Metabolic Dysfunction-Associated Steatotic Liver Disease in a Dish: Human Precision-Cut Liver Slices as a Platform for Drug Screening and Interventions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing healthcare problem with limited therapeutic options. Progress in this field depends on the availability of reliable preclinical models. Human precision-cut liver slices (PCLSs) have been employed to replicate the initiation of MASLD, but a comprehensive investigation into MASLD progression is still missing. This study aimed to extend the current incubation time of human PCLSs to examine different stages in MASLD. Healthy human PCLSs were cultured for up to 96 h in a medium enriched with high sugar, high insulin, and high fatty acids to induce MASLD. PCLSs displayed hepatic steatosis, characterized by accumulated intracellular fat. The development of hepatic steatosis appeared to involve a time-dependent impact on lipid metabolism, with an initial increase in fatty acid uptake and storage, and a subsequent down-regulation of lipid oxidation and secretion. PCLSs also demonstrated liver inflammation, including increased pro-inflammatory gene expression and cytokine production. Additionally, liver fibrosis was also observed through the elevated production of pro-collagen 1a1 and tissue inhibitor of metalloproteinase-1 (TIMP1). RNA sequencing showed that the tumor necrosis factor alpha (TNFα) signaling pathway and transforming growth factor beta (TGFß) signaling pathway were consistently activated, potentially contributing to the development of inflammation and fibrosis. In conclusion, the prolonged incubation of human PCLSs can establish a robust ex vivo model for MASLD, facilitating the identification and evaluation of potential therapeutic interventions.

The Value of Biological and Conditional Factors for Staging of Patients with Resectable Pancreatic Cancer Undergoing Upfront Resection: A Nationwide Analysis.

BACKGROUND: Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. PATIENTS AND METHODS: A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014-2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB-) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC-). Overall survival (OS) was assessed using Kaplan-Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95% confidence interval (CI). RESULTS: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19-23). OS was 14 months (95% CI 10 months-median not reached) in 20 RB+C+ patients (3%; HR 1.61, 95% CI 0.86-2.70), 13 months (95% CI 11-15) in 156 RB+C- patients (23%; HR 1.86, 95% CI 1.50-2.31), and 21 months (95% CI 12-41) in 47 RB-C+ patients (7%; HR 1.14, 95% CI 0.80-1.62) compared with 24 months (95% CI 22-27) in 465 patients with RB-C- PDAC (68%; reference). CONCLUSIONS: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC.

Nationwide Use and Outcome of Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy.

BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.

Systematic review on percutaneous aspiration and sclerotherapy versus surgery in symptomatic simple hepatic cysts.

BACKGROUND: Simple hepatic cysts (SHC) may cause pain and bloating and thus impair quality of life. Whereas current guidelines recommend laparoscopic cyst deroofing, percutaneous aspiration and sclerotherapy (PAS) may be used as a less invasive alternative. This review aimed to assess the efficacy of PAS and surgical management in patients with symptomatic SHC. METHODS: A systematic search in PubMed and Embase was performed according to PRISMA-guidelines. Studies reporting symptoms were included. Methodological quality was assessed by the MINORS-tool. Primary outcomes were symptom relief, symptomatic recurrence and quality of life, for which a meta-analysis of proportions was performed. RESULTS: In total, 736 patients from 34 studies were included of whom 265 (36%) underwent PAS, 348 (47%) laparoscopic cyst deroofing, and 123 (17%) open surgical management. During weighted mean follow-up of 26.1, 38.2 and 21.3 months, symptoms persisted in 3.5%, 2.1%, 4.2%, for PAS, laparoscopic and open surgical management, respectively. Major complication rates were 0.8%, 1.7%, and 2.4% and cyst recurrence rates were 0.0%, 5.6%, and 7.7%, respectively. CONCLUSION: Outcomes of PAS for symptomatic SHC appear to be excellent. Studies including a step-up approach which reserves laparoscopic cyst deroofing for symptomatic recurrence after one or two PAS procedures are needed.

Hyperthermia-induced changes in liver physiology and metabolism: a rationale for hyperthermic machine perfusion.

