ω‐3 Fatty Acids Prevent Hepatic Steatosis,Independent of PPAR‐α Activity,in a Murine Model of Parenteral Nutrition–Associated Liver Disease

Objectives: ω‐3 Fatty acids (FAs), natural ligands for the peroxisome proliferator‐activated receptor–α (PPAR‐α), attenuate parenteral nutrition–associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω‐3 FAs are still unknown. The aim of this study was to determine the effects of ω‐3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR‐α and microsomal triglyceride transfer protein (MTP) in this experimental setting. Methods: 129S1/SvImJ wild‐type or 129S4/SvJaePparatm/Gonz/J PPAR‐α knockout mice were fed chow and water (controls); oral, fat‐free PN solution only (PN‐O); PN‐O plus intraperitoneal (IP) ω‐6 FA‐predominant supplements (PN–ω‐6); or PN‐O plus IP ω‐3 FA (PN–ω‐3). Control and PN‐O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR‐α messenger RNA were assessed after 19 days. Results: In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN‐O and PN–ω‐6 groups accumulated significantly greater amounts of TG when compared with PN–ω‐3 mice. Studies in PPAR‐α null animals showed that PN feeding increases hepatic TG as in wild‐type mice. PPAR‐α null mice in the PN‐O and PN–ω‐6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω‐3 FAs. Conclusions: PN induces TG accumulation (steatosis) in wild‐type and PPAR‐α null mice. In PN‐fed wild‐type and PPAR‐α null mice given IP ω‐3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω‐3 FAs results from PPAR‐α–independent pathways.     

Effects of the ω‐6:ω‐3 Fatty Acid Ratio of Fat Emulsions on the Fatty Acid Composition in Cell Membranes and the Anti‐Inflammatory Action

Background: This study investigated the effects of parenterally administered fish oil (FO) on the fatty acid composition in rats to determine the optimal ω‐6:ω‐3 polyunsaturated fatty acid (PUFA) ratio of fat emulsions to achieve an anti‐inflammatory effect. Methods: Male Sprague‐Dawley rats were infused a parenteral nutrition (PN) solution containing fat emulsions with different ω‐6:ω‐3 PUFA ratios. The fatty acid content of phospholipids in the membranes of splenocytes was analyzed by gas chromatography (experiment 1). In addition, the amounts of leukotriene (LT) B₄ and LTB₅ released from peritoneal polymorphonuclear leukocytes (PMNs) were measured by high‐performance liquid chromatography (experiment 2). Results: In experiment 1, after infusion of the fat emulsion containing FO, the ω‐3 PUFA content in cell membranes rose to 70% of the peak value on day 1 and nearly reached a plateau on day 3. The highest ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) was achieved by administrating a PN solution with the smallest ω‐6:ω‐3 PUFA ratio. In experiment 2, a larger amount of LTB₅ was released from Ca‐ionophore‐stimulated PMNs taken from rats given a larger quantity of FO. The ratio of LTB₅:LTB₄ released from PMNs correlated positively with the EPA:AA ratio in the membranous phospholipid and in serum. Conclusions: The ω‐3 PUFAs were readily incorporated into the cell membrane within 3 days of infusion with the fat emulsion. The EPA:AA ratio in membranous phospholipid in PMNs was positively correlated with the LTB₅:LTB₄ production ratio and was a good indicator of anti‐inflammatory effects.     

