MICA: Novel approaches in optimising steatotic livers for transplantation

肝病是唯一仍在逐年增加的主要死因，在过去20年里，死于肝病的人数翻了一番。肝移植是治疗终末期肝病的成功方法，但受供体器官供应的限制。由于供体短缺，英国每两年就有20%的患者在等待名单上被移除或死亡。因此，找出使更多器官可用于移植的方法是非常重要的。实现这一目标的一种方法是利用更多的“边缘”或次优肝脏，接受较差结果的潜在风险。脂肪肝移植后预后不佳，因此大量肝脏被丢弃。据信，脂肪肝特别容易受到与移植前冷却器官储存相关的损伤。英国和全世界的肥胖水平正以惊人的速度增长。与此同时，脂肪性肝病的发病率也在增加，据估计，33%的英国人患有非酒精性脂肪性肝病。因此，供体池中脂肪肝的增加是不可避免的，确定优化和挽救这些肝脏用于移植的方法是必不可少的。脂肪肝移植成功的关键可能在于器官的保存。目前的做法是用冰和专门的保存溶液冷却器官，称为静态冷藏（SCS）。新技术涉及到在正常体温下用机器维持肝脏，为肝脏提供氧气和营养，被称为恒温机器灌注（NMP）。我们认为，NMP将通过以下方式实现脂肪肝的安全移植：1)避免冷却的有害影响；并且，2)能够在肝脏移植前将去脂剂输送到灌注回路以去除肝脏中的脂肪。目前，牛津大学正在领导一项多中心随机对照试验，比较SCS和NMP作为一种保存技术。作为研究的一部分，已经移植了几个脂肪肝，它们提供了一个独特的机会来比较通过两种保存技术移植的脂肪肝的结果，并将其与正常的非脂肪肝进行比较。作为研究方案的一部分，在保存期之前和结束时以及在受体肝脏植入之后进行肝脏活检。我将分析这些活组织切片，并比较每组三个时间点的脂肪含量。我还将能够评估移植后与冷却相关的损伤程度，并比较SCS组和NMP组脂肪肝的损伤程度。比较各组移植后患者及器官预后。获得的结果将为NMP对脂肪肝的影响提供独特的见解，这些数据迄今尚未报道。我还计划获得20个未移植的肝脏，因为脂肪含量高而被丢弃。将获得组织样本，并在实验室环境中验证和提炼用于人类细胞的去脂剂，这些去脂剂先前已被证明可以减少脂肪大鼠肝细胞的脂肪含量。一旦这些药物被优化，我计划通过NMP电路将它们应用于整个肝脏。通过在灌注期间的特定时间点检查来自回路的活检和灌注样本的脂肪含量，我将能够确定NMP +/-去脂剂对脂肪肝的影响。我的目标是通过研究肝脏中脂肪分解的关键过程来了解肝脏中脂肪分解的过程。通过以上实验，我计划证明NMP与去脂剂的联合使用可以实现安全可靠的脂肪肝移植。这将导致更多的肝脏被移植，并最终挽救生命。

Liver disease is the only major cause of death still increasing year-on-year and the number of people dying from liver disease has doubled in the last 20 years. Liver transplantation is a successful treatment for end-stage liver disease but is limited by donor organ availability. As a result of this donor shortage, 20% of patients are removed from, or die whilst on the UK waiting list every 2 years. It is therefore of great importance to identify ways of making more organs available for transplantation. One way of achieving this is through the utilisation of more "marginal" or suboptimal livers, accepting the potential risk of poorer outcomes. Fatty livers derive poor outcomes when transplanted and as a result, a large number are discarded. It is believed that fatty livers are particularly susceptible to the damage associated with cooling the organ for storage prior to transplantation. Obesity levels in the UK and worldwide are increasing at an alarming rate. With this, comes an increasing incidence of fatty liver disease and it is estimated that 33% of the UK population suffer from non-alcoholic fatty liver disease. An increase of fatty livers in the donor pool is therefore inevitable and identifying methods of optimising and salvaging these livers for transplantation is essential. The key to successful transplantation of fatty livers may lie in organ preservation. Current practice involves cooling the organ with ice and a specialised preservation solution, termed static cold storage (SCS). New technology involves maintaining the liver on a machine that provides oxygen and nutrition to the liver at normal body temperature, known as normothermic machine perfusion (NMP). We believe that NMP will allow the safe transplantation of fatty livers by: 1) avoiding the deleterious effects of cooling; and, 2) enabling the delivery of de-fatting agents to the perfusion circuit to remove the fat from the liver before it is transplanted. At present the University of Oxford are leading a multi-centre randomised controlled trial comparing SCS and NMP as a preservation technique. Several fatty livers have been transplanted as part of the study and they provide a unique opportunity to compare outcomes from fatty livers transplanted via the two preservation techniques and compare them to normal, non-fatty livers. As part of the study protocol, liver biopsies are obtained prior to and at the end of the preservation period and following implantation of the liver in the recipient. I will analyse these biopsies and compare the fat content at the three time points in each group. I will also be able to assess the degree of damage associated with cooling after transplantation and compare this for fatty livers in the SCS and NMP groups. Post-transplant patient and organ outcomes will be compared in each group. The results obtained will provide a unique insight into the effects of NMP on fatty human livers, data which has not been reported to date.I also plan to obtain 20 livers which have not been transplanted and discarded due to a high fat content. Tissue samples will be obtained and de-fatting agents which have previously shown to reduce the fat content of fatty rat liver cells will be validated and refined for human cells in a laboratory setting. Once the agents have been optimised, I plan to apply them to whole livers through the NMP circuit. By examining biopsy and perfusate samples from the circuit for fat content at specific time points during perfusion I will be able to establish the effect on NMP +/- de-fatting agents on fatty livers. I aim to gain an understanding of the process by which de-fatting occurs in the liver by investigating key processes of fat breakdown in the liver.Through the above experiments I plan to demonstrate that a combination of NMP and de-fatting agents will allow the safe and reliable transplantation of fatty livers. This will result in more livers being transplanted and ultimately, lives saved.