS) and NMR spectroscopy at baseline and NMR at the end of the trial will assess response to treatment and whether certain profiles predict response to SAMe. Aim 2: we will determine the effect of SAMe treatment on oxidative stress, and ER-stress induced mitochondrial DNA and cytochrome P450 2E1 enriched microparticles. Our application is novel and relevant to an un-met need area of research where no proven effective treatments are available. In addition, our proposal may unveil novel mechanistic insights on the effect of SAMe in alcoholic cirrhosis and the use of metabolomics in personalized treatment of these patients.