Parenteral Fish Oil Lipid Emulsions in the Critically Ill

Introduction: ω‐3 Polyunsaturated fatty acids contained in fish oils (FO) possess major anti‐inflammatory, antioxidant, and immunologic properties that could be beneficial during critical illness. We hypothesized that parenteral FO‐containing emulsions may improve clinical outcomes in the critically ill. Methods: We searched computerized databases from 1980–2012. We included randomized controlled trials (RCTs) conducted in critically ill adult patients that evaluated FO‐containing emulsions, either in the context of parenteral nutrition (PN) or enteral nutrition (EN). Results: A total of 6 RCTs (n = 390 patients) were included; the mean methodological score of all trials was 10 (range, 6–13). When the results of these studies were aggregated, FO‐containing emulsions were associated with a trend toward a reduction in mortality (risk ratio [RR], 0.71; 95% confidence interval [CI], 0.49–1.04; P = .08; heterogeneity I² = 0%) and a reduction in the duration of mechanical ventilation (weighted mean difference in days [WMD], ?1.41; 95% CI, ?3.43 to 0.61; P = .17). However, this strategy had no effect on infections (RR, 0.76; 95% CI, 0.42–1.36; P = .35) and intensive care unit length of stay (WMD, ?0.46; 95% CI, ?4.87 to 3.95; P = .84, heterogeneity I² = 75%). Conclusion: FO‐containing lipid emulsions may be able to decrease mortality and ventilation days in the critically ill. However, because of the paucity of clinical data, there is inadequate evidence to recommend the routine use of parenteral FO. Large, rigorously designed RCTs are required to elucidate the efficacy of parenteral FO in the critically ill.     

Effects on Varying Intravenous Lipid Emulsions on the Small Bowel Epithelium in a Mouse Model of Parenteral Nutrition

Background: Injectable fat emulsions (FEs) are a clinically dependable source of essential fatty acids (FA). ω‐6 FA is associated with an inflammatory response. Medium‐chain triglycerides (MCT, ω‐3 FA), fish oil, and olive oil are reported to decrease the inflammatory response. However, the effect of these lipids on the gastrointestinal tract has not been well studied. To address this, we used a mouse model of parenteral nutrition (PN) and hypothesized that a decrease in intestinal inflammation would be seen when either fish oil and MCT or olive oil were added. Methods: Three FEs were studied in adult C57BL/6 mice via intravenous cannulation: standard soybean‐based FE (SBFE), 80% olive oil ‐supplemented FE (OOFE), or a combination of a soybean oil, MCT, olive oil, and fish oil emulsion (SMOF). PN was given for 7 days, small bowel mucosa‐derived cytokines, animal survival rate, epithelial cell (EC) proliferation and apoptosis rates, intestinal barrier function and mucosal FA composition were analyzed. Results: Compared to the SBFE and SMOF groups, the best survival, highest EC proliferation and lowest EC apoptosis rates were observed in the OOFE group; and associated with the lowest levels of tumor necrosis factor‐α, interleukin‐6, and interleukin‐1β expression. Jejunal FA content showed higher levels of eicosapentaenoic and docosapentaenoic acid in the SMOF group and the highest arachidonic acid in the OOFE group. Conclusion: The study showed that PN containing OOFE had beneficial effects to small bowel health and animal survival. Further investigation may help to enhance bowel integrity in patients restricted to PN.     

Hepatic Indicators of Oxidative Stress and Tissue Damage Accompanied by Systemic Inflammation in Rats Following a 24‐Hour Infusion of an Unstable Lipid Emulsion Admixture

Background: Use of lipid emulsions in parenteral nutrition therapy is an important source of daily energy in substitution of potentially harmful glucose calories when given in excess in the intensive care unit. When added to parenteral nutrition (PN) admixtures as a total nutrient admixture (TNA), the stability and safety of the emulsion may be compromised. Development of a rat model of a stable vs unstable lipid infusion would enable a study of the potential risk. Design: Prospective, randomized, controlled study. Methods: Surgical placement of a jugular venous catheter for the administration of TNAs was performed. Two groups were studied: a stable or s‐TNA (n = 16) and an unstable or u‐TNA (n = 17) as a 24‐hour continuous infusion. Stability of TNAs was determined immediately before and after infusion using a laser‐based method approved by the United States Pharmacopeia. Results: Blood levels of aspartate aminotransferase, glutathione‐S‐transferase, and C‐reactive protein were significantly elevated in u‐TNA vs s‐TNA (P < .05). Also, liver tissue concentrations of malondialdehyde were significantly higher in the u‐TNA group (P < .05), and triglyceride tissue levels were also higher in u‐TNA and approached statistical significance (P = .077). Conclusions: Unstable lipid infusions over 24 hours produce evidence of hepatic accumulation of fat associated with oxidative stress, liver injury, and a low‐level systemic inflammatory response.     

