We read with interest the manuscript from Jadhav et al published in the Journal of Clinical and Experimental Hepatology, which examined the association between graded donor liver steatosis and the severity of ischaemia-reperfusion injury (IRI) after liver transplantation (LT).1 The topic is of paramount importance because although steatotic livers form an ever-increasing proportion of the donor pool, steatosis is one of the leading causes for declining donor livers worldwide.2,3
Steatosis favours an exacerbated IRI leading to an impaired early functional recovery after LT.4 Mechanistically, fat-laden hepatocytes submitted to ischaemia during static cold storage consume the cellular energetic stores. The steatosis-related impaired mitochondrial functioning affects negatively the cellular energetic replenishment and aggravates the production of reactive oxygen species (ROS), causing exacerbated oxidative tissue injury and the activation of the inflammatory response.4 In addition, the microcirculatory dysfunction, probably associated with the reduced sinusoidal diameter secondary to compression by fat-laden hepatocytes, perpetuates ischaemia even after reperfusion and worsens the cellular injury induced by the production of more ROS and activation of Kupffer cells.4,5
The authors must be commended for examining in the clinical setting the impact of graded donor liver steatosis on the severity of IRI – assessed histologically on liver biopsies sampled after graft reperfusion. Whilst authors have not found statistically significant association between IRI and macrovesicular steatosis (MaS), they acknowledge this finding is limited to patients with mild steatosis (94.7% of patients included).1 Biopsy-proven severely steatotic deceased donor organs (>60% MaS) were excluded and only two moderately steatotic organs (30–60% MaS) were included.1 Importantly, both cold and warm ischaemia times were associated with the severity of IRI. These findings are in accordance with the current literature considering mildly steatotic organs safe for transplantation.4, 5, 6
A study conducted in the United Kingdom in 2015 associated the presence of moderate steatosis on postreperfusion biopsy with IRI severity.7 Although biopsy-determined IRI impacted on liver graft survival, there was no survival difference in accordance with the severity of the biopsy steatosis.7 This is a valid discussion in view of varying outcomes of studies on the use of moderately steatotic donor livers, particularly with respect to graft survival and early graft dysfunction.2,8 Most importantly, in another study, similar patient and graft survival with an increase in the rate of postoperative complications was reported for moderately steatotic livers compared with nonsteatotic in the context of short cold ischaemia time (<8 h),9 which may function as a IRI-mitigator in accordance to the findings from Jadhav et al.1
To conclude, whilst the current evidence suggests that avoidance of the detrimental effects of IRI is of paramount importance to increase steatotic donor liver use, there is still need for further clinical studies on this subject. In addition, as suggested by the authors, these studies must preferably focus on moderate and severe steatosis. Interventions aiming to mitigate IRI and improve organ functioning before LT (e.g. dynamic organ preservation and defatting interventions) have gained growing attention of the scientific community and represent a promising future approach.4,10
Authors' contributions
Y.L.B. initiated the study and was responsible for the management of the research project. Y.L.B. and A.P.C.S.B. were responsible for writing the manuscript and its submission. All coauthors actively contributed to manuscript preparation and approved the final manuscript version.
Conflicts of interest
The authors have none to declare.
Funding
This research received no specific grant from any funding agency.
References
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