Liver transplantation is the standard treatment for end-stage liver disease. However, due to the ongoing disparity between supply and demand for optimal donor organs, there is increasing usage of extended criteria donor organs, including steatotic liver grafts. To mitigate the increased risks associated with extended criteria donor livers, ex situ oxygenated machine perfusion (MP) has received increasing attention in recent years as an emerging platform for dynamic preservation, reconditioning, and viability assessment to increase organ utilization. MP can be applied at different temperatures. During hypothermic MP (4-12°C), liver metabolism is reduced, while oxygenation restores the intracellular levels of adenosine triphosphate. The liver is quickly "recharged" to support metabolism when at normothermia (35-37°C) and to ameliorate the detrimental effects of ischemia/reperfusion injury during transplantation. During normothermia, MP can be applied to assess hepatocellular and cholangiocellular viability. MP at hyperthermic (>38°C) temperatures (HyMP), however, remains relatively understudied. The liver is an important component in the regulation of core body temperature and, as such, displays significant physiological and metabolic changes in response to different temperatures. Hyperthermia may promote vasodilation, increase aerobic metabolism and induce production of protective molecules such as heat shock proteins. Therefore, HyMP could provide an attractive reconditioning strategy for steatotic livers. In this review, we describe current literature on the physiological and metabolic effects of the liver at hyperthermia for human, rodents, and pigs and provide a rationale for using therapeutic HyMP during isolated liver machine perfusion to recondition extended criteria donor livers, including steatotic livers, before transplantation.

The effect of varying ratios of docosahexaenoic acid and arachidonic acid in the prevention and reversal of biochemical essential fatty acid deficiency in a murine model.

OBJECTIVE: Essential fatty acids (EFA) are necessary for growth, development, and biological function, and must be acquired through the diet. While linoleic acid (LA) and alpha-linolenic acid (ALA) have been considered the true EFAs, we previously demonstrated that docosahexaenoic acid (DHA) and arachidonic acid (AA) taken together as the sole source of dietary fatty acids can prevent biochemical essential fatty acid deficiency (EFAD). This study evaluates the effect of varying dietary ratios of DHA:AA in the prevention and reversal of biochemical EFAD in a murine model. METHODS: Using a murine model of EFAD, we provided mice with 2.1% of daily caloric intake in varying DHA:AA ratios (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) for 19 days in association with a liquid high-carbohydrate fat-free diet to evaluate the effect on fatty acid profiles. In a second experiment, we evaluated the provision of varying DHA:AA ratios (20:1, 200:1, 100:0) on the reversal of biochemical EFAD. RESULTS: Mice provided with DHA and AA had no evidence of biochemical EFAD, regardless of the ratio (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) administered. Biochemical EFAD was reversed with DHA:AA ratios of 20:1, 200:1, and 100:0 following 3 and 5 weeks of dietary provision, although the 20:1 ratio was most effective in the reversal and stabilization of the triene:tetraene ratio. CONCLUSION: Provision of DHA and AA, at 2.1% of daily caloric intake in varying ratios can prevent biochemical evidence of EFAD and hepatic steatosis over the short-term, with a ratio of 20:1 DHA:AA most effectively reversing EFAD.

Dietary fish oil aggravates paracetamol-induced liver injury in mice.

BACKGROUND: Paracetamol (APAP) hepatotoxicity remains the leading cause of drug-induced liver failure. Fish oil, which contains ω-3 fatty acids, has demonstrated therapeutic efficacy in several models of liver disease. Evidence for its use in APAP intoxication, however, is conflicting. The effects of fish oil supplementation on APAP-induced liver failure were investigated. METHODS: Ten C57BL6/J mice were fed a diet based on menhaden fish oil (MEN) or soybean oil (SOY) for 3 weeks followed by APAP intoxication. In a second experiment, the prefeeding period was reduced to 5 days. In a third experiment, 10 mice received the study diets for 3 weeks, after which they received chronic, low-dose APAP administration for another 4 weeks. Finally, 10 mice received oral parenteral nutrition supplemented with either intravenous (IV) soybean-based or fish oil-based lipid emulsion for 19 days, followed by APAP intoxication. RESULTS: The extent of hepatocellular necrosis (3.8 ± 0.2 vs 2.8 ± 0.2; P = .021) and serum alanine aminotransferase values (2807 ± 785 vs 554 ± 141 IU/L; P = .048) were significantly elevated in mice fed a MEN diet compared with SOY-diet fed controls. Long-term, low-dose APAP administration did not lead to liver injury irrespective of study diet. Pretreatment with soybean- or fish oil-based IV lipid emulsions followed by APAP intoxication demonstrated no significant differences in hepatic injury between groups. CONCLUSION: Within therapeutic ranges, APAP is harmless to the liver irrespective of dietary fat composition. IV use of fish oil did not increase APAP-induced hepatotoxicity, but animals fed a fish oil-based diet were more susceptible, rather than resistant, to APAP-induced hepatotoxicity.