Soybean and Fish Oil Mixture With Different ω‐6/ω‐3 Polyunsaturated Fatty Acid Ratios Modulates Dextran Sulfate Sodium–Induced Changes in Small Intestinal Intraepithelial γδT‐Lymphocyte Expression in Mice

Background: This study investigated the effect of different ω‐6/ω‐3 polyunsaturated fatty acid (PUFA) ratios on dextran sulfate sodium (DSS)–induced changes to small intestinal intraepithelial lymphocyte (IEL) γδT‐cell expression. Methods: Mice were assigned to 3 control and 3 DSS‐treated groups and were maintained on a low‐fat semipurified diet. One of the control (S) groups and a DSS (DS) group were provided with soybean oil; the other 2 control (Hω‐3 and Lω‐3) groups and 2 other DSS (DHω‐3 and DLω‐3) groups were fed either a soybean and fish oil mixture with a ω‐6/ω‐3 ratio of 2:1 or 4:1. After feeding the respective diets for 2 weeks, the DSS groups were given distilled water containing 2% DSS, and the control groups were given distilled water for 5 days. All groups were further provided distilled water 5 days for recovery, and the small intestinal IEL γδT‐cell subset was isolated for analysis. Results: DSS treatment resulted in a lower small intestinal IEL γδT‐cell percentage and higher messenger RNA (mRNA) expressions of Reg IIIγ, keratinocyte growth factor (KGF), and complement 5a receptor (C5aR) by IEL γδT cells. Fish oil administration enhanced the proportion of small intestinal IEL γδT cells. Compared with the DLω‐3 group, the DHω‐3 group had lower Reg IIIγ, KGF, and C5aR mRNA expressions and higher expression of peroxisome proliferator‐activated receptor (PPAR)–γ gene by small intestinal IEL γδT cells. Conclusions: Fish oil diets with a ω‐6/ω‐3 PUFA ratio of 2:1 were more effective than those with a ratio of 4:1 in improving DSS‐induced small intestinal injury, and activation of PPAR‐γ in IEL γδT cells may be associated with resolution of small intestinal inflammation.     

Intravenous ω‐3 Fatty Acids Plus Gemcitabine

Background: Marine‐derived ω‐3 fatty acids (ω‐3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω‐3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. Materials and Methods: Patients were administered gemcitabine 1000 mg/m³ weekly followed by up to 100 g (200 mg/mL) of ω‐3 rich lipid emulsion for 3 weeks followed by a rest week. This was continued for up to 6 cycles, progression, unacceptable toxicity, patient request, or death. The primary outcome measure was objective response rate, with secondary outcome measures of overall and progression free survival, QOL scores, and adverse events. Results: Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85.7%. Overall and progression free survival were 5.9 and 4.8 months, respectively. Increase in global health of > 10% over baseline was seen in 47.2% of patients. More than 50% of patients had > 10% increase in QOL scores in generic symptom scores and both disease‐specific domains. Grade 3/4 adverse events were thrombocytopenia (8%), neutropenia (12%), nausea or vomiting (4%), and chills (6%). Conclusion: Intravenous ω‐3FAs in combination with gemcitabine shows evidence of improved activity and benefit to QOL in patients with advanced pancreas cancer and is worthy of investigation in a randomized phase III trial.     

Impact of Providing a Combination Lipid Emulsion Compared With a Standard Soybean Oil Lipid Emulsion in Children Receiving Parenteral Nutrition

