番茄社区

SAN FRANCISCO -- Normothermic machine perfusion plus a variety of "de-fatting" interventions in steatotic livers was associated with improved liver function and a reduction in steatosis, a researcher said here.

A small study that examined a number of interventions on 18 "discarded" steatotic livers for transplant found that normothermic machine perfusion plus lipid apheresis filtration and "de-fatting" agents was linked with an increase in median fatty acid oxidation as measured by 3-hydroxybutyrate (a surrogate marker for oxidation) and a significant reduction in tissue triglyceride levels compared to livers only receiving one or two of these interventions, reported Carlo Ceresa, MBChB, of the University of Oxford in England.

At a press conference at the Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), he said that an estimated 1,000 out of the 6,000 livers for transplantation in the U.S. are discarded every year, as up to 20% of patients die while on the waiting list for new livers. In part due to the rising obesity epidemic, Ceresa explained that more fatty livers are winding up in the donor pool, but they are unable to be used.

"Identifying methods to salvage livers for transplantation are of great importance," Ceresa said.

Explaining the origins of the research, he said that when perfused discarded human steatotic livers were kept on a normothermic oxygenated circuit for 48 hours, he observed "alterations in the manipulations of liver fat metabolism."

Jordan Feld, MD, of the University of Toronto in Canada, who moderated the session but was not involved with the research, told 番茄社区 that intervening on an organ prior to transplantation "has been shown in other organs, but liver was a bit late to the game."

Indeed, Ceresa cited a randomized controlled trial published in Nature earlier this year, which , that met its primary endpoint. There was "less preservation injury and improved post-operative liver function" with normothermic machine perfusion, he said.

Researchers here examined 18 steatotic livers and perfused them for 48 hours, with frequent analysis and biopsies over that time period. They were divided into three treatment groups:

• Normothermic machine perfusion only
• Normothermic machine perfusion plus lipid apheresis filtration
• Normothermic machine perfusion plus lipid apheresis filtration and de-fatting agents

The apheresis filter removes lipoproteins, and can be used in patients with severe hypercholesterolemia that are refractory to medical treatment, with "the hypothesis that we could mechanically remove the fat that the liver releases," Ceresa said. The de-fatting agents were L-carnitine, which "increases fatty acid beta oxidation," and forskolin, to potentially reduce de novo lipogenesis, a process where the liver makes fat from non-lipid precursors, such as glucose.

Ceresa said that the goal was to try and attenuate the amount of glucose, and the amount of insulin, the main hormone that regulates de novo lipogenesis. This was the only group where a change in liver fat was observed -- and the only group with a reduction in de novo lipogenesis, he added.

Feld told 番茄社区 that "it's not that difficult to set up an ex vivo perfusion system," and that they are becoming more widely used in the U.S. and Europe.

"I think this has real potential clinical utility," he said. "The idea that you can now select organs more effectively and potentially intervene and affect the organ with perfusion is real."

"It's pretty cool," he said, explaining that while this might not become standard of care in every center, the model will soon start being employed to improve organ function ex vivo.

Ceresa said that because the drugs used were all straight-forward and commercially available, this intervention could be implemented quite easily.

"The crucial thing here is whether the drugs administered to the liver would be transmitted into the recipient, but if the agents are removed [prior to transplantation], it shouldn't have any implications on the recipient or the transplantation," he noted.

In the future, Ceresa suggested a potential clinical trial of only steatotic livers, where one group was treated with the intervention and one group only received a transplant, "just to see if there was [clinical] improvement seen in the recipient," he said.

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