Docosahexaenoic acid and arachidonic acid prevent essential fatty acid deficiency and hepatic steatosis.

OBJECTIVES: Essential fatty acids are important for growth, development, and physiologic function. α-Linolenic acid and linoleic acid are the precursors of docosahexaenoic and arachidonic acid, respectively, and have traditionally been considered the essential fatty acids. However, the authors hypothesized that docosahexaenoic acid and arachidonic acid can function as the essential fatty acids. METHODS: Using a murine model of essential fatty acid deficiency and consequent hepatic steatosis, the authors provided mice with varying amounts of docosahexaenoic and arachidonic acids to determine whether exclusive supplementation of docosahexaenoic and arachidonic acids could prevent essential fatty acid deficiency and inhibit or attenuate hepatic steatosis. RESULTS: Mice supplemented with docosahexaenoic and arachidonic acids at 2.1% or 4.2% of their calories for 19 days had normal liver histology and no biochemical evidence of essential fatty acid deficiency, which persisted when observed after 9 weeks. CONCLUSION: Supplementation of sufficient amounts of docosahexaenoic and arachidonic acids alone without α-linolenic and linoleic acids meets essential fatty acid requirements and prevents hepatic steatosis in a murine model.

Parenteral fish-oil-based lipid emulsion improves fatty acid profiles and lipids in parenteral nutrition-dependent children.

BACKGROUND: Total parenteral nutrition (PN), including fat administered as a soybean oil-based lipid emulsion (SOLE), is a life-saving therapy but may be complicated by PN-induced cholestasis and dyslipidemia. A fish-oil-based lipid emulsion (FOLE) as a component of PN can reverse PN-cholestasis and has been shown to improve lipid profiles. OBJECTIVE: The objective was to describe changes in the fatty acid and lipid profiles of children with PN-cholestasis who were treated with a FOLE. DESIGN: Lipid and fatty acid profiles of 79 pediatric patients who developed PN-cholestasis while receiving standard PN with a SOLE were examined before and after the switch to a FOLE. All patients received PN with the FOLE at a dose of 1 g · kg(-1) · d(-1) for ≥1 mo. RESULTS: The median (interquartile range) age at the start of the FOLE treatment was 91 (56-188) d. After a median (interquartile range) of 18.3 (9.4-41.4) wk of receiving the FOLE, the subjects' median total and direct bilirubin improved from 7.9 and 5.4 mg/dL to 0.5 and 0.2 mg/dL, respectively (P < 0.0001). Serum triglyceride, total cholesterol, LDL, and VLDL concentrations significantly decreased by 51.7%, 17.4%, 23.7%, and 47.9%, respectively. CONCLUSIONS: The switch from a SOLE to a FOLE in PN-dependent children with cholestasis and dyslipidemia was associated with a dramatic improvement in serum triglyceride and VLDL concentrations, a significant increase in serum omega-3 (n-3) fatty acids (EPA and DHA), and a decrease in serum omega-6 fatty acids (arachidonic acid). A FOLE may be the preferred lipid emulsion in patients with PN-cholestasis, dyslipidemia, or both. This trial is registered at clinicaltrials.gov as NCT00910104.

Comparison of 5 intravenous lipid emulsions and their effects on hepatic steatosis in a murine model.