Background: Soybean oil lipid emulsion may compromise immune function and promote hepatic damage due to its composition of long‐chain fatty acids, phytosterols, high proportion of ω‐6 fatty acids, and low α‐tocopherol levels. Combination lipid emulsions have been developed using medium‐chain triglyceride oil, fish oil, and/or olive oil, which provide adequate essential fatty acids, a smaller concentration of ω‐6 fatty acids, and lower levels of phytosterols. The purpose of this systematic review is to determine if combination lipid emulsions have a more favorable impact on bilirubin levels, triglyceride levels, and incidence of infection compared with soybean oil lipid emulsions in children receiving parenteral nutrition. Methods: This study comprises a systematic review of published studies. Data were sufficient and homogeneous to conduct a meta‐analysis for total bilirubin and infection. Results: Nine studies met the inclusion criteria. Meta‐analysis showed that combination lipid emulsion decreased total bilirubin by a mean difference of 2.09 mg/dL (95% confidence interval, –4.42 to 0.24) compared with soybean oil lipid emulsion, although the result was not statistically significant (P = .08). Meta‐analysis revealed no statistically significant difference in incidence of infection between the combination lipid emulsion and the soybean oil lipid emulsion groups (P = .846). None of the 4 studies that included triglyceride as an outcome detected a significant difference in triglyceride levels between the combination lipid emulsion and soybean oil lipid emulsion groups. Conclusion: There is inadequate evidence that combination lipid emulsions offer any benefit regarding bilirubin levels, triglyceride levels, or incidence of infection compared with soybean oil lipid emulsions.     

Long‐Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure–Associated Liver Disease

Background: Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF‐associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long‐term PN and FOLE therapy due to chronic IF. Materials and Methods: A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. Results: Of 215 patients with IFALD treated from 2004–2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight‐for age and length‐for‐age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. Conclusions: Children with IFALD who required long‐term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.     

Rapid Incorporation of ω‐3 Fatty Acids Into Colonic Tissue After Oral Supplementation in Patients With Colorectal Cancer

Background: The purpose of the study was to examine whether a preoperative supplement with ω‐3 fatty acids (FAs) leads to their incorporation into colonic tissue in patients scheduled for colorectal cancer surgery. This would be of interest because ω‐3 FAs have potential beneficial (local) immunological effects that might benefit these patients. Methods: In a randomized, double‐blind, prospective, placebo‐controlled, single‐center intervention trial, patients referred for elective colorectal cancer surgery received either an ω‐3 FA–enriched oral nutrition supplement (ONS) (200 mL twice daily) providing 2.0 g of eicosapentaenoic acid (EPA) and 1.0 g of docosahexaenoic acid (DHA) per day or a standard ONS for 7 days before surgery. Tissue samples from healthy colonic tissue (mucosa and muscular layer) were obtained during surgery, and tissue fatty acid composition was analyzed by gas chromatography. Results: EPA was significantly higher in colonic mucosa (P = .001) and in the colonic muscular layer (P = .004) in the ω‐3 FA group compared with controls. Patients in the ω‐3 FA group also tended to have higher docosapentaenoic acid and DHA levels in colonic tissue. Conclusions: EPA is incorporated rapidly into colonic mucosa and colonic muscular layer in patients given 3 g of ω‐3 FA daily for 7 days before surgery for colorectal cancer. This may lead to potential beneficially effects on (local) immune function, which might benefit these patients.     

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 ω‐6 polyunsaturated fatty acids (PUFAs). Mounting evidence indicates that the ω‐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 ω‐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.     

Fish Oil–Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence

Background. There is evidence from laboratory and animal studies that fish oil–containing intravenous lipid emulsions (FOC‐IVLEs) have a beneficial effect on inflammation and the immune response, suggesting a possible clinical benefit. Clinical studies of FOC‐IVLEs have reported mixed results. The aim of this review is to present findings from recent randomized controlled clinical trials and other quality clinical studies investigating the effects of administering intravenous fish oil alone or as part of a multilipid emulsion and to examine the quality of these studies in an objective, evidence‐based manner. Methods. Studies comparing FOC‐IVLEs with other IVLEs in adults were included. Thirty‐four clinical studies were evaluated: 19 investigated levels of inflammatory and immune markers as an endpoint; 13 investigated rates of infection or sepsis; 3 investigated clinical outcomes in septic patients; and 29 investigated general clinical outcomes. Results. There was conflicting evidence for a beneficial effect of fish oil on levels of inflammatory and immune markers and some evidence that fish oil decreased the rate of postoperative atrial fibrillation. Studies generally reported few statistical differences in clinical outcomes and rates of infection and sepsis with FOC‐IVLEs as compared with other IVLEs. The quality of reporting was generally poor, and the presented evidence for comparisons between FOC‐IVLEs and other IVLEs was inconclusive or weak. Conclusions. There is very little high‐quality evidence that FOC‐IVLEs have a more beneficial effect than other IVLEs on clinical outcomes in adult patients.     

