Introduction: Brain-death (BD) produces an inflammatory response, affecting pre-transplant, organ viability and determining organ quality and function in the post-transplant period. Cortisol is the main active hormone of the hypothalamic–pituitary–adrenal axis and has been described its protector effect against cell death in different liver diseases. However, BD injury can decrease cortisol levels resulting in the pathogenesis of liver diseases and inflammatory processes. The involvement of cortisol in liver transplantation from BD-donors has not been analyzed. Therefore, we sought to elucidate the effects of BD on circulating cortisol levels in steatotic and non-steatotic liver transplantation.
Materials and Methods: Steatotic and non-steatotic liver grafts from BD-donors were cold stored during 6 hours and then livers were implanted. Cortisol was pharmacologically modulated in liver grafts from BD-donors just after the induction of BD (to reflect current clinical practice) and before implantation of the hepatic graft in the recipient. After transplantation, the hepatic injury and inflammatory response were evaluated.
Results and Discussion: The induction of BD in non-steatotic liver showed a hepatic reduction of cortisol and increased cortisone levels in association with up-regulation of enzymes that inactivate cortisol. Nevertheless, the induction of BD in steatotic grafts exhibited increased cortisol and reduced cortisone levels, while levels of 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) were increased and hepatic levels of 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) were reduced. No changes were observed in 5α-reductase type 1 and 5β-reductase enzymes (5αR1 and 5βR), whereas 5α-reductase type 2 (5αR2) was down-regulated in steatotic liver grafts. Cortisol pre-treatment conferred protection against hepatic ischemia-reperfusion injury in steatotic livers from BD-donors. This effect was evidenced by the obstructed increase in transaminases and damage score and the marked reduction in the extent and number of necrotic areas in comparison with steatotic livers undergoing to transplantation without cortisol treatment via up-regulated the PI3K-protein kinase C (PKC), resulting in protection against the deleterious effects of BD-donors on damage and inflammatory response as well as increased survival of recipients.
Conclusion: The present study provides new mechanistic insights into the pathophysiology of LT from BD. The cortisol treatment is a feasible and highly protective strategy which is able to reduce the adverse effects of BD-donor livers in order to ultimately improve liver graft quality in the presence of steatosis, whereas cortisol treatment would not be recommended for non-steatotic liver grafts.