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