A New Intravenous Fat Emulsion Containing Soybean Oil,Medium‐Chain Triglycerides,Olive Oil,and Fish Oil

Background: SMOFlipid 20% is an intravenous lipid emulsion (ILE) containing soybean oil, medium‐chain triglycerides, olive oil, and fish oil developed to provide energy, essential fatty acids (FAs), and long‐chain ω‐3 FAs as a mixed emulsion containing α‐tocopherol. The aim was to assess the efficacy and safety of this new ILE in pediatric patients receiving home parenteral nutrition (HPN) compared with soybean oil emulsion (SOE). Methods: This single‐center, randomized, double‐blind study included 28 children on HPN allocated to receive either SMOFlipid 20% (n = 15) or a standard SOE (Intralipid 20%, n = 13). ILE was administered 4 to 5 times per week (goal dose, 2.0 g/kg/d) within a parenteral nutrition regimen. Assessments, including safety and efficacy parameters, were performed on day 0 and after the last study infusion (day 29). Lipid peroxidation was determined by measurement of thiobarbituric acid reactive substances (TBARS). Results: There were no significant differences in laboratory safety parameters, including liver enzymes, between the groups on day 29. The mean ± standard deviation changes in the total bilirubin concentration between the initial and final values (day 29 to day 0) were significantly different between groups: SMOFlipid group ?1.5 ± 2.4 µmol/L vs SOE group 2.3 ± 3.5 µmol/L, P < .01; 95% confidence interval [CI], ?6.2 to ?1.4). In plasma and red blood cell (RBC) phospholipids, the ω‐3 FAs C20:5ω‐3 (eicosapentaenoic acid) and + C22:6ω‐3 (docosahexaenoic acid) increased significantly in the SMOFlipid group on day 29. The ω‐3:ω‐6 FA ratio was significantly elevated with SMOFlipid 20% compared with SOE group (plasma, day 29: 0.15 ± 0.06 vs 0.07 ± 0.02, P < .01, 95% CI, 0.04–0.11; and RBC, day 29: 0.23 ± 0.07 vs 0.14 ± 0.04, P < .01, 95% CI, 0.04–0.13). Plasma α‐tocopherol concentration increased significantly more with SMOFlipid 20% (15.7 ± 15.9 vs 5.4 ± 15.2 µmol/L, P < .05; 95% CI, ?2.1 to 22.6). The low‐density lipoprotein–TBARS concentrations were not significantly different between both groups, indicating that lipid peroxidation did not differ between groups. Conclusions: SMOFlipid 20%, which contains 15% fish oil, was safe and well tolerated, decreased plasma bilirubin, and increased ω‐3 FA and α‐tocopherol status without changing lipid peroxidation.     

Effect of an Olive Oil–Based Lipid Emulsion Compared With a Soybean Oil–Based Lipid Emulsion on Liver Chemistry and Bile Acid Composition in Preterm Infants Receiving Parenteral Nutrition

Background: The pathogenesis of parenteral nutrition (PN)–associated liver dysfunction is multifactorial. Lipid emulsions may be one of the putative mechanisms. Our aim was to comparatively assess the effect of parenteral olive oil– and soybean oil–based lipid emulsions on liver chemistry and bile acid composition in preterm infants. Methods: We performed a double‐blind, randomized clinical study in which 103 preterm infants were randomly assigned to PN using either soybean oil–based lipid emulsion (SO; n = 51) or olive oil (OO)–based lipid emulsion (OO; n = 52). The primary end point was liver chemistry. The secondary end point was the plasma bile acid composition. Results: One hundred infants completed this study. In the SO group, the serum direct bilirubin was significantly higher after PN for 7 days compared with the OO group. Bile acids increased over time in both treatment groups. However, specific differences in the change in bile acid composition over time were noted between groups. Conclusions: Differences in direct bilirubin and bile acid composition were observed over time between the 2 groups. Considering the long‐term use of lipid emulsions in higher risk babies, these findings might be useful for understanding the pathogenesis of PN‐associated liver dysfunction.     

