MICA: Novel approaches in optimising steatotic livers for transplantation

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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.