Liver Defatting: An Alternative Approach to Enable Steatotic Liver Transplantation

Abstract

Macrovesicular steatosis in greater than 30% of hepatocytes is a significant risk factor for primary graft nonfunction due to increased sensitivity to ischemia reperfusion (I/R) injury. The growing prevalence of hepatic steatosis due to the obesity epidemic, in conjunction with an aging population, may negatively impact the availability of suitable deceased liver donors. Some have suggested that metabolic interventions could decrease the fat content of liver grafts prior to transplantation. This concept has been successfully tested through nutritional supplementation in a few living donors. Utilization of deceased donor livers, however, requires defatting of explanted organs. Animal studies suggest that this can be accomplished by ex vivo warm perfusion in a time scale of a few hours. We estimate that this approach could significantly boost the size of the donor pool by increasing the utilization of steatotic livers. Here we review current knowledge on the mechanisms whereby excessive lipid storage and macrosteatosis exacerbate hepatic I/R injury, and possible approaches to address this problem, including ex vivo perfusion methods as well as metabolically induced defatting. We also discuss the challenges ahead that need to be addressed for clinical implementation.

MicroRNAs in liver tissue engineering — New promises for failing organs

“…Strategies to improve such non-optimal organs imply donor pretreatments and ex vivo perfusion techniques to rescue Advanced Drug Delivery Reviews 88 (2015) [67][68][69][70][71][72][73][74][75][76][77] ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "MicroRNAs in tissue engineering and regenerative medicine". the diseased organs [3,[5][6][7]. On the other hand, tissue-engineered solutions have been developed and are under development to temporarily or definitively support or replace the diseased liver.…”

Assessing Steatotic Liver Function after Ischemia-Reperfusion Injury by In Vivo Multiphoton Imaging of Fluorescein Disposition

“…Because the obese population has been increasing, the number of individuals with hepatic steatosis has been growing accordingly, which may impact the availability of suitable liver donors (Nativ et al, 2012). Steatotic liver grafts are more susceptible to ischemia-reperfusion (I/R) injury, with increased lipid peroxidation (Vairetti et al, 2009;Ben Mosbah et al, 2010), increased release of proinflammatory mediators (Selzner and Clavien, 2001;Vairetti et al, 2009), and increased neutrophil infiltration (Nakano et al, 1997).…”

Review on Liver Steatosis and its Impact on Liver Transplantation

“…This would be greatly facilitated if a suitable cell culture model of hepatic steatosis were available to perform both screening and mechanistic studies in an efficient manner, prior to testing in actual livers. 106 While many challenges need to be overcome, liver defatting is a potentially promising approach to reduce the sensitivity of steatotic livers to I/R injury, and a new modality that may enable the successful recovery of a large number of livers that would otherwise be discarded.…”

“…Liver defatting: Multiple studies described what is called "liver defatting", which have been performed in attempts to optimize the steatotic liver grafts prior to LT. 106,110 Combined measures (Dietary, exercise and drug therapy): A short-term intensive treatment with protein-rich diet (1000kcal/day), exercise (600 kcal/day), and bezafibrate (400mg/day) for 2-8weeks in a small trial of 11donors led to threefold decrease in MaS and reduced body weight and BMI. Alternatively, the consumption of omega-3 FAs for 1month was used to decrease MaS in three candidates for LDLT who had biopsy-proven hepatic MaS >30% prior to donation.…”

“…73,105 It is worth noting that none of these studies investigated the possibility of combining several pharmacological agents at once; therefore, it is possible that doing so would lead to a more dramatic decrease in sensitivity to I/R injury. 102,106 Surgical preconditioning: in which, the major blood vessels to the liver are clamped momentarily (Pringle manoeuvre). This has been shown to reduce lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation after subsequent I/R injury when applied to steatotic livers.…”