A.S.P.E.N. Clinical Guidelines

Background: Children with severe intestinal failure and prolonged dependence on parenteral nutrition are susceptible to the development of parenteral nutrition–associated liver disease (PNALD). The purpose of this clinical guideline is to develop recommendations for the care of children with PN‐dependent intestinal failure that have the potential to prevent PNALD or improve its treatment. Method: A systematic review of the best available evidence to answer a series of questions regarding clinical management of children with intestinal failure receiving parenteral or enteral nutrition was undertaken and evaluated using concepts adopted from the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group. A consensus process was used to develop the clinical guideline recommendations prior to external and internal review and approval by the American Society for Parenteral and Enteral Nutrition Board of Directors. Questions: (1) Is ethanol lock effective in preventing bloodstream infection and catheter removal in children at risk of PNALD? (2) What fat emulsion strategies can be used in pediatric patients with intestinal failure to reduce the risk of or treat PNALD? (3) Can enteral ursodeoxycholic acid improve the treatment of PNALD in pediatric patients with intestinal failure? (4) Are PNALD outcomes improved when patients are managed by a multidisciplinary intestinal rehabilitation team?     

Preventing the Progression of Intestinal Failure–Associated Liver Disease in Infants Using a Composite Lipid Emulsion: A Pilot Randomized Controlled Trial of SMOFlipid

Background: To examine whether SMOFlipid prevents progression of intestinal failure–associated liver disease (IFALD) in parenteral nutrition (PN)–dependent infants with early IFALD (conjugated bilirubin 17–50 µmol/L, 1‐3 mg/dL). Study Design: Pilot multicenter blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin. Results: Twenty‐four infants (mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment (P = .99). At trial conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, –59 µmol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 µmol/L than those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes between the groups. Conclusions: Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.     

Immune modulation by parenteral lipid emulsions

Total parenteral nutrition is the final option for nutritional support of patients with severe intestinal failure. Lipid emulsions constitute the main source of fuel calories and fatty acids (FAs) in parenteral nutrition formulations. However, adverse effects on patient outcomes have been attributed to the use of lipids, mostly in relation to impaired immune defenses and altered inflammatory responses. Over the years, this issue has remained in the limelight, also because technical advances have provided no safeguard against the most daunting problems, ie, infectious complications. Nevertheless, numerous investigations have failed to produce a clear picture of the immunologic characteristics of the most commonly used soybean oil-derived lipid emulsions, although their high content of n-6 polyunsaturated FAs (PUFAs) has been considered a drawback because of their proinflammatory potential. This concern initiated the development of emulsions in which part of the n-6 FA component is replaced by less bioactive FAs, such as coconut oil (rich in medium-chain saturated FAs) or olive oil (rich in the n-9 monounsaturated FA oleic acid). Another approach has been to use fish oil (rich in n-3 PUFA), the FAs of which have biological activities different from those of n-6 PUFAs. Recent studies on the modulation of host defenses and inflammation by fish-oil emulsions have yielded consistent data, which indicate that these emulsions may provide a tool to beneficially alter the course of immune-mediated conditions. Although most of these lipids have not yet become available on the US market, this review synthesizes available information on immunologic characteristics of the different lipids that currently can be applied via parenteral nutrition support.     

No Clinical or Biochemical Evidence for Essential Fatty Acid Deficiency in Home Patients Who Depend on Long‐Term Mixed Olive Oil– and Soybean Oil–Based Parenteral Nutrition

