PROJECT SUMMARY
Liver transplantation offers the only definitive cure for end stage liver disease, but the organ shortage leaves
half of the wait list untransplanted, and 15-20% die before a liver becomes available. Over 60,000 more a year
die without ever making it to the wait list. Unfortunately, many donated livers are untransplantable, 40-60%
because of fatty infiltration, or steatosis, which has increasingly adverse effects on outcomes with increasing
severity. At 60% steatosis, poor function prohibits transplantation, and even at lower percent fat, outcomes are
sub-optimal and exacerbated by other risk factors, such as extended cold ischemia times. Steatosis in donors
will only increase with time, as the prevalence of fatty liver disease continues to rise, having more than doubled
over the last 20 years.
Normothermic machine perfusion (NMP) has been shown to decrease discard rates of liver donated for
transplantation by 50%. NMP has even been used to rescue livers that have declined for transplantation in
smaller case series. Unfortunately, only a small number of livers in those reports were steatotic, and there is
very little information on the effect of NMP on steatotic livers. Poor outcomes after fatty liver transplantation are
attributed to abnormalities in the microvascular circulation and increased sensitivity to ischemia reperfusion injury
(IRI), including impaired ATP recovery, increased oxidative damage, and eventual hepatocyte death. As
steatotic livers have intrinsic defects, and not just ischemic injury, it is not clear whether NMP would have the
same salutary effect as it does for other types. We have performed research NMP on a large number of discarded
steatotic livers and that 50-80% of them would be considered viable for transplantation based on criteria used in
these trials that had good post-transplant outcomes, so we propose a small pilot study to transplant such livers
in appropriate recipients and also perform transcriptomic and metabolomic analysis, comparing transplantable
and non-transplantable livers.
The ability to safely transplant fatty livers would expand the donor pool significantly and save thousands of
patients per year. In addition, the transcriptomic and metabolomic data obtained from these models will provide
strategies for rescuing non-transplantable livers and new insight into the treatment and prevention of fatty liver
disease, ultimately decreasing the need for liver transplantation.