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

多学科方法对接受肝移植的重症酒精性肝炎患者进行研究

• 批准号: 10093975
• 负责人: ANDREW M. CAMERON
• 金额: $ 163.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093975
• 关键词: Abstinence; Accounting; Acute; Address; Adopted; Adoption; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Animals; Antibodies; Applications Grants; Autoantibodies; Behavior Therapy; Biological; Caring; Cirrhosis; Clinical; Communities; Country; Critical Illness; Development; Disease; Ensure; Ethical Analysis; Ethical Issues; Ethics; Exposure to; Functional disorder; Guidelines; Heavy Drinking; Human; Immune system; Immunologics; In Vitro; Institutes; Intervention; Knowledge; Length; Life; Liver; Liver Regeneration; Liver diseases; Medical; Molecular; Organ Donations; Outcome; Paper; Patient Selection; Patients; Perception; Phenotype; Pilot Projects; Policies; Population; Prognosis; Program Research Project Grants; Proteins; Proteomics; Protocols documentation; Provider; Public Opinion; Research; Resources; Risk Factors; Role; Savings; Selection Criteria; Series; Severity of illness; Standardization; Steroids; Suspensions; Syndrome; Therapeutic; Time; Tissues; Transplant Recipients; Transplantation; United States; United States National Institutes of Health; Work; alcohol exposure; alcohol research; base; behavioral pharmacology; candidate selection; cohort; collaborative approach; evidence base; insight; interdisciplinary approach; liver transplantation; mortality; multidisciplinary; novel; organ allocation; patient subsets; policy implication; post-transplant; preventable death; problem drinker; prospective; recidivism; response; risk minimization; sobriety; stem cells; substance abuse treatment; transplant centers; transplant model; treatment strategy

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.

总结 酒精性肝病是肝移植（LT）最常见的适应症之一，占LT的1/4以上。 每年在美国举行。考虑到移植后复发的担忧以及临床 移植前的改善与禁欲，移植中心要求6个月的清醒记录之前， 中尉然而，一部分患有严重酒精性肝炎（SAH）的患者需要紧急和 积极的医疗管理。如果他们对基于类固醇的药物治疗没有反应，LT是唯一的救命方法。 选项.没有LT，SAH患者有70-80%的3个月死亡率，因此6个月清醒规则排除了这些 我们已经通过一项试点研究和世界上最大的系列研究证明，LT SAH提供了极好的短期生存率和相似的复发率，与LT相比，酒精中毒患者有6 几个月的清醒 对于SAH的LT是罕见且有争议的，因为在大多数中心，标准的6个月清醒期是移植 候选人资格要求。然而，对6个月标准的批评者强调，这是一个任意的时间长度， 不可靠的累犯预测。为了尽量减少公众对器官捐赠的看法，仔细分析 LT选择标准对于确保分配给具有最大生存获益和最高机会的患者至关重要。 保持清醒。以符合伦理的方式，适当的候选人选择标准对于识别选择SAH至关重要 患者将从LT中获益。 在这项拨款申请中，我们将量化结果，并确定SAH患者LT后生存率差的风险因素。我们将 比较SAH患者与其他终末期肝病患者的LT结局，并确定伦理问题， 评估公众对SAH患者早期LT的意见，以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复发率，并比较不同的复发率。 行为和药物干预，以确定最佳实践护理。我们还建议研究来自 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SAH的病理生理学。最后，我们寻求利用小动物模型的肝移植， 与酒精接触，以回答有关肝再生，干细胞和免疫系统的问题，不能 直接从我们的病人那里得到答案。这项工作目前正在我们新成立的“DELTA”的主持下进行。 中心”（交付早期肝移植治疗酒精性肝炎）在约翰霍普金斯。 与其他LT接受者相比，SAH中LT的生存获益的量化将为支持 医学界支持在这一人群中推广LT。这些临床方面，除了公众的识别 关于SAH的早期LT的意见将允许在国家水平上推进SAH患者的治疗。