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Weight gain poses a rising concern post-liver transplantation (LT), and metabolic dysfunction-associated steatotic liver disease might impair graft health. The timing is crucial when considering bariatric surgery (BS) in a population with liver disease or transplantation. BS can be considered for post-LT weight gain, although the evidence is limited and the long-term outcome still uncertain. We conducted a national retrospective analysis in 5 Belgian transplant centers and included 25 patients with an LT followed by a bariatric procedure. A total of 187 LT patients without BS were included for comparison. Clinical, biochemical, and outcome data were retrospectively retrieved. In our nationwide cohort, 25 patients had undergone BS post-LT, at a median 3.5 years after LT. Twenty-one (84.0%) patients received a sleeve gastrectomy (SG). Patients were predominantly male (72.0%), with a lower age at time of transplantation compared with the non-BS population (54.5 vs. 60.6, p <0.001). Weight loss was significant and sustained, with a decrease in body mass index from 41.0±4.5 pre-BS to 32.6±5.8 1-3 years post-BS ( p <0.001) and 31.1±5.8 3-5 years post-BS ( p <0.001). Three pre-BS (12.0%) patients presented with recurrent and one (4.0%) de novo metabolic dysfunction-associated steatotic liver disease after LT, with 100% resolution post-BS ( p =0.016). Notable reductions were observed in alanine transaminase levels (40.5±28.5 U/L to 27.1±25.1 U/L post-BS, p =0.05) and HbA1c levels (6.9±1.6 to 6.0±1.4 post-BS, p <0.001). Three patients were re-transplanted, and eight patients died, of which five (20.0%) due to a nonhepatic malignancy and one (4.0%) due to liver failure. SG is the favored BS post-LT and has proven to be safe and feasible in a post-LT setting with favorable metabolic consequences. SG post-LT is a valid treatment for de novo and recurrent metabolic dysfunction-associated steatotic liver disease post-LT. Although we report on the largest cohort to date, there is still a need for larger cohorts to examine the effect of BS on patient and graft survival., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction: Despite superior outcomes with liver transplantation, cirrhotic patients with HCC may turn to other forms of definitive treatment. To understand perioperative outcomes, we examined perioperative mortality and major morbidity after hepatectomy for HCC among cirrhotic and non-cirrhotic patients., Method: ology: The American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database was queried for liver resection for HCC. Multivariable logistic regression was performed to determine the association between liver texture and risk of major non-infectious morbidity, post-hepatectomy liver failure (PHLF) and 30-day mortality., Results: From 2014 to 2018, 2203 patients underwent hepatectomy: 58.6 % cirrhotic, 12.8 % fatty and 28.6 % normal texture. Overall 30 day-mortality was 2.1 % (n = 46), although higher among fatty liver (2.8 %) and cirrhotic (2.6 %; p = 0.025) patients. The incidence of PHLF was 6.9 %, with hepatectomy type, cirrhosis, and platelet count as major risk factors. Age, resection type, and platelet count were associated with major complications. Trisegmentectomy and right hepatectomy (OR = 3.60, OR = 3.46, respectively) conferred a greater risk of major noninfectious morbidity compared to partial hepatectomy. Among cirrhotics alone, hepatectomy type, platelet count, preoperative sepsis and ASA class were associated with major morbidity., Discussion: Hepatic parenchymal disease/texture and function, presence of portal hypertension, and the extent of the liver resection are critical determinants of perioperative risk among HCC patients., Competing Interests: Declaration of competing interest None, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The use of marginal donor livers, particularly steatotic livers, could help to resolve the problem of organ shortage and wait list mortality. Ischemia-free liver transplant with the potential to avoid ischemiareperfusion injury and related complications, particularly early allograft dysfunction, could positively encourage the use of marginal donorlivers and extend the donor pool. Here, we describe the first case in a Western country of ischemia-free liver transplant of a marginal donor liver. To date, a research team in China is the only group to have described and used this technique. The technical and setup aspects are illustrated, and present controversies are discussed. A 58-year-old female patient received a transplant of a >60% steatotic donor liver. The transplant was accomplished with the ischemia-free liver transplant technique, and the donor liver was procured and transplanted under continuous normothermic machine perfusion. The donor liver functional parameters under normothermic machine perfusion were reassuring, and recipient recovery was uneventful. Although ischemia-free liver transplant is a technically and organizationally demanding procedure, our case demonstrates the feasibility of the ischemia-free liver transplant technique and encourages the development and expansion of its use.

Background and Aims: Biopsy-proven severe graft steatosis is associated with adverse outcomes after liver transplantation. The concomitant presence of metabolic risk factors might further increase this risk. We studied the association between graft steatosis and metabolic risk factors in the donor, with recipient outcomes after liver transplantation., Methods: We analyzed data from all consecutive first adult full-graft donation after brain death (DBD) liver transplantations performed in the Eurotransplant region between 2010 and 2020. The presence of graft steatosis and metabolic risk factors was assessed through a review of donor (imaging) reports, and associations with recipient retransplantation-free survival were studied through survival analyses., Results: Of 12 174 transplantations, graft steatosis was detected in 2689 (22.1%), and donor diabetes mellitus (DM), hypertension, and dyslipidemia were present in 1245 (10.2%), 5056 (41.5%), and 524 (4.3%). In multivariable Cox regression analysis, graft steatosis (adjusted HR [aHR] 1.197, p < 0.001) and donor DM (aHR 1.157, p = 0.004) were independently associated with impaired retransplantation-free survival. Graft steatosis and donor DM conferred an additive risk of retransplantation or death (DM alone, aHR: 1.156 [p = 0.0185]; steatosis alone, aHR: 1.200 [p < 0.001]; both steatosis and DM, aHR: 1.381 [p < 0.001]). Findings were consistent in sensitivity analyses focusing on retransplantation-free survival within 7 days., Conclusions: Graft steatosis and donor diabetes mellitus additively increase the risk of retransplantation or death in adult DBD liver transplantation. Future studies should focus on methods to assess and improve the quality of these high-risk grafts. Until such time, caution should be exercised when considering these grafts for transplantation., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) and related steatohepatitis (MASH) are common among obese patients and may improve after metabolic/bariatric surgery (MBS). 93 Patients undergoing MBS in 2021-2022 were prospectively enrolled. Liver stiffness measurement (LSM; via vibration-controlled transient elastography [VCTE], point [pSWE] and 2D [2DSWE] shear wave elastography) and non-invasive steatosis assessment (via controlled attenuation parameter [CAP]) were performed before (baseline [BL]) and three months (M3) after surgery. 93 patients (median age 40.9 years, 68.8% female, median BL-BMI: 46.0 kg/m 2 ) were included. BL-liver biopsy showed MASLD in 82.8% and MASH in 34.4% of patients. At M3 the median relative total weight loss (%TWL) was 20.1% and the median BMI was 36.1 kg/m 2 . LSM assessed by VCTE and 2DSWE, as well as median CAP all decreased significantly from BL to M3 both in the overall cohort and among patients with MASH. There was a decrease from BL to M3 in median levels of ALT (34.0 U/L to 31 U/L; p = 0.025), gamma glutamyl transferase (BL: 30.0 to 21.0 U/L; p < 0.001) and MASLD fibrosis score (BL: - 0.97 to - 1.74; p < 0.001). Decreasing LSM and CAP, as well as liver injury markers suggest an improvement of MASLD/MASH as early as 3 months after MBS., (© 2024. The Author(s).)

