Multidisciplinary approach to study of patients with Severe Alcoholic Hepatitis Undergoing Liver Transplantation

摘要 酒精性肝病是肝移植(LT)最常见的适应症之一，占肝移植的四分之一以上 在美国每年演出一次。考虑到对移植后复发的担忧，以及临床上 改善移植前禁欲，移植中心要求6个月有文件记录的戒酒情况 中校。然而，一部分正在接受治疗的重型酒精性肝炎(SAH)患者需要紧急和 积极的医疗管理。如果他们对以类固醇为基础的治疗没有反应，LT是唯一的救命药物 选择。如果没有LT，SAH患者三个月的死亡率为70%-80%，因此6个月的戒酒规则排除了这些 患者来自救命的LT。我们已经通过一项试点研究和世界上最大的系列证明，LT for 在酒精性肝硬变患者中，SAH的短期存活率和复发率与LT相似，后者为6% 几个月的戒酒时间。 对于SAH的治疗是罕见的，也是有争议的，因为在大多数中心，标准的6个月戒酒期是一种移植 候选人资格要求。然而，批评6个月标准的人强调，这是一个武断的时间长度和 不可靠的累犯率预测指标。为了尽量减少公众对器官捐赠的认知风险，仔细分析 LT选择标准是确保分配给那些具有最大生存利益和最高机会的人的关键 保持清醒。以合乎道德的方式选择合适的候选人标准，对于确定选定的SAH至关重要 将从LT中显著受益的患者。 在这项赠款提案中，我们将量化结果，并确定SAH中LT术后存活率较低的风险因素。我们会 比较SAH患者和其他终末期肝病患者的肝移植结果，并确定伦理问题和 评估公众对SAH患者早期肝移植的意见，以努力确定更合理的国家政策。 此外，我们建议更严格地检查移植后患者的再犯罪率，并比较不同的 行为和药物干预，以确定最佳实践护理。我们还建议研究从 接受移植的患者在蛋白质、抗体和分子水平上的变化可能有助于 阐明蛛网膜下腔出血的病理生理学。最后，我们寻求利用小动物模型的肝移植联合 通过酒精暴露回答有关肝脏再生、干细胞和免疫系统的问题，这些问题不可能 直接从我们的病人那里得到答复。这项工作现在是在我们新成立的德尔塔航空公司的主持下进行的 约翰霍普金斯大学的“酒精性肝炎早期肝脏移植”项目。 将自发性蛛网膜下腔出血患者接受肝移植的生存益处与其他接受肝移植的患者进行比较，这将为 在这一人群中扩大LT的医学界。这些临床方面除了识别公众 关于SAH的早期LT的意见将允许在全国范围内推进SAH患者的治疗。

Summary Alcoholic liver disease is among the most common indications for liver transplant (LT), accounting for over ¼ of LTs performed annually in the United States. Given concerns of post-transplant recidivism and also the possibility for clinical improvement pre-transplant with abstinence, transplant centers have required 6 months of documented sobriety prior to LT. However, a subset of patients present for medical care with severe alcoholic hepatitis (SAH), requiring urgent and aggressive medical management. If they are unresponsive to steroid-based medical treatment, LT is the only life-saving option. Without LT, SAH patients have a 70-80% three-month mortality, therefore a 6-month sobriety rule precludes these patients from life-saving LT. We have demonstrated through a pilot study and the largest series in the world, that LT for SAH provides excellent short-term survival and similar recidivism rates in comparison to LT for alcoholic cirrhotics with 6 months sobriety. LT for SAH is rare and controversial, because at most centers, the standard 6-month sobriety period is a transplant candidacy requirement. However, critics of the 6 month criteria emphasize that it is an arbitrary length of time and an unreliable predictor of recidivism. In order to minimize risk to the public perception of organ donation, careful analysis of LT selection criteria is crucial to ensure allocation to those with the greatest survival benefit and highest chance of maintained sobriety. Appropriate candidate selection criteria, in an ethical manner, is paramount to identify select SAH patients who would significantly benefit from LT. In this grant proposal we will quantify outcomes and identify risk factors for poor survival after LT in SAH. We will compare outcomes of LT in SAH patients with other end-stage liver disease patients, and determine the ethical issues and evaluate public opinion regarding early LT in SAH patients in an effort to determine a more rational national policy. Further, we propose to more rigorously examine recidivism in our patients post-transplant and compare differing behavioral and pharmacologic interventions to identify best practice care. We also propose to study explanted livers from patients undergoing transplant to characterize at the protein, antibody, and molecular level changes that may help articulate the pathophysiology of SAH. Lastly, we seek to utilize small animal models of liver transplantation in conjunction with alcohol exposure to answer questions about liver regeneration, stem cells, and the immune system that cannot be answered directly from our patients. This work is now being conducted under the auspices of our newly formed “DELTA Center” (Delivery of Early Liver Transplant for Alcoholic Hepatitis) at Johns Hopkins. The quantification of survival benefit of LT in SAH compared to other LT recipients will provide a context for support in the medical community for LT expansion in this population. These clinical aspects in addition to the identification of public opinion regarding early LT for SAH will allow for advancement in the treatment of SAH patients at a national level.