BACKGROUND: Plant-based intravenous lipid emulsions have been shown to contribute to parenteral nutrition-associated liver disease (PNALD). There is mounting evidence that fish oil-based emulsions may prevent this liver injury. This study compares 5 emulsions with different fat compositions and their effect on hepatic steatosis, one of the first hits in PNALD. METHODS: C57BL/6J mice were placed on a fat-free diet and randomized into 5 equal groups. Each group received one of the commercially available intravenous lipid emulsions (Intralipid [Baxter/Fresenius Kabi, Deerfield, Ill], Liposyn II [Hospira Inc, Lake Forest, Ill], ClinOleic [Baxter/Clintec Parenteral SA, Cedex, France], SMOFlipid [Fresenius Kabi, Bad Homburg, Germany], or Omegaven [Fresenius Kabi Deutschland GmbH]) or normal saline. Liver enzymes, degree of steatosis, and fatty acid compositions were analyzed after 19 days. RESULTS: Intralipid, Liposyn II, ClinOleic, and SMOFlipid groups all demonstrated moderate steatosis with hepatic fat contents of 17.4%, 21.9%, 22.5%, and 12.6%, respectively. Omegaven mice, however, had normal livers. Saline control mice developed biochemical evidence of essential fatty acid deficiency (EFAD). Lipid supplementation with Intralipid, Liposyn II, and Omegaven prevented the onset of biochemical EFAD, whereas administration of ClinOleic and SMOFlipid did not. CONCLUSION: The fish oil-based lipid emulsion Omegaven prevented hepatic steatosis and EFAD in this murine model. ω-3 fatty acids may be efficacious in preventing PNALD and should be explored in the development of novel lipid emulsions.

Surgical intervention in the setting of parenteral nutrition-associated cholestasis may exacerbate liver injury.

PURPOSE: This study compares postoperative markers of liver injury in patients receiving intravenous fish oil (IFO) with parenteral nutrition (PN)-associated cholestasis (PNAC) to patients with resolved PNAC. METHODS: A retrospective review of all cholestatic-IFO patients undergoing abdominal laparotomy between March 1, 2007, and July 1, 2009, led to inclusion of 23 patients who collectively underwent 27 abdominal operations (13 pre-PNAC resolution and 14 post-PNAC resolution). Direct bilirubin (DB), total bilirubin, and alanine aminotransferase levels were examined over time in relation to operations. The time to resume presurgical trend of decreasing DB was calculated. RESULTS: Sixty-nine percent (9/13) of pre-PNAC resolution procedures were associated with postoperative increase in DB compared with 7% (1/14) of post-PNAC resolution procedures associated with a recurrence of cholestasis (P = .02; odds ratio, 29.3; 95% confidence interval, 2.79-306.8). The median time to return to the preoperative downward trend of DB was 21 days. CONCLUSIONS: Operations before PNAC resolution may be associated with an increased postoperative DB, possibly reflecting an exacerbation of liver injury. Operations post-PNAC resolution on IFO had a comparatively low incidence of postoperative cholestasis recurrence. Excepting clinical indication otherwise, it may be advisable to delay surgical intervention in the setting of PNAC in certain cases.

Parenteral fish oil as monotherapy improves lipid profiles in children with parenteral nutrition-associated liver disease.

BACKGROUND: Parenteral nutrition (PN) is a life-saving therapy but has been associated with dyslipidemia. Because fish oil has been shown to have positive effects on lipid profiles, the authors hypothesize that a parenteral fish oil lipid emulsion will improve lipid profiles in children who are PN dependent. METHODS: The authors examined the lipid profiles of a unique cohort of 10 children who were exclusively administered a fish oil-based lipid emulsion while on PN for a median duration of 14 weeks. Longitudinal data analysis with a generalized estimating equations approach was used to determine the sterol and bilirubin levels based on duration of the fish oil-based lipid emulsion. RESULTS: After 14 weeks of fish oil monotherapy, children had a 24% increase in high-density lipoprotein. Compared to baseline, serum low-density lipoprotein, very low-density lipoprotein, total cholesterol, and triglyceride levels all significantly decreased by 22%, 41%, 17%, and 46%, respectively. Eight children had their bilirubin improved with a decreased direct bilirubin from 6.9 mg/dL (range, 4.4-10.7) at baseline to 2.3 mg/dL (range, 1.3-4.0) after 14 weeks, and a decrease in total bilirubin from 8.7 mg/dL (range, 5.5-13.7) to 3.8 mg/dL (range, 2.2-6.5). CONCLUSION: A fish oil-based lipid emulsion used as monotherapy in children who exclusively depended on PN for survival was associated with significant improvement in all major lipid panels as well as improvement of hyperbilirubinemia. Parenteral fish oil may be the preferred lipid source in children with dyslipidemia.