Patients post liver transplant (LT) with progressive familial intrahepatic cholestasis type 1 (PFIC-1) often develop progressive graft steatohepatitis, intractable diarrhea, and growth failure. A total internal biliary diversion (TIBD) during an LT may prevent or reverse these adverse events. Children with PFIC-1 who underwent an LT at our institute were divided into 2 groups, A and B based on the timeline where we started offering a TIBD in association with LT. Pre-LT parameters, intraoperative details, and posttransplant complications like graft steatosis and diarrhea were also analyzed between the 2 groups, and their growth velocity was measured in the follow-up period. Of 550 pediatric LT performed between 2011 and 2022, 13 children underwent LT for PFIC-1. Group A had 7 patients (A1-A7) and group B had 6 (B1-B6). Patients A1, A4, B4, and B5 had a failed partial internal biliary diversion before offering them an LT. Patients A1, A2, and A6 in group A died in the post-LT period (2 early allograft dysfunction and 1 posttransplant lymphoproliferative disorder) whereas A3, A4, and A5 had graft steatosis in the follow-up period. A4 was offered a TIBD 4 years after LT following which the graft steatosis fully resolved. In group B, B1, B2, B5, and B6 underwent TIBD during LT, and B3 and B4 had it 24 and 5 months subsequently for intractable diarrhea and graft steatosis. None of the patients in group B demonstrated graft steatosis or diarrhea and had good growth catch-up during follow-up. We demonstrate that simultaneous TIBD in patients undergoing LT should be a standard practice as it helps dramatically improve outcomes in PFIC-1 as it prevents graft steatosis and/or fibrosis, diarrhea, and improves growth catch-up., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction: Preoperative weight loss through a very low-calorie diet (VLCD) has been shown to reduce liver volume and technical difficulty in patients undergoing metabolic and bariatric surgery (MBS). However, the effect of preoperative VLCD on liver histology and other outcomes is not well demonstrated. Our study aimed to explore the effect of a 2-week preoperative VLCD, compared with no-dietary intervention, on hepatic steatosis, fibrosis, weight loss, and other postoperative outcomes of MBS. Materials and Methods: This retrospective study was conducted at the Chulalongkorn Bariatric and Metabolic Institute, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. The medical records of patients with severe obesity (body mass index ≥50 kg/m 2 ) attending the clinic from January 2005 to December 2020 were reviewed. Clinical data and laboratory investigations were collected at baseline and at each follow-up visit, up to 5 years postoperatively. Hepatic steatosis and fibrosis were assessed by liver biopsy intraoperatively. Results: A total of 181 patients were included in this study. Preoperative VLCD was prescribed in 65 patients (VLCD group) and 116 patients received their usual diet (control group). Mean preoperative weight loss was 9.1 ± 6.1 kg in the VLCD group versus 0.0 ± 0.0 kg in the control group ( P  = .000). The VLCD group had significantly less number of patients with moderate and severe liver steatosis from the liver biopsy specimens (16.2% versus 46.3%; P  = .008). However, there was no significant difference in fibrosis grade between those with VLCD and control (≥F2-fibrosis; 2.7% versus 7.5%; P  = .118). Moreover, preoperative VLCD could reduce operating time in patients who underwent both laparoscopic Roux-en-Y gastric bypass (LRYGB; VLCD 163.4 ± 38.2 minutes versus control 215.1 ± 67.4 minute, P  = .000) and laparoscopic sleeve gastrectomy (LSG; VLCD 110.8 ± 20.0 minutes versus control 131.0 ± 38.1 minutes, P  = .004). During the 5-year follow-up, there were a significant difference of HbA1C between the VLCD and the control group (coefficient: -0.24 with 95% confidence interval [CI]: -0.44 to -0.04, P  = .019), particularly in patients who underwent LRYGB (Coefficient: -0.26 with 95% CI: -0.49 to -0.03, P  = .028), but not LSG. However, long-term weight loss outcomes and other biochemical outcomes were not different between the VLCD and the control group. Conclusion: Preoperative VLCD was associated with reduced liver steatosis and operative time in patients who underwent LRYGB and LSG. Moreover, preoperative VLCD significantly decreased HbA1C during a 5-year follow-up period. Therefore, it should be considered in patients with severe obesity, who will undergo MBS.

Background and Aims: Due to a lack of donor grafts, steatotic livers are used more often for liver transplantation (LT). However, steatotic donor livers are more sensitive to ischemia-reperfusion (IR) injury and have a worse prognosis after LT. Efforts to optimize steatotic liver grafts by identifying injury targets and interventions have become a hot issue., Methods: Mouse LT models were established, and 4D label-free proteome sequencing was performed for four groups: normal control (NC) SHAM, high-fat (HF) SHAM, NC LT, and HF LT to screen molecular targets for aggravating liver injury in steatotic LT. Expression detection of molecular targets was performed based on liver specimens from 110 donors to verify its impact on the overall survival of recipients. Pharmacological intervention using small-molecule inhibitors on an injury-related target was used to evaluate the therapeutic effect. Transcriptomics and metabolomics were performed to explore the regulatory network and further integrated bioinformatics analysis and multiplex immunofluorescence were adopted to assess the regulation of pathways and organelles., Results: HF LT group represented worse liver function compared with NC LT group, including more apoptotic hepatocytes (P < 0.01) and higher serum transaminase (P < 0.05). Proteomic results revealed that the mitochondrial membrane, endocytosis, and oxidative phosphorylation pathways were upregulated in HF LT group. Fatty acid binding protein 4 (FABP4) was identified as a hypoxia-inducible protein (fold change > 2 and P < 0.05) that sensitized mice to IR injury in steatotic LT. The overall survival of recipients using liver grafts with high expression of FABP4 was significantly worse than low expression of FABP4 (68.5 vs. 87.3%, P < 0.05). Adoption of FABP4 inhibitor could protect the steatotic liver from IR injury during transplantation, including reducing hepatocyte apoptosis, reducing serum transaminase (P < 0.05), and alleviating oxidative stress damage (P < 0.01). According to integrated transcriptomics and metabolomics analysis, cAMP signaling pathway was enriched following FABP4 inhibitor use. The activation of cAMP signaling pathway was validated. Microscopy and immunofluorescence staining results suggested that FABP4 inhibitors could regulate mitochondrial membrane homeostasis in steatotic LT., Conclusions: FABP4 was identified as a hypoxia-inducible protein that sensitized steatotic liver grafts to IR injury. The FABP4 inhibitor, BMS-309403, could activate of cAMP signaling pathway thereby modulating mitochondrial membrane homeostasis, reducing oxidative stress injury in steatotic donors., (© 2024. The Author(s).)

Objectives: To construct a nomogram prediction model using common preoperative indicators for early weight loss (EWL) 1 year after laparoscopic sleeve gastrectomy (LSG). Methods: Relevant data of obese patients who had undergone LSG from January 2015 to May 2022 in Fujian Medical University Union Hospital and Quanzhou First Hospital Affiliated Fujian Medical University were analyzed. Patients with a history of major abdominal surgery, severe gastroesophageal reflux disease, pregnancy within 1 year after surgery, or who were lost to follow-up were excluded, resulting in a total of 200 patients in the study (190 from Fujian Medical University Union Hospital and 10 from Quanzhou First Hospital Affiliated Fujian Medical University). The participants were 51 men and 149 women of a mean age 29.9±8.2 years and a body mass index (BMI) 38.7±6.5 kg/m 2 . All patients in this group underwent standardized LSG procedure. Achieving ideal weight (BMI≤25 kg/m 2 ) 1 year after LSG was defined as goal of EWL. Logistic regression analyses were performed to identify factors that independently influenced EWL. These factors were incorporated into the nomogram model. Receiver operating characteristic (ROC) curves (the larger the area under the curve [AUC], the better the predictive ability and accuracy of the model), likelihood ratio test (higher likelihood ratio indicates greater model homogeneity), decision curve analysis (higher net benefit indicates a better model), Akaike information criterion (AIC; smaller AIC indicates a better model), and Bayesian information criterion (BIC; smaller BIC indicates a better model) were used to validate the predictive ability of the column line diagram model. Results: In this study of 200 obese patients who underwent LSG surgery, 136 achieved EWL goal, whereas the remaining 64 did not. The rate of EWL goal achievement of the entire group was 68.0%. Compared with patients who did not achieve EWL goal, those who did had lower BMI, alanine transaminase, aspartate transaminase, triglycerides, and higher cholesterol. Additionally, the proportion of female was higher and the proportions of patients with fatty liver and hypertension lower in those who achieved EWL goal (all P <0.05). Univariate and multivariate logistic regression analysis revealed that preoperative BMI (OR=0.852, 95%CI: 0.796-0.912, P <0.001), alanine transaminase (OR=0.992, 95%CI: 0.985-0.999, P =0.024), presence of fatty liver (OR=0.185, 95%CI: 0.038-0.887, P =0.035) and hypertension (OR=0.374, 95%CI: 0.144-0.969, P =0.043) were independently associated with failure to achieve EWL goal. Cholesterol (OR=1.428, 95%CI: 1.052-1.939, P =0.022) was independently associated with achieving EWL goal. We used the above variables to establish an EWL nomogram model. ROC analysis, the likelihood ratio test, decision curve analysis, and AIC all revealed that the predictive value of the model was better than that of BMI alone (nomogram model vs. BMI: area under the curve 0.840 vs. 0.798, P=0.047; likelihood ratio: 58.785 vs. 36.565, AIC: 193.066 vs. 207.063, BIC: 212.856 vs. 213.660). Conclusion: Our predictive model is more accurate in predicting EWL after LSG compared with using BMI.

