PENTOXIFYLLINE FOR CIRRHOTIC PATIENTS WITH HEPATOPULMONARY SYNDROME

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。慢性肝病及其并发症导致严重的发病率和死亡率，是美国十大死亡原因之一。一个独特的并发症是肝肺综合征（HPS），在8-15%的肝硬化患者中发现，当肺内微血管扩张导致低氧血症时就会发生。目前还没有有效的治疗HPS的药物。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非HPS患者，特别是在严重的情况下。尽管HPS普遍存在，而且一旦HFS引起中度低氧血症，UNOS的政策就会增加移植的优先级，但关于流行病学、自然史、发病机制、治疗和移植疗效的基本问题和缺乏前瞻性数据仍然存在。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。HPS模型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以及确定己酮茶碱是否改善气体交换异常提供了理论依据。该项目的总体目标是了解HPS的流行病学、自然史和发病机制，以便最大限度地提高患者的治疗效果并开发有效的治疗方法。为实现这一目标，将采取以下具体目标。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)建立组织基础设施，b)定义诊断标准，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，我们将利用该联盟来研究HPS的临床结果、发病机制和治疗方法：a)启动前瞻性评估、数据和标本收集以及临床随访；b)确定特定候选基因的遗传多态性是否与HPS易感性相关；c)设计并启动一项开放标签的试点试验，用于治疗严重HPS。从完成这些目标中获得的数据将用于设计和提交HPS调查小组的RO-1申请。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 HFS 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. The data obtained from completion of these aims will be used to design and submit an RO-1 application by the HPS Investigative Group.