Parenteral fish oil monotherapy in the management of patients with parenteral nutrition-associated liver disease.

OBJECTIVES: To update knowledge on the management of parenteral nutrition-associated liver disease (PNALD) and to review the clinical data on the use of parenteral fish oil for reversal of PNALD. DATA SOURCES: A literature review was conducted by searching the MEDLINE database (May 1, 2009) using the keywords parenteral nutrition-associated liver disease, fish oil, omega-3, Omegaven, and lipid emulsion. STUDY SELECTION: All articles reporting clinical cases with the use of parenteral fish oil for management of PNALD. DATA EXTRACTION: Three reviewers independently analyzed the epidemiological, clinical, and treatment data of the articles. DATA SYNTHESIS: Six case reports (10 patients) and 2 cohort studies (12 and 18 patients) were analyzed. CONCLUSIONS: Fish oil-derived emulsions have been demonstrated to reverse preexisting PNALD and to prevent and treat essential fatty acid deficiency. Its ability to prevent PNALD is currently under investigation. Although the mechanism has yet to be fully understood, the advantages of fish oil-based lipid emulsions over soybean oil-based lipid emulsions seen to date suggest that fish oil-based emulsions would be better suited for use in long-term parenteral nutrition.

Innovative parenteral and enteral nutrition therapy for intestinal failure.

Children with intestinal failure (IF) suffer from insufficient intestinal length or function, making them dependent on parenteral nutrition (PN) for growth and survival. PN and its components are associated with many complications ranging from simple electrolyte abnormalities to life-threatening PN-associated liver disease, which is also called intestinal failure-associated liver disease (IFALD). From a nutrition perspective, the ultimate goal is to provide adequate caloric requirements and make the transition from PN to full enteral nutrition (EN) successful. Upon review of the literature, we have summarized the most effective and innovative PN and EN therapies for this patient population. Antibiotic-coated catheters and antibiotic or ethanol locks can be implemented, as they appear effective in reducing catheter-related infection and thus further reduce the risk of IFALD. Lipid emulsions should be given judiciously. The use of an omega-3 fatty acid-based formulation should be considered in patients who develop IFALD. Trophic feeding is important for intestinal adaptation, and EN should be initiated early to help wean patients from PN. Long-term management of children with IF continues to be an emerging field. We have entered uncharted territory as more children survive complications of IF and IFALD. Careful monitoring and individualized management to ensure maintenance of growth while avoiding complications are the keys to successful patient outcomes.

Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury.

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

Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the Boston experience.

Parenteral nutrition-associated liver disease (PNALD) is the most prevalent and most severe complication of long-term parenteral nutrition. Its underlying pathophysiology, however, largely remains to be elucidated. The currently approved parenteral lipid emulsions in the United States contain safflower or soybean oils, both rich in omega-6 polyunsaturated fatty acids (PUFAs). Mounting evidence indicates that the omega-6 PUFAs originating from plant oils in these lipid emulsions may play a role in the onset of liver injury. Fish oil-based lipid emulsions, in contrast, are primarily composed of omega-3 PUFAs, thus providing a promising alternative. The authors review the literature on the role of lipid emulsions in the onset of PNALD and discuss prevention and treatment strategies using a fish oil-based lipid emulsion. They conclude that a fish oil-based emulsion is hepatoprotective in a murine model of PNALD, and it appears to be safe and efficacious for the treatment of this type of liver disease in children. A prospective randomized trial that is currently under way at the authors' institution will objectively determine the place of fish oil monotherapy in the prevention of PNALD.