Introduction: The aim of the current randomized control trial was to assess the efficacy of donor lifestyle optimization on liver regeneration and outcome following live donor liver transplantation., Methods: Live liver donors (LLDs) who were fit with no or minimal steatosis were randomized to receive either a customized low-calorie diet with calorie intake equalling their basal requirement along with exercise for 2 weeks before surgery versus to continue their normal routine lifestyle. Primary objectives were the difference in the day of normalization of serum bilirubin and PT-International normalized ratio and the percentage growth of the liver at postoperative day 7 and 14. Secondary objectives were differences in intraoperative liver biopsy, liver-regeneration markers, blood loss, hospital stay, the complication rate in LLDs, and rates of early graft dysfunction (EGD) in recipients., Results: Sixty-two consecutive LLDs were randomized (28 in intervention vs. 34 in control). Baseline parameters and graft parameters were similar in both groups. LLDs in the intervention arm had significantly decreased calorie intake ( P <0.005), abdominal girth ( P <0.005), BMI ( P =0.05), and weight ( P <0.0005). The mean blood loss ( P =0.038), day of normalization of bilirubin ( P =0.005) and International normalized ratio ( P =0.061), postoperative peak aspartate transaminase ( P =0.003), Alanine transaminase ( P =0.025), and steatosis ( P <0.005) were significantly less in the intervention group. There was significantly higher volume regeneration ( P =0.03) in donors in the intervention arm. The levels of TNF-α, IL-6, and IL-10 levels were significantly higher, while the TGF-β level was lower in donors in the intervention group. The rate of EGD was significantly higher in recipients in the control group ( P =0.043)., Conclusion: Lifestyle optimization of LLD is simple to comply with, improves liver regeneration in LLDs, and decreases EGD in recipients, thus can enhance donor safety and outcomes in live donor liver transplantation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

End-ischemic viability testing by normothermic machine perfusion (NMP) represents an effective strategy to recover liver grafts having initially been discarded for liver transplantation (LT). However, its results in the setting of significant (≥30%) macrovesicular steatosis (MaS) have not been specifically assessed. Prospectively maintained databases at two high-volume LT centers in Northern Italy were searched to identify cases of end-ischemic NMP performed to test the viability of livers with MaS ≥ 30% in the period from January 2019 to January 2022. A total of 14 cases were retrieved, representing 57.9% of NMP and 5.7% of all machine perfusion procedures. Of those patients, 10 (71%) received transplants. Two patients developed primary nonfunction (PNF) and required urgent re-LT, and both were characterized by incomplete or suboptimal lactate clearance during NMP. PNF cases were also characterized by higher perfusate transaminases, lower hepatic artery and portal vein flows at 2 h, and a lack of glucose metabolism in one case. The remaining eight patients showed good liver function (Liver Graft Assessment Following Transplantation risk score, -1.9 [risk, 13.6%]; Early Allograft Failure Simplified Estimation score, -3.7 [risk, 2.6%]) and had a favorable postoperative course. Overall, NMP allowed successful transplantation of 57% of livers with moderate-to-severe MaS. Our findings suggest that prolonged observation (≥6 h) might be required for steatotic livers and that stable lactate clearance is a fundamental prerequisite for their use., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Partial hepatectomy has been widely used to investigate liver regeneration in mice, but the isolation of high yields of viable hepatocytes for downstream single-cell applications is challenging. A marked accumulation of lipids within regenerating hepatocytes is observed during the first 2 days of normal liver regeneration in mice. This so-called transient regeneration-associated steatosis (TRAS) is temporary but partially overlaps the major proliferative phase. Density-gradient purification is the backbone of most existing protocols for the isolation of primary hepatocytes. As gradient purification relies on the density and size of cells, it separates non-steatotic from steatotic hepatocyte populations. Therefore, fatty hepatocytes often are lost, yielding non-representative hepatocyte fractions. The presented protocol describes an easy and reliable method for the in vivo isolation of regenerating hepatocytes regardless of their lipid content. Hepatocytes from male C57BL/6 mice are isolated 24-48 h after hepatectomy by a classic two-step collagenase perfusion approach. A standard peristaltic pump drives the warmed solutions via the catheterized inferior vena cava into the remnant, using a retrograde perfusion technique with outflow through the portal vein. Hepatocytes are dissociated by collagenase for their release from the Glisson's capsule. After washing and careful centrifugation, the hepatocytes can be used for any downstream analyses. In conclusion, this paper describes a straightforward and reproducible technique for the isolation of a representative population of regenerating hepatocytes after partial hepatectomy in mice. The method may also aid the study of fatty liver disease.

Objectives: To evaluate the effects of steatotic donor livers on the safety of donors and the prognosis of donors and recipients in pediatric living donor liver transplantation. Methods: A total of 814 pediatric living donor liver transplantations were performed between January 2013 and December 2020 at Department of Pediatric Organ Transplantation,Tianjin First Central Hospital.The clinical data were collected and a retrospective study was conducted.The recipients and the donors were divided into non-steatotic donor liver group( n =733) and steatotic donor liver group( n =81) according to whether the donor graft had steatosis. The recipients and the donors in the steatotic donor liver group were further divided into mild and moderate steatosis groups based on the degree of liver steatosis.Among the donors of non-steatosis donor group,there were 307 males and 426 females,with a median age of 30 years(range:18 to 57 years);the recipients included 351 males and 382 females,with a median age of 7 months(range:4 month to 14 years).Among the donors of steatosis donor group,there were 41 males and 40 females,with a median age of 31 years(range:22 to 51 years);the recipients included 34 males and 47 females,with a median age of 8 months(range:5 months to 11 years).The donors and the recipients were followed up regularly by means of outpatient reexamination and questionnaire survey after operation.Statistical analysis of data between groups was performed using t -test,Wilcoxon rank-sum test,repeated measures ANOVA,χ 2 test,or Fisher's exact test,respectively.The survival curves of recipients and grafts in different groups were created by Kaplan-Meier method,and the survival rates of the steatotic donor liver group and the non-steatotic donor liver group were compared by Log-rank method. Results: There was no significant difference in the gender of donors in both groups ( P =0.132).There were significant differences in the age and blood type distribution as well as body weight and body mass index(all P <0.05) between the two groups.No significant difference was seen in the recovery of liver function markers ALT and AST at 1,2,5 days and 1 month after operation (all P >0.05) between the two groups.The steatotic donor liver group showed longer operation time ((294±75) minutes vs. (264±81) minutes; t =3.149, P =0.002),increased incidence of postoperative biliary leakage (3.7%(3/81) vs. 0.5% (4/733); P =0.025) and delayed incision healing (7.4%(6/81) vs. 2.0%(15/733); P =0.013).There were no significant differences in gender,age,blood type distribution,height,weight and pediatric end-stage liver disease score of recipients between the two groups (all P >0.05).As compared to the non-steatotic donor liver group,the steatotic donor liver group showed similar levels of ALT, AST and total bilirubin within 2 weeks after operation(all P >0.05). The cumulative recipient survival rates in both groups were both 96.3%,the cumulative graft survival rates were 96.3% and 95.5%,respectively,without significant difference(both P >0.05). No statistical difference was observed in the incidence of major complications between the two groups (all P >0.05). There was no significant difference in the recovery of liver function markers of donors and recipients between mild and moderate steatosis groups(all P >0.05).The cumulative recipient survival rates were both 95.9% and the cumulative graft survival rates were both 100% in mild and moderate steatosis groups,without significant difference( P =0.592). Conclusions: The application of mild to moderate steatotic donor livers in pediatric living donor liver transplantation may prolong the operation time of donors,increase the incidence of complications such as biliary leakage and delayed incision healing. But there is no significant impact of mild to moderate steatotic donor livers on the overall postoperative recovery of donors and recipients,and the prognosis is ideal.

