Background: Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH).Purposeand Aim: This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

Objective: The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (ILE) in the treatment of parenteral nutrition-associated liver disease (PNALD). Summary and Background Data: PNALD can be a lethal complication in children with short bowel syndrome (SBS). ILE based on soybean oil administered with parenteral nutrition (PN) may contribute to its etiology. Methods: We performed an open-labeled trial of a fish oil-based ILE in 42 infants with SBS who developed cholestasis (serum direct bilirubin >2 mg/dL) while receiving soybean oil-based ILE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean ILE only. The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin ≤2 mg/dL). Results: Three deaths and 1 liver transplantation occurred in the fish oil cohort, compared with 12 deaths and 6 transplants in the soybean oil cohort (P = 0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19 of 38 patients in the fish oil cohort versus 2 of 36 patients in the soybean oil cohort. Based on Cox models, subjects receiving fish oil-based ILE experienced reversal of cholestasis 6 times faster (95% CI: 2.0–37.3) than those receiving soybean oil-based ILE. The provision of fish oil-based ILE was not associated with hypertriglyceridemia, coagulopathy, or essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal international normalized ratio levels were more common among controls. Conclusions: Fish oil-based ILE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.

Background: The risk of major hepatic resection in patients with hepatic steatosis remains controversial. A meta-analysis was performed to establish the best estimate of the impact of steatosis on patient outcome following major hepatic surgery. Methods: A systematic search was performed following Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Risk ratios (RRs) for complication and mortality rates were calculated for patients with no, less than 30 per cent and at least 30 per cent steatosis, and a meta-analysis was carried out. Results: Of six observational studies identified, four including a total of 1000 patients were subjected to meta-analysis; two others were tabulated separately. Compared with patients without steatosis, those with less than 30 per cent and at least 30 per cent steatosis had a significantly increased risk of postoperative complications, with a RR of 1·53 (95 per cent confidence interval (c.i.) 1·27 to 1·85) and 2·01 (1·66 to 2·44) respectively. Patients with at least 30 per cent steatosis had an increased risk of postoperative death (RR 2·79, 95 per cent c.i. 1·19 to 6·51). Conclusion: Patients with steatosis had an up to twofold increased risk of postoperative complications, and those with excessive steatosis had an almost threefold increased risk of death.

Ex situ normothermic machine perfusion (NMP) is increasingly used for viability assessment of high‐risk donor livers, whereas dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia‐reperfusion injury. We aimed to resuscitate and test the viability of initially‐discarded, high‐risk donor livers using sequential DHOPE and NMP with two different oxygen carriers: an artificial hemoglobin‐based oxygen carrier (HBOC) or red blood cells (RBC). In a prospective observational cohort study of 54 livers that underwent DHOPE‐NMP, the first 18 procedures were performed with a HBOC‐based perfusion solution and the subsequent 36 procedures were performed with an RBC‐based perfusion solution for the NMP phase. All but one livers were derived from extended criteria donation after circulatory death donors, with a median donor risk index of 2.84 (IQR 2.52–3.11). After functional assessment during NMP, 34 livers (63% utilization), met the viability criteria and were transplanted. One‐year graft and patient survival were 94% and 100%, respectively. Post‐transplant cholangiopathy occurred in 1 patient (3%). There were no significant differences in utilization rate and post‐transplant outcomes between the HBOC and RBC group. Ex situ machine perfusion using sequential DHOPE‐NMP for resuscitation and viability assessment of high‐risk donor livers results in excellent transplant outcomes, irrespective of the oxygen carrier used.