Background: Home parenteral nutrition (HPN) patients depend on lipid emulsions as part of their parenteral nutrition regimen to provide essential fatty acids (EFAs). Mixed‐oil sources are used in modern lipid emulsions to decrease the amount of proinflammatory EFAs, mainly linoleic acid, which is present in large amounts in soybean oil. It is unknown whether patients who fully depend on such mixed lipids have adequate EFA supply. We therefore evaluated whether HPN patients who depend on mixed olive oil– and soybean oil–based HPN show clinical or biochemical evidence of EFA deficiency. Materials and Methods: Fatty acid status was assessed in plasma phosphatidylcholine (PC) and peripheral blood mononuclear cells from 30 patients receiving mixed olive oil– and soybean oil–based HPN (>3 months, ≥5 times per week) and 30 healthy controls. Innate immune cell functions were evaluated by assessing expression of surface membrane molecules, and reactive oxygen species, and cytokine production. Results: None of the patients or controls showed clinical evidence (skin rash) or biochemical evidence (increased Holman index [>0.2]) for EFA deficiency. The Holman index in plasma PC (median [25th–75th percentile]) was significantly higher in patients (0.019 [0.015–0.028]) compared with controls (0.015 [0.011–0.017]). No differences were found in innate immune cell functions between groups, except for a 3.6‐fold higher tumor necrosis factor–α production in patients. Conclusion: We found no clinical or biochemical evidence that HPN patients who fully and long‐term depend on mixed olive oil– and soybean oil–based lipids have an increased risk for EFA deficiency.     

Parenteral Plant Sterols Accumulate in the Liver Reflecting Their Increased Serum Levels and Portal Inflammation in Children With Intestinal Failure

Background: Parenteral plant sterols (PSs) are considered hepatotoxic; however, liver PSs and their associations with liver injury in patients with intestinal failure (IF) have not been reported. Materials and Methods: We analyzed liver and serum PS (avenasterol, campesterol, sitosterol, and stigmasterol) concentrations and ratios to cholesterol and their associations with biochemical and histologic liver damage in children with IF during (n = 7) parenteral nutrition (PN) and after weaning off it (n = 9), including vegetable oil–based lipid emulsions. Results: Liver avenasterol, sitosterol, and total PS concentrations and cholesterol ratios were 2.4‐fold to 5.6‐fold higher in PN‐dependent patients (P < .05). Parenteral PS delivery reflected liver avenasterol and sitosterol ratios to cholesterol (r = 0.83–0.89, P = .02–.04), while serum and liver total PS levels were positively interrelated (r = 0.98, P < .01). Any liver histopathology was equally common while portal inflammation more frequent (57 vs 0%, P = .02) in PN‐dependent patients. All liver PS fractions correlated positively with histologic portal inflammation (r = 0.53–0.66, P < .05), and their total concentration was significantly (P = .01) higher among patients with versus without portal inflammation. In PN‐dependent patients, liver fibrosis and any histopathology correlated with liver campesterol and stigmasterol levels (r = 0.79–0.87, P ≤ .03). Conclusion: Among children with IF, parenteral PSs accumulate in the liver, reflect their increased serum levels, and relate with biochemical liver injury, portal inflammation, and liver fibrosis, thus supporting their role in promoting liver damage.     

Lipid Emulsion Use in Pediatric Patients Requiring Long-Term Parenteral Nutrition

The ability to deliver nutrients via parenteral nutrition (PN) has markedly improved the prognosis of infants and children with intestinal failure. Technical refinements and advances in knowledge have led to the development of highly sophisticated PN solutions that are tailored to meet the needs of pediatric patients. However, children who require long-term PN have an increased risk of complications such as catheter-related sepsis, liver disease, and bone disease. Although the pathogenesis of intestinal failure associated liver disease (IFALD) is multifactorial, studies have identified a possible link between the dose of lipid emulsions based on soybean oil and cholestasis, shown to occur with a significantly higher frequency in patients receiving >1 g lipids/kg/d. Potential contributing factors include oxidative stress, high ω-6 polyunsaturated fatty acid (PUFA) and phytosterol content, and relatively low α-tocopherol levels. Lipid emulsions containing fish oil offer potential advantages compared with traditional emulsions with a high soybean oil content, such as decreased ω-6 and increased ω-3 PUFA concentrations, high concentrations of α-tocopherol, and reduced phytosterol content. Studies in PN-dependent children at risk for IFALD have shown that lipid emulsions containing fish oil reduce the risk of cholestasis and improve biochemical measures of hepatobiliary function compared with pure soybean oil emulsions. This review summarizes evidence regarding the role of lipid emulsions in the management of pediatric patients with intestinal failure requiring long-term PN, with a particular focus on the prevention and treatment of IFALD.