Background: Nonalcoholic hepatic steatosis is found in most obese patients and has a strong association with metabolic syndrome. The Roux-en-Y gastric bypass and the sleeve gastrectomy are the two techniques of bariatric surgery. Patients who underwent bariatric surgery have regression of nonalcoholic steatohepatitis due to a reduction in body mass index and changes in incretin hormones., Aims: This study aimed to analyze the acuity of elastography in the regression of hepatic steatosis and fibrosis in obese patients undergoing Roux-en-Y gastric bypass and sleeve gastrectomy 2 months after surgery., Methods: Patients in the preoperative period of bariatric surgery underwent an anthropometric evaluation and hepatic elastography to quantify fibrosis and hepatic steatosis. Two months after surgery, the same evaluation was performed again., Results: All 17 patients who met the inclusion criteria participated in the study. Out of this, nine underwent sleeve gastrectomy, and eight underwent Roux-en-Y gastric bypass. The Roux-en-Y gastric bypass group had lower fibrosis levels postoperatively compared to preoperatively (p=0.029, p<0.05). As for steatosis, patients who underwent Roux-en-Y gastric bypass had lower postoperative values (p=0.01, p<0.05). There was also a reduction in fibrosis postoperatively in the sleeve gastrectomy group compared to preoperatively (p=0.037, p<0.05)., Conclusions: Elastography accurately demonstrated decreased hepatic steatosis and fibrosis in the early postoperative period of bariatric surgery. Moreover, Roux-en-Y gastric bypass and sleeve gastrectomy are suitable surgical methods to improve hepatic steatosis and fibrosis within 2 months postoperatively.

Background: The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is increased after sleeve gastrectomy (SG). Rat and clinical studies support, while mouse studies refute, a role for GLP-1R signaling after SG. Therefore, we developed a global GLP-1R knockout (KO) rat to test the hypothesis that a functional GLP-1R is critical to induce weight loss and metabolic disease improvement after SG., Methodology: A 4 bp deletion was created in exon 2 of the GLP-1R gene on a Lewis strain background to create a global GLP-1R KO rat. KO and Lewis rats were placed on a high-fat or low-fat diet and phenotyped followed by SG or Sham surgery and assessed for the effect of GLP-1R KO on surgical and metabolic efficacy., Results: Loss of the GLP-1R created an obesity-prone rodent without changes in energy expenditure. Both male and female KO rats had significantly greater insulin concentrations after an oral glucose gavage, augmented by a high-fat diet, compared to Lewis rats despite similar glucose concentrations. GLP-1R KO caused hepatomegaly and increased triglyceride deposition compared to Lewis rats. We found no difference between SG GLP-1R KO and Lewis groups when considering efficacy on body weight, glucose tolerance, and a robustly preserved improvement in fatty liver disease., Conclusions: Loss of the GLP-1R in rats resulted in increased adiposity, insulin resistance, and severe steatosis. A functional GLP-1R is not critical to the metabolic efficacy of SG in Lewis rats, similar to mouse studies, but importantly including steatosis, supporting a GLP-1R-independent mechanism for the improvement in fatty liver disease after SG., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: Donor BMI above 30 is generally considered contraindication for donor hepatectomy. We compared the donor outcomes based on BMI threshold and weight loss., Patients and Methods: All potential donors were identified and data were collected retrospectively. Steatosis was assessed based on liver-spleen Hounsfield unit difference and absolute liver intensity values. We compared BMI≥30 (n = 53) and BMI < 30 (n = 64) donor outcomes. Donors with weight loss (WL) prior to surgery were also analyzed separately. Complications were graded by Clavien-Dindo classification., Results: All donors underwent open right donor hepatectomy. There was no difference between BMI≥30 and < 30 groups except female predominance in BMI≥30 group (P = .006). Both groups had similar rates of complication rates in all categories, similar remnant volume, operative time, length of stay and similar postoperative liver function recovery (all P > .05). On the other hand, donors with WL were more commonly male, had smaller graft size, and higher biliary complications rates compared to no-WL donors (all P < .05). Multivariate binary logistics regression analysis revealed no association between BMI or WL and outcomes., Conclusion: We demonstrate that donors with BMI≥30 have similar outcomes compared to BMI < 30 donors with our defined selection criterion, therefore BMI≥30 is not an absolute contraindication to donate right liver, provided that there is no significant steatosis and remnant liver is satisfactory. For potential overweight donors, WL down to BMI < 30 is a reasonable target. Higher biliary complication rates after WL should be investigated further., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Weight loss improves fatty liver disease. No randomized trial has compared the effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on liver fat content and fibrosis., Objective: To compare the 1-year effects of SG and RYGB on hepatic steatosis and fibrosis., Design: Single-center, randomized, controlled trial (Oseberg [ O besity S urg e ry in Tøns berg ]). (ClinicalTrials.gov: NCT01778738)., Setting: Tertiary care obesity center in Norway., Participants: 100 patients (65% female; mean age, 47.5 years; mean body mass index, 42 kg/m 2 ) with type 2 diabetes mellitus (T2DM)., Intervention: From January 2013 to February 2018, patients were randomly assigned (1:1 ratio) to SG or RYGB., Measurements: The primary outcome was remission of T2DM (previously published). Predefined secondary outcomes in the present study were hepatic steatosis and fibrosis assessed by magnetic resonance imaging (liver fat fraction), enhanced liver fibrosis (ELF) test, noninvasive indices, and liver enzymes., Results: Liver fat fraction declined similarly after SG (-19.7% [95% CI, -22.5% to -16.9%]) and RYGB (-21.5% [CI, -24.3% to -18.6%]) from surgery to 1-year follow-up, and almost all patients (SG, 94%; RYGB, 100%) had no or low-grade steatosis at 1 year. The ELF score category remained stable in 77% of patients, but 18% experienced worsening of fibrosis at 1 year, with no substantial between-group difference., Limitations: Single-center study, short follow-up time, and lack of power for secondary outcomes., Conclusion: With an almost complete clearance of liver fat 1 year after surgery, RYGB and SG were both highly effective in reducing hepatic steatosis. Bariatric surgery had less influence on degree of fibrosis in the short term, but assessment of long-term progression is warranted., Primary Funding Source: Vestfold Hospital Trust and the South-Eastern Norway Regional Health Authority.

