Normothermic Machine Perfusion Can Salvage Fatty Livers For Transplantation

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SAN FRANCISCO – Data from a new study presented this week at The Liver Meeting® – held by the American Association for the Study of Liver Diseases – found that using normothermic machine perfusion to preserve steatotic livers leads to altered lipid structure and metabolism and may result in more successful transplantation of these organs.

Steatotic, or fatty, livers may lead to poor outcomes after transplant. As a result, many of these organs are discarded. The global obesity epidemic will likely increase the proportion of steatotic livers in the donor pool. One potential method to salvage these livers for transplantation is normothermic machine perfusion, which maintains the liver in a fully functioning state ex situ, providing oxygen and nutrition at 98.6°F (37°C). This allows functional liver assessment and provides the potential for therapeutic interventions that may optimize the graft.

Researchers at the University of Oxford in the United Kingdom evaluated the impact of normothermic machine perfusion and de-fatting adjuncts on human steatotic livers and studied how grafts could be enhanced to enable successful transplantation.

“Unfortunately, due to a shortage of suitable donor livers, many patients die while awaiting liver transplantation. Identifying methods to maximize the donor pool by facilitating the safe and reliable transplantation of higher-risk livers are, therefore, of great importance,” says Carlo Ceresa, MBChB, MRCS, clinical research training fellow at the University of Oxford, and the study’s co-author. “Steatotic (fatty) livers form the greatest proportion of organ discards, and the ability to salvage these livers for transplantation would, therefore, be of great benefit.”

The researchers selected 16 human livers that had been declined for transplantation due to steatosis. The livers were perfused on a normothermic, oxygenated, blood-based circuit for 48 hours. The livers were divided into three groups: Six were perfused with normothermic machine perfusion alone, five were perfused with normothermic machine perfusion plus lipid apheresis filtration, and five were perfused with normothermic machine perfusion, lipid apheresis filtration and de-fatting agents. Donor demographics and pre-perfusion total macrovesicular steatosis levels were similar between all three groups of livers. All the livers demonstrated similar patterns of metabolic and synthetic function, ensuring valid comparisons of the fat metabolism based on these interventions.

The researchers found that adding a lipid apheresis filter to normothermic machine perfusion resulted in a significant reduction in circulating triglycerides by 48 hours compared to using normothermic machine perfusion alone. This reduction was also seen when comparing the livers perfused with a lipid apheresis filter and de-fatting agents and those perfused with normothermic machine perfusion alone. The lipid apheresis filter groups also demonstrated a significant reduction in perfusate total cholesterol compared to the group perfused with normothermic machine perfusion alone.

In the livers where de-fatting agents were added, there was an increase in median fatty acid oxidation compared to the other two groups. This group of livers also showed an average reduction in tissue triglyceride level, a significant finding compared to the other two groups.

The study’s findings demonstrate that normothermic machine preservation of steatotic livers for 48 hours shows altered lipid structure and metabolism and may result in more successful transplantation of these organs.

“We were able to significantly reduce the amount of DNL fatty acids in the liver over 48 hours by changing glucose and insulin concentrations. This resulted in an overall reduction of liver fat,” explains Dr. Ceresa. “Furthermore, through the addition of l-carnitine, we were able to increase mitochondrial fatty acid oxidation, whereby the liver can use fatty acids for energy production. Next, we would like to plan a clinical trial to establish whether clinical outcomes can be improved through these ex situ interventions on steatotic livers. It will be important to establish if all steatotic livers can be salvaged and if not, what steps can be taken to do so. Through further gene expression analysis, we hope to identify other potential drug targets to explore in the pursuit of de-fatting.”

Dr. Ceresa will present these findings at AASLD’s press conference in Room 312-314 at the George R. Moscone Convention Center in San Francisco on Saturday, November 10 from 4:00 PM – 5:30 PM. The study entitled “Exploring the Structural and Functional Effects of Normothermic Machine Perfusion and De-Fatting Interventions on Human Steatotic Livers” will be presented on Sunday, November 11 at 8:00 AM in Hall D. The corresponding abstract (number 0003) can be found in the journal, HEPATOLOGY.