Cold stress-induced ferroptosis in liver sinusoidal endothelial cells determines liver transplant injury and outcomes.

Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.

Perioperative Oral ß-Hydroxy-ß-Methylbutyrate Supplementation Ameliorates Sarcopenia in Rats Undergoing Major Hepatectomy.

ß-Hydroxy-ß-methylbutyrate (HMB), a metabolite of leucine, is known to increase muscle mass and strength. However, the effect of perioperative HMB supplementation in liver surgery is unclear. Moreover, the impact of HMB on the skeletal muscle fiber type also remains unclear. We investigated the impact of HMB on the body composition and skeletal muscle fiber type in sarcopenic rats undergoing major hepatectomy. Nine-week-old male F344/NSlc rats were maintained in hindlimb suspension (HLS) and were forcedly supplemented with HMB calcium salt (HMB-Ca, 0.58 g/kg×2 times) or distilled water in addition to free feeding. After 2 wk of HLS, the rats underwent 70% hepatectomy and were sacrificed 3 d after surgery. Body composition factors and the proportion of slow-twitch fibers in hindlimb muscles were evaluated. HMB maintained the body composition and hindlimb force and acted against their deterioration in sarcopenic rats, exerting a particular effect on lean mass weight, which was significant. In the histological study, HMB significantly increased the proportion of slow-twitch fibers in the soleus (p=0.044) and plantaris (p=0.001) of sarcopenic rats. HMB ameliorated deterioration of the body composition and increased the proportion of slow-twitch fibers in sarcopenic rats undergoing major hepatectomy.

Visceral adiposity is an independent risk factor for high intra-operative blood loss during living-donor liver transplantation; could preoperative rehabilitation and nutritional therapy mitigate that risk?

BACKGROUND & AIMS: Blood loss during liver transplantation (LT) is one of the major concerns of the transplant team, given the potential negative post-transplant outcomes related to it. Blood loss was reported to be higher in certain body compositions, such as obese patients, undergoing LT. Therefore, we aimed to study the risk factors for high blood loss (HBL) during adult living donor liver transplant (ALDLT) including the body composition markers; visceral-to-subcutaneous adipose tissue area ratio (VSR), skeletal muscle index and intramuscular adipose tissue content. In June 2015, an aggressive perioperative rehabilitation and nutritional therapy (APRNT) program was prescribed in our institute for the patients with abnormal body composition. METHODS: We retrospectively analyzed 394 patients who had undergone their first ALDLT between 2006 and 2019. Risk factors for HBL were analyzed in the total cohort. Differences in blood loss and risk factors were analyzed in relation to the APRNT. RESULTS: Multivariate risk factor analysis in the total cohort showed that a high VSR (odds ratio (OR): 1.98, 95% confidence interval (CI): 1.19-3.29, P = 0.009), was an independent risk factor for HBL during ALDLT, as well as a history of upper abdominal surgery, simultaneous splenectomy and the presence of a large amount of ascites. After the introduction of the APRNT, a significantly lower blood loss was observed during the ALDLT recipient operation (P = 0.003). Moreover, the significant difference in blood loss observed between normal and high VSR groups before the application of the APRNT (P < 0.001), was not observed with the APRNT (P = 0.85). Likewise, before the APRNT, only high VSR was a risk factor for HBL by multivariate analysis (OR: 2.34, CI: 1.33-4.09, P = 0.003). Whereas with the APRNT, high VSR was no longer a significant risk factor for HBL even by univariate analysis (OR: 0.89, CI: 0.26-3.12, P = 0.86). CONCLUSION: Increased visceral adiposity was an independent risk factor for high intraoperative blood loss during ALDLT recipient operation. With APRNT, high VSR was not associated with high blood loss. Therefore, APRNT might have mitigated the risk of high blood loss related to high visceral adiposity.