Purpose of Review: Due to a persistent shortage of donor livers, attention has turned toward ways of utilizing marginal grafts, particularly those with steatosis, without incurring inferior outcomes. Here we review the evaluation and utilization of steatotic liver allografts, highlight recently published data, and discuss novel methods of graft rehabilitation., Recent Findings: Although severe liver allograft (>60%) steatosis has been associated with inferior graft and recipient outcomes, mild (<30%) steatosis has not. There is ongoing debate regarding safe utilization of grafts with moderate (30-60%) steatosis. Presently, no established protocols for evaluating steatosis in donor candidates or utilizing such grafts exist. Liver biopsy is accepted as the gold standard technique, though noninvasive methods have shown promise in accurately predicting steatosis. More recently, machine perfusion has been shown to enhance ex situ liver function and reduce steatosis, emerging as a potential means of optimizing steatotic grafts prior to transplantation., Summary: Steatotic liver allografts constitute a large proportion of deceased donor organs. Further work is necessary to define safe upper limits for the acceptable degree of steatosis, develop standardized evaluation protocols, and establish utilization guidelines that prioritize safety. Machine perfusion has shown promise in rehabilitating steatotic grafts and offers the possibility of expanding the deceased donor pool., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Autophagy is the primary intracellular catabolic process for degrading and recycling long-lived proteins and damaged organelles, which maintains cellular homeostasis. Autophagy has key roles in development and differentiation. By using the mouse with liver specific knockout of autophagy related gene 5 (Atg5), a gene essential for autophagy, we investigated the possible role of autophagy in liver regeneration after 70% partial hepatectomy (PHx). Ablation of autophagy significantly impaired mouse liver regeneration, and this impairment was associated with reduced hepatocellular proliferation rate, down-regulated expression of cyclins and tumor suppressors, and increased hepatocellular apoptosis via the intrinsic apoptotic pathway. Ablation of autophagy does not affect IL-6 and TNF-α response after PHx, but the altered hepatic and systemic metabolic responses were observed in these mice, including reduced ATP and hepatic free fatty acid levels in the liver tissue, increased glucose level in the serum. Autophagy is required to promote hepatocellular proliferation by maintaining normal hepatic and systemic metabolism and suppress hepatocellular apoptosis in liver regeneration., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: The objective of our study was to determine the concordance rates of steatosis staging by controlled attenuation parameter (CAP) scores from transient elastography (TE) in comparison with liver histology in patients with chronic liver disease and to determine the optimal CAP cutoffs to predict the severity of steatosis and identify those with nonalcoholic steatohepatitis (NASH)., Methods: Patients (n = 217) who had both CAP scores and liver biopsy within a period of 90 days were retrospectively studied. Histology was graded in a blinded fashion by a single pathologist; steatosis was graded on a scale from 0 to 3. Nonalcoholic fatty liver disease activity scores (NAS) scores were calculated for all patients. Optimal CAP cut-points were selected by maximum Youden's index., Results: Area under receiver operating characteristic curve (AUROC) for CAP (using cutoff value ≥ 278 dB/m) in differentiating steatosis 1-3 from 0 was 0.82 (95% CI 0.75-0.89), and 0.79 (95% CI 0.70-0.88) in differentiating steatosis 0-1 from 2 to 3 using CAP cutoff value ≥ 301 dB/m. With CAP cutoff value ≥ 301 dB/m, CAP identified NAS 3 or above with AUROC of 0.82 (95% CI 0.74-0.89). The AUROC for TE in differentiating fibrosis (cutoff 11.9 kPa) 3-4 from 0 to 2 was 0.85 (95% CI 0.77-0.92), and 0.84 (95% CI 0.74-0.93) in differentiating (cutoff 14.4 kPa) 4 from 0 to 3., Conclusions: Transient elastography is a good modality to accurately diagnose steatosis and NASH and can also differentiate advanced liver fibrosis from early stages.

Blood loss is associated with the degree of damage in liver stiffness. Severe liver steatosis is a matter of concern in liver surgery, but does not correlate with liver stiffness. This study aimed to assess the relationship between blood perfusion of the liver and blood loss in liver pathologies. Data from elective liver resection for liver cancer were analyzed. All patients underwent preoperative assessments including perfusion CT. Patients were divided into 4 groups in accordance with the pathological background of liver parenchyma. Relationships between portal flow as assessed by perfusion CT and perioperative variables were compared. Factors correlating with blood loss were analyzed. In 166 patients, portal flow from perfusion CT correlated positively with platelet count and negatively with indocyanine green retention rate at 15 min. Background liver pathology was normal liver (NL) in 43 cases, chronic hepatitis (CH) in 56, liver cirrhosis (LC) in 42, and liver steatosis (LS) in 25. Rates of hepatitis viral infection and pathological hepatocellular carcinoma were more frequent in LC and CH groups than in the other groups (p < 0.05). LC and LS showed significantly worse liver function than the NL and CH groups. Portal flow from perfusion CT correlated positively with damage to liver parenchyma and negatively with blood loss at liver transection. Low portal flow on perfusion CT predicts blood loss during liver transection.

Background and Aims: The regulation of hepatic very-low-density lipoprotein (VLDL) secretion is vital for lipid metabolism whose pathogenetic status is involved in fatty liver disease and dyslipidemia seen in hepatic steatosis. Accumulated evidence suggest that apolipoprotein E (ApoE) is closely related to hepatic VLDL secretion. Here, we report that the expression of patatin-like phospholipase domain containing protein 7 (PNPLA7) is strongly induced by hepatic steatosis and positively correlates with plasma triacylglycerol (TAG) levels in the human subjects, whereas the role of PNPLA7 in hepatic VLDL secretion is unknown., Approach and Results: Herein, with genetic manipulation in the mice, the deficiency of hepatic PNPLA7 expression resulted in reduced VLDL secretion accompanied by enhanced hepatic lipid accumulation and decreased hepatic ApoE expression. Furthermore, knockdown of PNPLA7 in the livers of the db/db mice also resulted in significant reduction in plasma TAG level but aggravated hepatic steatosis. Importantly, we observed that PNPLA7 interacted with ApoE and presumably at the site of endoplasmic reticulum. Mechanistically, we have shown that PNPLA7 could modulate polyubiquitination and proteasomal-mediated degradation of ApoE. Overexpressed ApoE restored the impaired VLDL-TAG metabolism in PNPLA7-knockdown primary hepatocytes., Conclusion: PNPLA7 plays a critical role in regulating hepatic VLDL secretion by modulating ApoE stability through its interaction with ApoE., (© 2020 by the American Association for the Study of Liver Diseases.)

The study focuses on radiological-pathological correlation between imaging of ex vivo samples obtained by a 7-T scanner and histological examination. The specimens will be derived from native explanted cirrhotic livers, liver grafts excluded from donation because of severe steatosis, and primary pancreatic tumours. Magnetic resonance imaging (MRI) examinations will be performed within 24 h from liver or pancreatic lesion surgical removal. The MRI protocol will include morphological sequences, quantitative T1, T2, and fat-, water-fraction maps with Cartesian k-space acquisition, and multiparametric methods based on a transient-state "MRI fingerprinting". Finally, the specimen will be fixed by formalin. Qualitative imaging analysis will be performed by two independent blinded radiologists to assess image consistency score. Quantitative analysis will be performed by drawing regions of interest on different tissue zones to measure T1 and T2 relaxation times as well as fat- and water-fraction. The same tissue areas will be analysed by the pathologists. This study will provide the possibility to improve our knowledge about qualitative and quantitative abdominal imaging assessment at 7 T, by correlating imaging characteristics and the corresponding histological composition of ex vivo specimens, in order to identify imaging biomarkers. Trial registration: ClinicalTrials.gov : 13646. Registered 9 July 2019-retrospectively registered.

Background and Objective: Liver transplantation (LT) is the gold-standard treatment for end-stage liver disease; however, late-onset complications such as fatty liver can occur in the absence of metabolic comorbidities. We report a unique case of post-transplant hepatic steatosis developing in only a part of the liver graft., Case Report: A 1-year-old boy underwent ABO-incompatible living donor liver transplantation (LDLT) with a left lateral liver graft donated from his mother for biliary atresia. The biliary tract was reconstructed by hepaticojejunostomy using the previous Roux-en-Y limb. Liver function tests increased by up to 2-fold of the upper normal limit after the second year. He developed segmental steatosis in a part of the liver graft 2 years after LDLT. Venous blood drained into the area of the liver graft from veins in the Roux-en-Y limb of the jejunum. Pathologic findings from a liver biopsy showed fatty depositions without steatohepatitis, acute rejection, or tumors. Portal vein stricture (PVS) subsequently became apparent, which was complicated by the symptoms of portal hypertension, such as gastrointestinal varices. We treated PVS with 2 sessions of percutaneous transhepatic portal vein angioplasty (PTPA), after which the segmental steatosis disappeared. We hypothesize that PVS caused local hemodynamic anomalies, leading to fatty deposition in a part of the liver graft., Conclusion: We experienced a case of post-LT with segmental steatosis that was successfully treated by portal vein flow modification with PTPA. Steatosis of the graft might indicate a vascular abnormality, and further examinations should be performed after LT., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To investigate whether exercise improves outcomes of surgery on fatty liver, and whether pharmacological approaches can substitute exercising programs., Summary of Background Data: Steatosis is the hepatic manifestation of the metabolic syndrome, and decreases the liver's ability to handle inflammatory stress or to regenerate after tissue loss. Exercise activates adenosine monophosphate-activated kinase (AMPK) and mitigates steatosis; however, its impact on ischemia-reperfusion injury and regeneration is unknown., Methods: We used a mouse model of simple, diet-induced steatosis and assessed the impact of exercise on metabolic parameters, ischemia-reperfusion injury and regeneration after hepatectomy. The same parameters were evaluated after treatment of mice with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Mice on a control diet served as age-matched controls., Results: A 4-week-exercising program reversed steatosis, lowered insulin levels, and improved glucose tolerance. Exercise markedly enhanced the ischemic tolerance and the regenerative capacity of fatty liver. Replacing exercise with AICAR was sufficient to replicate the above benefits. Both exercise and AICAR improved survival after extended hepatectomy in mice challenged with a Western diet, indicating protection from resection-induced liver failure., Conclusions: Exercise efficiently counteracts the metabolic, ischemic, and regenerative deficits of fatty liver. AICAR acts as an exercise mimetic in settings of fatty liver disease, an important finding given the compliance issues associated with exercise. Exercising, or its substitution through AICAR, may provide a feasible strategy to negate the hepatic consequences of energy-rich diet, and has the potential to extend the application of liver surgery if confirmed in humans.

