Integrated multi-omic analysis identifies fatty acid binding protein 4 as a biomarker and therapeutic target of ischemia-reperfusion injury in steatotic liver transplantation.

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.

Effect of Preoperative Very Low-Calorie Diets on Hepatic Steatosis, Fibrosis, and Perioperative Outcomes of Bariatric Surgery.

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/m2) 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.

[Establishment of a nomogram prediction model using common preoperative indicators for early weight loss after laparoscopic sleeve gastrectomy].

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/m2. All patients in this group underwent standardized LSG procedure. Achieving ideal weight (BMI≤25 kg/m2) 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.

Lifestyle Optimization Leads to Superior Liver Regeneration in Live Liver Donors and Decreases Early Allograft Dysfunction in Recipients: A Randomized Control Trial.

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-ß 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.

Viability assessment and transplantation of fatty liver grafts using end-ischemic normothermic machine perfusion.

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.

Isolation of Regenerating Hepatocytes after Partial Hepatectomy in Mice.

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.

[The effect of steatotic donor livers on the prognosis of donors and recipients after pediatric living donor liver transplantation].

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,χ2 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.

ACCURACY OF ELASTOGRAPHY IN THE ASSESSMENT OF REDUCTION IN LIVER STEATOSIS AND FIBROSIS IN THE EARLY POSTOPERATIVE PERIOD AFTER BARIATRIC SURGERY.

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.

Outcomes of right lobe donors with BMI≥30 for living donor liver transplantation.

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.

Sleeve Gastrectomy Improves High-Fat Diet-Associated Hepatic Steatosis Independent of the Glucagon-like-Petpide-1 Receptor in Rats.

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.

Resolution of Severe Graft Steatosis Before Living-Donor Liver Transplant After 86 Pounds of Weight Loss.

Living-donor liver transplant allows for expedited transplant, with outcomes shown to be superior compared with deceased-donor liver transplant due to earlier intervention, with reduced hospital costs. However, they only comprise about 5% of liver transplants nationally. This is due to a limited pool of willing donors and donor exclusions for medical and psycho-social reasons. The leading reason for why potential living liver donors are not eligible is nonalcoholic fatty liver disease. Donor hepatic steatosis limits the number of potential living-donor liver transplants because it is associated with perioperative complications in both donors and recipients. Here, we describe a 37-year-old male potential living donor who presented with hepatic steatosis based on preoperative imaging. Over a 1-year period, he was able to completely reverse his hepatic steatosis by losing about 86 pounds (from 279 to 193 pounds), reducing his body mass index from 40 to 28.55 kg/m². Computed tomography and biopsy results after his weight loss showed that he had no hepatic steatosis, allowing him to become a living donor for his mother. Postoperative periods for both the donor and recipient were uncomplicated. This case suggests that the pool of living liver donors could be expanded through dietary and behavior modifications, thus increasing the number of potential living donors and providing potential recipients with more transplant options. Enlarging this pool of donors will also improve transplant outcomes for donors and recipients and lower overall health care costs compared with deceased-donor liver transplant.

Gastric Bypass Versus Sleeve Gastrectomy in Type 2 Diabetes: Effects on Hepatic Steatosis and Fibrosis : A Randomized Controlled Trial.

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 [ObesitySurgery in Tønsberg]). (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/m2) 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.

Contemporary strategies to assess and manage liver donor steatosis: a review.

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.

Altered metabolism by autophagy defection affect liver regeneration.

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.

Hígado agudo graso del embarazo: reporte de caso / Acute fatty liver of pregnancy: case report

El hígado graso del embarazo es una patología poco frecuente en la especialidad obstétrica, cuyo diagnóstico se realiza basado en los criterios de Swansea, muchas veces es un diagnóstico que se realiza por exclusión; usualmente se presenta entre las semanas 30 y 35 del embarazo, y la cura definitiva se realiza con la interrupción expedita del mismo; con una tasa de recuperación casi del 100% si se realiza la interrupción oportuna y una tasa de mortalidad materno fetal actual del 10%. Es importante estar atentos a la ganancia ponderal de la embarazada durante el control prenatal, la epigastralgia, y los signos clínicos asociados a hipoglicemia(AU)

Fatty liver of pregnancy is a rare pathology in obstetrics, whose diagnosis is made based on the Swansea criteria, many times it is a diagnosis that is made by exclusion; It usually occurs between weeks 30 and 35, and the definitive cure is carried out with the expeditious interruption of pregnancy; with a recovery rate of almost 100% if timely interruption is made and a current maternal-fetal mortality rate of 10%. It is important to be attentive to the weight gain of the pregnant woman during prenatal control, epigastric pain, and clinical signs associated with hypoglycemia

How Good Are Controlled Attenuation Parameter Scores from Fibroscan to Assess Steatosis, NASH, and Fibrosis?

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.

7-T MRI of explanted liver and ex-vivo pancreatic specimens: prospective study protocol of radiological-pathological correlation feasibility (the EXLIPSE project).

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.

Predictive value of perfusion CT for blood loss in liver resection.

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.