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: 10560540
• 负责人: ANDREW M. CAMERON
• 金额: $ 160.38万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560540
• 关键词: Abstinence; Accounting; Acute; Address; Adopted; Adoption; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Animals; Antibodies; Applications Grants; Articulation; Autoantibodies; Behavior Therapy; Behavioral; Biological; Caring; Cirrhosis; Clinical; Communities; Country; Critical Illness; Development; Disease; Ensure; Ethical Analysis; Ethical Issues; Ethics; Functional disorder; Guidelines; Heavy Drinking; Human; Immune system; Immunologics; In Vitro; Intervention; Knowledge; Length; Life; Liver; Liver Regeneration; 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; Selection Criteria; Series; Severity of illness; Standardization; Steroids; Suspensions; Syndrome; Therapeutic; Time; Tissue Banks; Tissues; Transplant Recipients; Transplantation; United States; United States National Institutes of Health; Work; alcohol exposure; alcohol research; candidate selection; cohort; collaborative approach; end stage liver disease; evidence base; improved; insight; interdisciplinary approach; liver transplantation; mortality; multidisciplinary; novel; organ allocation; patient subsets; pharmacologic; 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.

概括 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 考虑到移植后累犯以及临床的可能性，每年在美国进行一次。 为了改善移植前的禁欲，移植中心要求在移植前有 6 个月的清醒记录。 然而，有一部分患有严重酒精性肝炎 (SAH) 的患者需要紧急治疗。 如果他们对基于类固醇的药物治疗没有反应，LT 是唯一挽救生命的方法。 如果没有 LT，SAH 患者的三个月死亡率为 70-80%，因此 6 个月的清醒规则可以排除这些情况。 我们通过一项试点研究和世界上最大的系列研究证明了 LT 对于挽救生命的患者。 对于 6 的酒精性肝硬化患者，SAH 与 LT 相比具有出色的短期生存率和相似的累犯率 几个月的清醒。 SAH 的 LT 很少见且有争议，因为在大多数中心，标准的 6 个月清醒期是移植 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，并且 累犯的不可靠预测 为了尽量减少公众对器官捐献的看法的风险，需要仔细分析 LT 选择标准对于确保分配给那些具有最大生存效益和最高机会的人至关重要 以道德的方式保持清醒的候选人选择标准对于识别 SAH 至关重要。 将从 LT 中显着受益的患者。 在本拨款提案中，我们将量化结果并确定 SAH LT 后生存不良的风险因素。 比较 SAH 患者与其他终末期肝病患者的 LT 结局，并确定伦理问题和 评估公众对 SAH 患者早期 LT 的看法，以制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累犯情况，并比较不同的情况 我们还建议研究移植肝脏的行为和药物干预措施，以确定最佳护理实践。 接受移植的患者表征蛋白质、抗体和分子水平的变化，这可能有助于 最后，我们寻求结合使用小动物肝移植模型。 与酒精接触来回答有关肝再生、干细胞和免疫系统的问题，这些问题是无法回答的 这项工作目前正在我们新成立的“DELTA”的主持下进行。 约翰霍普金斯大学的“中心”（酒精性肝炎早期肝移植的实施）。 与其他 LT 接受者相比，SAH 中 LT 的生存获益的量化将为以下方面的支持提供背景： 除了公众的识别之外，医学界还对 LT 的扩展进行了这些临床方面的研究。 关于 SAH 早期 LT 的意见将有助于在国家层面上推进 SAH 患者的治疗。