Background: The principle in right lobe living donor liver transplantation is to use "near-perfect" grafts to maximize recipient benefit with minimal donor risk. Whether and what degree of graft macrovesicular steatosis is safe for both recipient and donor is debatable., Methods: We compared donor and recipient outcomes in 623 primary right lobe living donor liver transplantations, using grafts with (Group A; 10%-20% steatosis, n = 92) and without (Group B; <10%, n = 531) significant macrovesicular steatosis, on pre- or intraoperative biopsy., Results: Group A donors had higher body mass index, transaminases, fasting blood sugar, triglyceride, low density lipoprotein level, and lower high density lipoprotein, and liver attenuation index on CT scan, and similar future liver remnant. Mean postoperative day (POD) 7, aspartate aminotransferase (61.13 + 24.77 vs 73.17 + 53.71 IU/L; P = 0.04), and prothrombin time-international normalized ratio (1.16 + 0.36 vs 1.28 + 0.24; P = 0.0001) were lower in Group A donors. POD3 of 7 total bilirubin and alanine aminotransferase; POD3 aspartate aminotransferase and prothrombin time-international normalized ratio; postoperative morbidity (Dindo-Clavien >3b), hospital stay were similar in both groups. Recipients in both groups had similar age, model for end-stage liver disease score. Right lobe graft weight (764.8 + 145.46 vs 703.24 + 125.53 grams; P < 0.0001) and GRWR (1.09 + 0.29 vs 1.00 + 0.21; P = 0.0004) were higher in Group A. All biochemical parameters at POD 3 of 7, as well as hospital stay, 30-day mortality were similar in recipients of both groups, even after matching both groups for age, model for end-stage liver disease, and GRWR., Conclusions: Use of well-selected right lobe grafts (adequate future liver remnant in donor, GRWR in recipient), with up to 20% macrovesicular steatosis, does not compromise graft function and outcomes and is safe for the donor.

BACKGROUND Acute fatty liver of pregnancy is an obstetric emergency characterized by liver dysfunction, which can lead to severe maternal and fetal complications. CASE REPORT A 34-year-old woman, 37 weeks and 2 days pregnant, reported symptoms of nausea, vomiting, jaundice, and prostration. Laboratory findings revealed liver dysfunction and coagulopathy. A clinical diagnosis of acute fatty liver was made and an emergency cesarean section was performed. The postoperative period was complicated by disseminated intravascular coagulation, acute hepatic and renal insufficiency, and pancreatitis. CONCLUSIONS Early recognition of this pathology, the interruption of pregnancy, and intensive therapy led to a favorable outcome.

Recent years have demonstrated a surging interest in normothermic ex situ liver perfusion, with iterative experimental and clinical studies establishing this technology as providing obvious advantages over static cold storage. In particular, the safe prolongation of liver graft preservation even up to 1 week opens up possibilities of 'on circuit' interventions, which may radically change the logistics and scope of liver transplant practice. Such approaches are rife with potential, and have yet to be fully explored. Possibilities may include, but are not limited to mitochondrial enhancing strategies, steatotic graft defatting, on circuit addition of anti-aging compounds, altering graft immunogenic potential and gene silencing with siRNA, stem cell and nanoparticle therapies as well as ischemia free liver preservation. Ex situ machine perfusion technology as a platform for advanced graft modification strategies opens up the possibility of very specific, personalized transplant medicine, as well as the possibility of a future where organ grafts are re-used and repaired, providing utility to numerous successive surgical recipients, indefinitely.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and insulin resistance. There is currently no pharmacological treatment validated in steatosis. The combination of weight loss and adequate physical activity can improve liver steatosis. In randomized trials and cohort studies, a weight loss of at least 7% and a diet approaching the Mediterranean diet have been associated with an improvement in hepatic fat content, an improvement in hepatic biomarkers, and regression of histological signs of steatosis. Bariatric surgery by losing weight can lead to an improvement in hepatic fat content., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Organ shortage is a major cause of delayed liver transplantation and increased waitlist time. The level of donor steatosis is a significant determinant in organ selection. Scarcity of organs has led some programs to expand their acceptable criteria for the percentage of steatosis. We report two cases of liver transplantation of steatotic donor organs that resulted in mortality within hours from transplantation. Postmortem analysis showed evidence of diffuse pulmonary fat microemboli likely originating from the donor organ, with marked preservation reperfusion injury. The mechanism of diffuse fat microemboli in this setting and possible relationship to other perioperative syndromes (transfusion-related lung injury, acute kidney injury, and postreperfusion syndrome) is discussed., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: Adequate liver retraction is an essential step in bariatric surgery, with technical challenges due to an enlarged, fatty liver. Traditional methods utilize externally fixed, rigid retractors with inherent drawbacks including an extra incision, pain, scarring, and liver injury. Advancement of laparoscopic techniques for liver retraction methods has focused on simplicity, reproducibility, safety, and effective use to avoid patient comorbidity. Our study is a retrospective evaluation of the safety and efficacy of a totally internal, atraumatic bulldog liver retractor versus standard retraction in a large series of patients undergoing laparoscopic bariatric surgery., Methods: A retrospective chart review was performed on all patients undergoing bariatric surgery from April 2010 to December 2017. Standard retraction was used in 108 subjects and a bulldog retractor system attached to the pars flaccida, and anterior abdominal wall was used in 483 subjects. Any operations with additional procedures, re-do operations, or missing data were excluded., Results: Five hundred fifty-one procedures were included between 2010 and 2017. In unadjusted analysis, no significant differences were found in AST/ALT elevation, need for additional retraction, length of stay (LOS), or operative times between the bulldog and standard retraction. Adjustment for demographics and Roux-en-Y gastric bypass versus sleeve gastrectomy in a multivariable logistic regression model, the standard retractor showed higher odds of AST/ALT elevation post-op and higher odds of needing additional retraction compared with those of the bulldog retractor., Discussions/conclusion: The bulldog retractor system can be used safely and effectively to expose the gastroesophageal junction in morbidly obese patients with advancements on the customary approach.

