Reversal of Parenteral Nutrition–Associated Liver Disease With a Fish Oil–Based Lipid Emulsion (Omegaven) in an Adult Dependent on Home Parenteral Nutrition

Patients with intestinal failure and short bowel syndrome usually require chronic parenteral nutrition (PN). PN is associated with risks, including infections, vascular thrombosis, and liver disease. PN‐associated liver disease (PNALD) can progress from steatosis to chronic hepatitis and ultimately to cirrhosis. The etiology of PNALD is not completely understood. Therapies for PNALD include carbohydrate or lipid calorie reduction, antibiotics, or the use of ursodeoxycholic acid. When these efforts fail, therapeutic options are limited and liver transplantation may be required. The transition from a soybean‐ to a fish oil–based lipid formulation, such as the ω‐3 parenteral lipid formulation (Omegaven), has shown a dramatic reversal of PNALD within the pediatric population. This is the first report of a PN‐dependent adult in the United States complicated by PNALD and hepatic failure who had improvement of liver disease with an ω‐3 fish oil–based parenteral formulation.     

Low‐Dose Parenteral Soybean Oil for the Prevention of Parenteral Nutrition–Associated Liver Disease in Neonates With Gastrointestinal Disorders

Background: Neonates with gastrointestinal disorders (GDs) are at high risk for parenteral nutrition–associated liver disease (PNALD). Soybean‐based intravenous lipid emulsions (S‐ILE) have been associated with PNALD. This study's objective was to determine if a lower dose compared with a higher dose of S‐ILE prevents cholestasis without compromising growth. Materials and Methods: This multicenter randomized controlled pilot study enrolled patients with GDs who were ≤5 days of age to a low dose (~1 g/kg/d) (LOW) or control dose of S‐ILE (~3 g/kg/d) (CON). The primary outcome was cholestasis (direct bilirubin [DB] >2 mg/dL) after the first 7 days of age. Secondary outcomes included growth, PN duration, and late‐onset sepsis. Results: Baseline characteristics were similar between the LOW (n = 20) and CON groups (n = 16). When the LOW group was compared with the CON group, there was no difference in cholestasis (30% vs 38%, P = .7) or secondary outcomes. However, mean ± SE DB rate of change over the first 8 weeks (0.07 ± 0.04 vs 0.3 ± 0.09 mg/dL/wk, P = .01) and entire study (0.008 ± 0.03 vs 0.2 ± 0.07 mg/dL/wk, P = .02) was lower in the LOW group compared with the CON group. Conclusion: In neonates with GDs who received a lower dose of S‐ILE, DB increased at a slower rate in comparison to neonates who received a higher dose of S‐ILE. Growth was comparable between the groups. This study demonstrates a need for a larger, randomized controlled trial comparing 2 different S‐ILE doses for cholestasis prevention in neonates at risk for PNALD.     

Parenteral Soy Oil and Fish Oil Emulsions

Background: Parenteral nutrition (PN)–associated liver disease (PNALD) remains a significant cause of morbidity and mortality for neonates dependent on PN. Total fat emulsion dose and composition, particularly the large amount of ω‐6 long‐chain polyunsaturated fatty acids in plant oils, have been proposed as risk factors for PNALD. We hypothesized restriction of the dose of emulsion would prevent PNALD, regardless of the composition, but growth could be compromised. Methods: Using a neonatal piglet model, we compared conventional soy oil emulsion (Intralipid), dosed high (SO10, n = 8: 10 g/kg/d) and low (SO5, n = 6: 5 g/kg/d), with fish oil (Omegaven), dosed low (FO5, n = 8: 5 g/kg/d). Piglets were given isonitrogenous PN for 14 days. The normal range for all parameters was determined by measurement in equivalent aged sow‐reared piglets. Results: Bile flow was lower with high‐dose Intralipid, outside the normal range, while higher for the other groups (SO10, 5.4 µg/g; SO5, 8.6 µg/g; FO5, 13.4 µg/g; P = .010; normal range, 6.5–12.2 µg/g). Total body weight was low in all treatment groups (SO10, 4.4 kg; SO5, 4.5 kg; FO5, 5.0 kg; P = .038; normal range, 5.2–7.3 kg). Brain weight was not different between groups (SO10, 40.3 g; SO5, 36.0 g; FO5, 36.6 g; P = .122; normal range, 41.8–51.4 g). Corrected for body weight, brain weight was lowest in the fish oil group (SO10, 9.3 g/kg; SO5, 8.0 g/kg; FO5, 7.3 g/kg; P < .001; normal range, 5.9–9.0 g/kg). Conclusion: Low‐dose fat emulsions reduce the risk of developing PNALD. Further investigation of the risk to brain development in neonates exposed to dose restriction, particularly with fish oil, is required.     

