Hepatopulmonary Syndrome Investigative Group

描述（由申请人提供）： 慢性肝病及其并发症导致显著的发病率和死亡率，并在美国排名前十位的死亡原因之一。一种独特的并发症是肝硬化综合征（HPS），其在8-15%的肝硬化患者中发现，并且当肺内微血管扩张导致低氧血症时产生。HPS没有有效的治疗方法。肝移植是唯一的治疗选择，尽管HPS患者的围手术期死亡率似乎高于无HPS的患者，特别是在严重时。尽管HPS的患病率和UNOS政策增加移植的优先级，一旦中度低氧血症由于HPS是目前，基本问题和缺乏前瞻性的数据仍然流行病学，自然史，发病机制，治疗和移植的疗效。这些问题和这种疾病的独特性质突出了发展具有特定经验和兴趣的肝移植中心网络来研究这种综合征的重要性。在HPS模型中的实验工作为探索特定的遗传多态性作为易感性的贡献者和定义是否pendrifylline改善气体交换异常提供了理论基础。该项目的广泛目标是了解HPS的流行病学，自然史和发病机制，以最大限度地提高患者的预后并开发有效的治疗方法。为实现这一目标，将实现以下具体目标。在目标1中，我们将建立一个具有晚期肝病、肝移植和肺血管疾病专业知识的学术中心联盟，通过a）开发组织基础设施，B）定义诊断标准和c）标准化评估和建立临床组织和标本采集来研究HPS。在目标2中，我们将利用该联盟研究HPS的临床结局、发病机制和治疗，方法是：a）启动前瞻性评价、数据和标本收集以及临床随访，B）确定特定候选基因中的遗传多态性是否与HPS易感性相关，以及c）设计并启动一项在重度HPS中使用戊氨酰茶碱的开放标签先导试验。3-HPS调查组将使用完成这些目标所获得的数据来设计和提交R 01申请。

DESCRIPTION (provided by applicant): Chronic liver disease and its complications cause significant morbidity and mortality and rank among the top ten causes of death in the United States. One unique complication is the hepatopulmonary syndrome (HPS) which is found in 8-15% of patients with cirrhosis and results when intrapulmonary microvascular dilatation results in hypoxemia. There are no effective medical therapies for HPS. Liver transplantation is the sole treatment option, although peri-operative mortality appears higher in patients with HPS than in patients without HPS, particularly when severe. Despite the prevalence of HPS and the UNOS policy of increasing priority for transplantation once moderate hypoxemia due to HPS is present, fundamental questions and a lack of prospective data remain regarding epidemiology, natural history, pathogenesis, therapy and the efficacy of transplantation. These questions and the unique nature of this disorder highlight the importance of developing a network of liver transplantation centers with specific experience and interest to study this syndrome. Experimental work in HPS models provides a rationale for exploring specific genetic polymorphisms as contributors to susceptibility and for defining whether pentoxifylline ameliorates gas exchange abnormalities. The broad goal of this project is to understand the epidemiology, natural history, and pathogenesis of HPS in order to maximize patient outcomes and develop effective therapies. To accomplish this goal, the following specific aims will be undertaken. In Aim 1, we will establish an alliance of academic centers with expertise in advanced liver disease, liver transplantation and pulmonary vascular disease to study HPS by a) developing an organizational infrastructure, b) defining diagnostic criteria and c) standardizing evaluation and establishing clinical tissue and specimen acquisition. In Aim 2, we will use the alliance to investigate clinical outcomes, pathogenesis and therapy of HPS by a) initiating prospective evaluation, data and specimen collection and clinical follow up, b) defining if genetic polymorphisms in specific candidate genes are associated with susceptibility to HPS and c) designing and initiating an open label pilot trial of pentoxifylline in severe HPS. 3-he data obtained from completion of these aims will be used to design and submit an R01 application by the HPS Investigative Group.