The impact of postreperfusion syndrome (PRS) during liver transplantation (LT) using donor livers with significant macrosteatosis is largely unknown. Clinical outcomes of all patients undergoing LT with donor livers with moderate macrosteatosis (30%-60%) (N = 96) between 2000 and 2017 were compared to propensity score matched cohorts of patients undergoing LT with donor livers with mild macrosteatosis (10%-29%) (N = 96) and no steatosis (N = 96). Cardiac arrest at the time of reperfusion was seen in eight (8.3%) of the patients in the moderate macrosteatosis group compared to one (1.0%) of the patients in the mild macrosteatosis group (P = .02) and zero (0%) of the patients in the no steatosis group (P = .004). Patients in the moderate macrosteatosis group had a higher rate of PRS (37.5% vs 18.8%; P = .004), early allograft dysfunction (EAD) (76.4% vs 25.8%; P < .001), renal dysfunction requiring continuous renal replacement therapy following transplant (18.8% vs 8.3%; P = .03) and return to the OR within 30 days (24.0% vs 7.3%; P = .002), than the no steatosis group. Both long-term patient (P = .30 and P = .08) and graft survival (P = .15 and P = .12) were not statistically when comparing the moderate macrosteatosis group to the mild macrosteatosis and no steatosis groups. Recipients of LT using livers with moderate macrosteatosis are at a significant increased risk of PRS. If patients are able to overcome the initial increased perioperative risk of using these donor livers, long-term graft survival does not appear to be different than matched recipients receiving grafts with no steatosis., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Key Points: Non-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity., Abstract: Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized in part by excessive hepatic triglyceride accumulation (i.e. hepatic steatosis), the incidence of NAFLD is increasing - in line with the growing obesity epidemic. The role of the autonomic nervous system in NAFLD remains unclear. Here, we show that chronic hepatic sympathetic overactivity mediates hepatic steatosis. Direct multiunit recordings of hepatic sympathetic nerve activity were obtained in high fat diet and normal chow fed male C57BL/6J mice. To reduce hepatic sympathetic nerve activity we utilized two approaches including pharmacological ablation of the sympathetic nerves and phenol-based hepatic sympathetic nerve denervation. Diet-induced NAFLD was associated with a nearly doubled firing rate of the hepatic sympathetic nerves, which was largely due to an increase in efferent nerve traffic. Furthermore, established high fat diet-induced hepatic steatosis was effectively reduced with pharmacological or phenol-based removal of the hepatic sympathetic nerves, independent of changes in body weight, caloric intake or adiposity. Ablation of liver sympathetic nerves was also associated with improvements in liver triglyceride accumulation pathways including free fatty acid uptake and de novo lipogenesis. These findings highlight an unrecognized pathogenic link between liver sympathetic outflow and hepatic steatosis and suggest that manipulation of the liver sympathetic nerves may represent a novel therapeutic strategy for NAFLD., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

From 1991 to 2013, Mississippi was without liver transplant services. In 2013, a new liver transplant program was established at the University of Mississippi Medical Center. Here, we describe our experience with the first 150 transplants over a 4.5-year period. This study is a review of 147 patients who underwent the first 150 liver transplants at the University of Mississippi Medical Center between March 5, 2013, and January 4, 2018. There were no exclusion criteria for this study. Donor, recipient, and outcome variables were analyzed. Recipients were 46% female and 74% white. Age at the time of transplant was 57 [IQR 49-63]. BMI at transplant was 30 [IQR 25-35]. Thirty per cent of transplants were for alcoholic cirrhosis, 25% non-alcoholic steatohepatitis, 24% hepatitis C, and 12% cholestatic. Mean model for end-stage liver disease (MELD) at the time of transplant was 20 [95% confidence interval 19-21] and MELD-Na was 22 [95% confidence interval 20-23]. One-year patient- and graft survival were 89% and 87%, respectively, which were as expected based on Scientific Registry of Transplant Recipient reports after risk adjustment. The data published here verifies it is possible to establish a new liver transplant center in an underserved area previously lacking comprehensive liver care and to achieve results similar to other high-volume centers across the country.

Acute fatty liver of pregnancy (AFLP) often resolves after pregnancy delivery but can progress to acute liver failure necessitating liver transplantation. We performed a retrospective review of the national Scientific Registry of Transplant Recipients (SRTR) data to identify all women in the United States undergoing liver transplantation (LT) for acute liver failure (ALF) from AFLP from 1991 to 2015, and compared to outcomes in women of childbearing age undergoing transplant for ALF from acetaminophen and ALF from other etiologies. Women with AFLP were likely to be on life support at time of LT and had high rates of renal dysfunction (median Cr 2.1, IQR 1.2-2.3), and hyperbilirubinemia (median bilirubin 17.1, IQR 11.0, 19.9). Although their early and late LT survival outcomes were comparable to the other indications for LT, cumulative 5-year graft survival was numerically lower among AFLP patients (54%, 95% CI, 27-76) compared to APAP (70%, 95% CI, 63-77) and "Other ALF" (76%, 95% CI, 72-80) groups. In conclusion, although AFLP is a rare indication for LT, AFLP patients were as sick or sicker than other women of childbearing age undergoing LT for ALF. Worsened graft survival may be related to higher rates of rejection in the AFLP group., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose: Weight loss before bariatric surgery with a low-calorie diet (LCD) has several advantages, including reduction of liver volume and an improved access to the lesser sac. Disadvantages include performing surgery in a state of undernutrition, side effects, costs and patient compliance. Omega-3 fatty acids may serve as an alternative to reduce liver steatosis., Materials and Methods: A randomised controlled open-label trial was done to compare the effects of a LCD with Modifast (800 kcal/day) during 2 weeks with 2 g of omega-3 fatty acids a day and a normal diet (2000 kcal/day) during 4 weeks. Total liver volume (TLV) and volume of the left liver lobe (LLL), visceral fat area (VFA) and muscle area (SMA) at the L3-L4 level were measured with MRI before and after preoperative treatment., Results: Sixty-two morbidly obese women undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) were recruited. In both groups, there was a significant decrease in LLL, TLV and VFA. For LLL and TLV reduction, the LCD had a significantly larger effect (p < 0.05). Only in the LCD group was there a significant decrease in SMA with significantly more side effects and worse compliance., Conclusion: Both the LCD and omega-3 diet reduced LLL, TLV and VFA. The LCD outperformed the omega-3 diet in LLL and TLV reduction, but induced significant loss of SMA and had worse compliance due to more side effects. Omega-3 fatty acids may provide a safe and more patient-friendly alternative for a LCD and further research is indicated., Trial Registration: The study is registered at www.clinicaltrials.gov (NCT02206256).

Roux-en-Y Gastric Bypass (RYGB) remains one of the most effective options in treatment of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are not clear yet. Here, we evaluated the relationship among hepatic mechanistic target of rapamycin (mTOR)-AKT2-insulin-induced gene 2 (Insig2) signaling, lipogenic transcription factors and lipid synthesis enzymes in obese mice with or without RYGB operation. Hepatic mTOR activity and Insig2a were stimulated, while AKT2, sterol response element-binding protein 1c (SREBP1c), peroxisome proliferator-activated receptor γ (PPARγ), lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were decreased by Roux-en-Y Gastric Bypass in both DMSO and rapamycin treated diet-induced obese (DIO) mice. Increment of hepatic lipogenesis and decline of mTOR signaling induced by rapamycin were significantly reversed by RYGB in DIO mice. RYGB significantly improved high-fat diet- and rapamycin- induced hepatic steatosis by suppression of de novo lipogenesis. Administration of adenovirus-mediated p70 ribosomal protein subunit 6 kinase 1 (Ad-S6K1) from tail vein improved hepatic steatosis. Infusion of Ad-S6K1 suppressed AKT2, SREBP1c, PPARγ, and lipogenesis-related genes while stimulating Insig2a in DIO mice. Ad-S6K1 decreased oleic acid-induced lipid deposition in primary mouse hepatocytes. Our results suggest that mTOR-AKT2-Insig2 signaling pathway contributes to the improvement effect of RYGB on hepatic steatosis induced by high-fat diet., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Because of the shortage of liver grafts available for transplantation, the restrictions on graft quality have been relaxed, and marginal grafts, such as steatotic livers, are now accepted. However, this policy change has not solved the problem, because steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly. Adipocytokines differentially modulate steatosis, inflammation, and fibrosis and are broadly present in hepatic resections and transplants. The potential use of adipocytokines as biomarkers of the severity of steatosis and liver damage to aid the identification of high-risk steatotic liver donors and to evaluate hepatic injury in the postoperative period are discussed. The hope of finding new therapeutic strategies aimed specifically at protecting steatotic livers undergoing surgery is a strong impetus for identifying the mechanisms responsible for hepatic failure after major surgical intervention. Hence, the most recently described roles of adipocytokines in steatotic livers subject to I/R injury are discussed, the conflicting results in the literature are summarized, and reasons are offered as to why strategic pharmacologic control of adipocytokines has yet to yield clinical benefits. After this, the next steps needed to transfer basic knowledge about adipocytokines into clinical practice to protect marginal livers subject to I/R injury are presented. Recent strategies based on adipocytokine regulation, which have shown efficacy in various pathologies, and hold promise for hepatic resection and transplantation are also outlined.