Supplemental Parenteral Vitamin E Into Conventional Soybean Lipid Emulsion Does Not Prevent Parenteral Nutrition–Associated Liver Disease in Full‐Term Neonatal Piglets

Background: Parenteral nutrition–associated liver disease (PNALD) continues to cause morbidity and mortality for neonates with intestinal failure. Lipid peroxidation is one potential etiological factor. This study was designed to test if supplementing vitamin E into conventional soy‐based lipid would reduce the risk of PNALD. Methods: Sixteen piglets, aged 2–5 days and weighing 1.8–2.5 kg, were randomized to parenteral nutrition (PN) with soy lipid (SO, n = 8) or the same lipid plus α‐tocopherol, the most bioactive form of vitamin E (SO+E, n = 8). After 17 days, bile flow, liver chemistry, gene expression associated with bile acid metabolism, and bile acid composition were assessed. C‐reactive protein (CRP) and oxidative stress markers, including plasma 8‐isoprostane, were measured. All results were compared with a sow‐reared control group (CON). Results: Comparing PN‐treated groups, SO vs SO+E mean bile flow (5.91 vs 5.54 µL/g liver; P = .83), serum bile acid concentration (39.2 vs 26.6 µmol/L; P = .12), and total bilirubin (35.2 vs 26.9 µmol/L; P = .56) were not different. Gene expression related to bile acid metabolism and bile composition was not different between PN groups. There was no difference in CRP (41.8 vs 36.8 µg/mL; P = .22) or in plasma 8‐isoprostane (27.9 vs 26.1 pg/mL; P = .77). Conclusions: In term neonatal piglets, supplemental vitamin E did not prevent cholestasis. Additional vitamin E was not associated with reduced inflammation or oxidative stress. The benefit of supplementing vitamin E into conventional lipid, vs adding fish oil, to prevent early onset of PNALD requires further clarification.     

Glucagon‐Like Peptide 2 Improves Cholestasis in Parenteral Nutrition–Associated Liver Disease

Background: Parenteral nutrition‐associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon‐like peptide‐2 (GLP‐2) is being advanced as therapy, the effect of GLP‐2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP‐2 administration on hepatic function in a neonatal piglet model of PNALD. Methods: Neonatal piglets (aged 2–6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN). Piglets were allocated to 2 groups: group 1 (n = 8) received saline while group 2 (n = 7) received GLP‐2 (at 11 nmol/kg/d). After 17 days, piglets underwent terminal laparotomy, and bile flow was measured. Liver specimens were analyzed histologically and with immunoperoxidase staining. Age‐matched sow‐reared control piglets (group 3, n = 8) were used for comparison. Results: Both groups 1 and 2 receiving PN developed cholestasis relative to sow‐reared controls, as evidenced by a decrease in bile flow and increase in serum total bilirubin. However, group 2 had improved bile flow (1.35 vs 0.73 µL/g; P = .02) and diminished bilirubin (38.0 vs 78.5 µmol/L; P = .008) compared with group 1. Group 2 also had lower serum alanine aminotransferase levels, a marker of liver injury. Histologically, the liver specimens in group 1 had marked hepatocyte pigmentation, which was decreased in group 2 specimens. Conclusions: The exogenous administration of GLP‐2 is associated with the improvement of cholestasis and liver injury. This study introduces a novel role for GLP‐2 in improving PNALD in the setting of prolonged PN duration.     

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.     

Liver Disease,Systemic Inflammation,and Growth Using a Mixed Parenteral Lipid Emulsion,Containing Soybean Oil,Fish Oil,and Medium Chain Triglycerides,Compared With Soybean Oil in Parenteral Nutrition–Fed Neonatal Piglets

Background: The optimal parenteral lipid emulsion for neonates should reduce the risk of intestinal failure–associated liver disease and inflammation, while supporting growth and development. This could be best achieved by balanced content of ω‐6 and ω‐3 polyunsaturated fatty acids (PUFAs). Using a neonatal piglet model of parenteral nutrition (PN), we compared a 100% soy oil–based emulsion (ω‐6:ω‐3 PUFA: 7:1) with a mixed lipid emulsion comprising 30% soy oil, 30% medium‐chain triglycerides, 25% olive oil, and 15% fish oil (ω‐6:ω‐3 PUFA: approximately 2.5:1) with regard to liver disease, inflammation, and fatty acid content in plasma and brain. Method: Neonatal piglets, 3–6 days old, underwent jugular catheter insertion for isonitrogenous, isocaloric PN delivery over 14 days. The IL group (n = 8) was treated with Intralipid; the ML group (n = 10) was treated with the mixed lipid (SMOFlipid). Bile flow, liver chemistry, C‐reactive protein (CRP), and PUFA content in plasma phospholipids and brain were compared. Results: Compared with the IL group, ML‐treated piglets had increased bile flow (P = .008) and lower total bilirubin (P = .001) and CRP (P = .023) concentrations. The ω‐6 long‐chain PUFA content was lower in plasma and brain for the ML group. The key ω‐3 long‐chain PUFA for neonatal development, docosahexaenoic acid (DHA), was not different between groups. Conclusion: The mixed lipid, having less ω‐6 PUFA and more ω‐3 PUFA, was able to prevent liver disease and reduce systemic inflammation in PN‐fed neonatal piglets. However, this lipid did not increase plasma or brain DHA status, which would be desirable for neonatal developmental outcomes.     

