(620a) Metabolic Modeling of Ischemic Livers Using Nash Equilibrium

End-stage liver disease claims up to 60,000 lives annually in the US [1]. Many patients become too ill to tolerate liver transplantation, and even if transplantation were indicated, there is a severe shortage of viable donor organs and only 28% of the wait-listed patients receive transplants [2]. These numbers could be reduced dramatically should the donor organ pool be expanded by rendering marginal cases, such as ischemic livers from Donors obtained after Cardiac Death (DCD), transplantable. It is estimated that about 6,000 livers/yr are only marginally damaged by ischemia and could be resuscitated for transplantation [3]. There is evidence from our lab and others that Normothermic Extracorporeal Liver Perfusion (NELP) is a very promising approach for recovering marginal organs that would be otherwise rejected from the donor pool.

In this talk, a mathematical model for liver metabolism is presented in order to study the behavior of cold and warm ischemic livers. The model attributes include (1) the presence of co-factors, (2) electrolyte solution behavior, (3) charge balancing, (4) feedback, allosteric, and other forms of inhibition, (5) explicit enzyme-substrate reactions, (6) up/down regulation of enzymes, (7) effects of mutations and/or re-engineered enzymes, (8) up-scaled genetic information, and in many cases, (9) compartmentalization and transport between cell compartments. The resulting metabolic network is treated as a Nash Equilibrium, in which individual pathways are iteratively solved to quasi-steady-state chemical equilibrium until all feedback and transport variables are converged. Fluxes, concentrations, amounts generated/consumed, pH, energy charge, and other metrics are computed for all metabolites/co-factors, and enzymes in the model. In particular, energy charge and ATP production/consumption are used to measure the viability of the ischemic liver model at various temperatures and experimental data is used to validate the model.

1) Asrani, S.K., et al., Underestimation of liver-related mortality in the United States. Gastroenterology, 2013. 145(2): p. 375-82 e1-2.

2) Organ Procurement and Transplantation Network Accessed 15 January 2016; optn.transplant.hrsa.gov ]. Available from: optn.transplant.hrsa.gov.

3) Abt, P.L., et al., Survival following liver transplantation from non-heart-beating donors. Annals of Surgery, 2004. 239(1): p. 87-92.