Objectives: Apolipoprotein A-1 (ApoA-1) is involved in regulating both lipid and energy metabolism, which may play important roles in liver regeneration, especially for the liver with steatosis. We here intended to investigate the role of ApoA-1 in regeneration of small-for-size fatty liver graft and to explore the underlying mechanism., Methods: The association of ApoA-1 expression with liver regeneration was studied in rat liver transplantation models using small-for-size normal graft or small-for-size fatty graft. The direct role of ApoA-1 in liver regeneration was studied in mouse hepatectomy model in vivo and hepatocytes in vitro., Results: Compared to small-for-size normal graft, decreased expression of ApoA-1 associated with delayed regeneration were detected in small-for-size fatty liver graft after transplantation. In functional study, the expression of ApoA-1 was decreased in hepatocytes with steatosis and was inversely associated with the concentration of oleic acid. The ApoA-1 administration effectively attenuated hepatocytes steatosis and accelerated hepatocytes proliferation. In mouse model, ApoA-1 treatment promoted liver regeneration at day 2 after major hepatectomy. In addition, the treatment of ApoA-1 increased the expressions of PGC-1α and its target genes Tfam, Ucp2 and SDHB., Conclusions: ApoA-1 may accelerate regeneration of small-for-size fatty liver graft at day 2 after transplantation through regulating mitochondrial function. ApoA-1 may be the potential new therapy of promoting liver regeneration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis., Methods: Severe hepatic steatosis was performed by 12-14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured., Results: Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%)., Conclusions: Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.

To explore subclinical fatty liver disease (FLD) in donors as a possible mechanism leading to FLD in recipients of living donor liver transplantation (LDLT), we extracted thirty donor-recipient pairs' serum DNA and explored the presence of CYP2R1 single nucleotide polymorphism (SNP) rs10741657 and vitamin D receptor (VDR) SNP rs2228530 A/G alleles using real-time polymerase chain reaction. We measured the serum 25(OH)D concentrations and investigated the CYP2R1 and VDR genotypes of the donors and recipients before and after LDLT for comparison with the histological findings from the donors on wedge biopsy, the recipients' removed native liver, and selective liver biopsy after LDLT. There was a significant difference in low serum 25(OH)D concentration between the donors and recipients before LDLT and in the recipients before versus after LDLT (13.90 ± 8.85 versus 47.9 ± 14.88 versus 11.82 ± 10.36, P < 0.001), and significant difference in FLD was detected on wedge biopsy from the donors and the native liver from the recipients as well as the native liver and follow-up biopsy from the recipients ( P < 0.001). CYP2R1 and VDR genotype were predominant, both for the AG and for the GG alleles. For the donor VDR SNP rs2228570, low serum 25(OH)D was significantly different between genotypes AA and AG ( P = 0.024) as well as between genotypes AA and AG plus GG ( P = 0.042). Our data suggest that donors' VDR rs2228570 AA alleles may play a major role in low serum 25(OH)D regarding pathological FLD in recipients after LDLT.

Introduction: Hepatic resection is performed for various benign and malignant liver tumors. Over the last several decades, there have been improvements in the surgical technique and postoperative care of patients undergoing liver surgery. Despite this, liver failure following an extended hepatic resection remains a critical potential postoperative complication. Patients with underlying parenchymal liver diseases are at particular risk of liver failure due to impaired liver regeneration with an associated mortality risk as high as 60 to 90%. In addition, live donor liver transplantation requires a thorough presurgical assessment of the donor liver to minimize the risk of postoperative complications., Results and Conclusion: Recently, cross-sectional imaging assessment of diffuse liver diseases has gained momentum due to its ability to provide both anatomical and functional assessments of normal and abnormal tissues. Various imaging techniques are being employed to assess diffuse liver diseases including magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound (US). MRI has the ability to detect abnormal intracellular and molecular processes and tissue architecture. CT has a high spatial resolution, while US provides real-time imaging, is inexpensive, and readily available. We herein review current state-of-the-art techniques to assess the underlying non-tumorous liver. Specifically, we summarize current approaches to evaluating diffuse liver diseases including fatty liver alcoholic or non-alcoholic (NAFLD, AFLD), hepatic fibrosis (HF), and iron deposition (ID) with a focus on advanced imaging techniques for non-invasive assessment along with their implications for patient management. In addition, the role of and techniques to assess hepatic volume in hepatic surgery are discussed.

Objective: Changes in liver fatty acid metabolism are important in understanding the mechanisms of diabetes remission and metabolic changes after bariatric surgery., Research Design and Methods: Liver fatty acid uptake (LFU), blood flow, and fat content (LFC) were measured in 25 obese subjects before bariatric surgery and 6 months after using positron emission tomography/computed tomography and MRS; 14 lean individuals served as the control subjects., Results: The increased LFU in obese subjects was associated with body adiposity. LFU was reduced postoperatively but was still high compared with the control subjects. LFC was normalized. Liver blood flow (per unit volume) was higher in obese subjects than in the control subjects at baseline and was further increased postoperatively; however, the total organ blood flow was unchanged as the liver volume decreased., Conclusions: The findings suggest that in a postoperative state, intrahepatic fatty acids are not stored in the liver but are used for oxidation to provide energy. Changes in perfusion may contribute to improved liver metabolism postoperatively., (© 2017 by the American Diabetes Association.)

Thyroid hormones (THs) as a therapeutic intervention to treat obesity has been tried but the effect of THs on body weight and the mechanistic details of which are far from clear. This study was designed to determine and elucidate the mechanistic details of metabolic action of THs in high-fat diet (HFD) fed Sprague Dawley (SD) rats. Rats were made surgically hypothyroid (thyroidectomy, Thx). Body weights and food and water intake profoundly decreased in HFD fed thyroidectomized group (HN Thx). Results showed that delayed insulin response, increased total cholesterol, high-density lipoprotein, and low-density lipoprotein in HN Thx. Unexpectedly, however, Thx reduced serum and hepatic triglyceride concentrations. Further studies revealed that Thx dramatically increased circulating GLP-1 as well as increased expressions of GLP-1 in small intestine. Diminished hepatic expressions of lipogenic genes, were observed in HN Thx group. Beta-catenin and glutamine synthetase, a known target of β-catenin, were up-regulated in the liver of HN Thx group. The expressions of gluconeogenic genes G6P and PCK were reduced in the liver of HN Thx group. The results may suggest that surgery-induced hypothyroidism increases GLP-1, the actions of which may in part be responsible for the reduction in water intake, appetite and hepatic steatosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: Hypothalamic obesity is a severe condition without any effective therapy. Bariatric operations appear as an alternative treatment, but the effects of this procedure are controversial. We, herein, investigated the effects of duodeno-jejunal bypass (DJB) surgery upon the lipid profile and expression of genes and proteins, involved in the regulation of hepatic lipid metabolism, in hypothalamic obese (HyO) rats., Methods: During the first 5days of life, male newborn Wistar rats received subcutaneous injections of monosodium glutamate [4g/kg body weight, HyO group] or saline (control, CTL group). At 90days of life, HyO rats were randomly submitted to DJB (HyO DJB) or Sham-operations (HyO Sham group). Six months after DJB, adiposity, hepatic steatosis and lipid metabolism were verified., Key Findings: HyO Sham rats were obese, hyperinsulinemic, insulin resistant and dyslipidemic. These rats had higher liver contents of trygliceride (TG) and presented disorganization of the hepatocyte structures, in association with higher hepatic contents of acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 mRNAs and protein. DJB surgery normalized insulinemia, insulin resistance, and dyslipidemia in HyO rats. TG content in the liver and the hepatic microscopic structures were also normalized in HyO DJB rats, while the expressions of ACC and FASN proteins were decreased in the liver of these rodents., Significance: The DJB-induced amelioration in hepatic steatosis manifested as a late effect in HyO rats, and was partly associated with a downregulation in hepatic de novo lipogenesis processes, indicating that DJB protects against liver steatosis in hypothalamic obesity., (Copyright © 2017 Elsevier Inc. All rights reserved.)