Steatotic Donor Transplant Livers: Preservation Strategies to Mitigate against Ischaemia-Reperfusion Injury

Abstract

Liver transplantation (LT) is the only definitive treatment for end-stage liver disease, yet the UK has seen a 400% increase in liver disease-related deaths since 1970, constrained further by a critical shortage of donor organs. This shortfall has necessitated the use of extended criteria donor organs, including those with evidence of steatosis. The impact of hepatic steatosis (HS) on graft viability remains a concern, particularly for donor livers with moderate to severe steatosis which are highly sensitive to the process of ischaemia-reperfusion injury (IRI) and static cold storage (SCS) leading to poor post-transplantation outcomes. This review explores the pathophysiological predisposition of steatotic livers to IRI, the limitations of SCS, and alternative preservation strategies, including novel organ preservation solutions (OPS) and normothermic machine perfusion (NMP), to mitigate IRI and improve outcomes for steatotic donor livers. By addressing these challenges, the liver transplant community can enhance the utilisation of steatotic donor livers which is crucial in the context of the global obesity crisis and the growing need to expand the donor pool.

Keywords: defatting; ischaemia-free liver transplantation; normothermic machine perfusion; organ preservation solution.

Figure 1

Pathophysiological mechanisms of cell injury and death occurring during cold preservation and reperfusion injury. Oxygen free radical generation results from the subsequent accumulation of ATP breakdown products including hypoxanthine. Cellular acidosis ensues and is characterised by an interruption of cellular mechanisms that are both energy and pH dependant. These include disruptions in function of transmembrane ion pumps (Na⁺/K⁺ and Ca²⁺) which are responsible for maintaining cellular integrity through regulation of intracellular ion composition. There is an influx of Na⁺, Cl^– and water with increased cell swelling and loss of membrane potential. Injury to the cell membrane is propagated by lysosomal enzymes (due to intracellular acidosis) and free radicals (due to oxidative injury). There is a rise in intracellular Ca²⁺ due to membrane pump failure causing activation of deleterious proteases and phospholipases. This initiates a cascade of mitochondrial membrane injury with release of cytochrome C with resultant apoptotic cell death. Overall, the mitochondrial dysfunction driven by acidosis, increasing intracellular Ca²⁺ and Fe²⁺ and lysosomal activation are significant contributors to the pro-oxidant milieu driving oxidative stress and reactive oxygen species (ROS) production at organ reperfusion. Figure modified from Fuller et al. [103]. Source: reproduced with permission from Elsevier [108].