Elevated Alkaline Phosphatase in Infants With Parenteral Nutrition–Associated Liver Disease Reflects Bone Rather Than Liver Disease

Background: Elevated serum alkaline phosphatase (ALP) in infants with intestinal failure (IF) can be due to parenteral nutrition–associated liver disease (PNALD) or metabolic bone disease (MBD). The purpose of the study was to determine the utility of serum ALP in the diagnostic criteria for PNALD by measuring tissue‐specific levels in infants with IF and PNALD. Methods: A retrospective review of patient data for 15 infants diagnosed with PNALD between December 2012 and August 2013 was performed. PNALD was defined as the presence of 2 consecutive direct bilirubin (DB) levels >2 mg/dL. Fractionated serum alkaline phosphatase was measured in each patient, while the DB was >2 mg/dL. Parathyroid hormone (PTH), vitamin D₃, calcium, and phosphate levels were recorded where available. Results: In 15 infants with PNALD, elevation in total ALP was due to marked elevations in bone‐specific ALP. The median liver‐specific ALP remained within the normal range. PTH, vitamin D₃, calcium, and phosphate levels were within normal limits. Conclusion: While elevated ALP can reflect biliary stasis, the ALP elevation observed in infants with IF and PNALD is predominantly of bone rather than hepatic origin. An elevated unfractionated ALP in infants with PNALD should therefore raise suspicion of underlying bone disease, rather than being attributed to liver disease alone.     

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.     

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.     

Incidence,Prevention, and Treatment of Parenteral Nutrition–Associated Cholestasis and Intestinal Failure–Associated Liver Disease in Infants and Children

Background: Cholestasis is a significant life‐threatening complication in children on parenteral nutrition (PN). Strategies to prevent/treat PN‐associated cholestasis (PNAC) and intestinal failure–associated liver disease (IFALD) have reached moderate success with little supporting evidence. Aims of this systematic review were (1) to determine the incidence of PNAC/IFALD in children receiving PN for ≥14 days and (2) to review the efficacy of measures to prevent/treat PNAC/IFALD. Methods: Of 4696 abstracts screened, 406 relevant articles were reviewed, and studies on children with PN ≥14 days and cholestasis (conjugated bilirubin ≥ 2 mg/dL) were included. Analyzed parameters were (1) PNAC/IFALD incidence by decade and by PN length and (2) PNAC/IFALD prevention and treatment (prospective studies). Results: Twenty‐three articles (3280 patients) showed an incidence of 28.2% and 49.8% of PNAC and IFALD, respectively, with no evident alteration over the last decades. The incidence of PNAC was directly proportional to the length of PN (from 15.7% for PN ≤1 month up to 60.9% for PN ≥2 months; P < .0001). Ten studies on PNAC met inclusion criteria. High or intermediate‐dose of oral erythromycin and aminoacid‐free PN with enteral whey protein gained significant benefits in preterm neonates (P < .05, P = .003, and P < .001, respectively). None of the studies reviewed met inclusion criteria for treatment. Conclusions: The incidence of PNAC/IFALD in children has no obvious decrease over time. PNAC is directly correlated to the length of PN. Erythromycin and aminoacid‐free PN with enteral whey protein have shown to prevent PNAC in preterm neonates. There is a lack of high‐quality prospective studies, especially on IFALD.     

Choline Alleviates Parenteral Nutrition–Associated Duodenal Motility Disorder in Infant Rats

Background:Parenteral nutrition (PN) has been found to influence duodenal motility in animals. Choline is an essential nutrient, and its deficiency is related to PN‐associated organ diseases. Therefore, this study was aimed to investigate the role of choline supplementation in an infant rat model of PN‐associated duodenal motility disorder. Materials and Methods: Three‐week‐old Sprague‐Dawley male rats were fed chow and water (controls), PN solution (PN), or PN plus intravenous choline (600 mg/kg) (PN + choline). Rats underwent jugular vein cannulation for infusion of PN solution or 0.9% saline (controls) for 7 days. Duodenal oxidative stress status, concentrations of plasma choline, phosphocholine, and betaine and serum tumor necrosis factor (TNF)–α were assayed. The messenger RNA (mRNA) and protein expression of c‐Kit proto‐oncogene protein (c‐Kit) and membrane‐bound stem cell factor (mSCF) together with the electrophysiological features of slow waves in the duodenum were also evaluated. Results: Rats on PN showed increased reactive oxygen species; decreased total antioxidant capacity in the duodenum; reduced plasma choline, phosphocholine, and betaine; and enhanced serum TNF‐α concentrations, which were reversed by choline intervention. In addition, PN reduced mRNA and protein expression of mSCF and c‐Kit, which were inversed under choline administration. Moreover, choline attenuated depolarized resting membrane potential and declined the frequency and amplitude of slow waves in duodenal smooth muscles of infant rats induced by PN, respectively. Conclusion: The addition of choline to PN may alleviate the progression of duodenal motor disorder through protecting smooth muscle cells from injury, promoting mSCF/c‐Kit signaling, and attenuating impairment of interstitial cells of Cajal in the duodenum during PN feeding.     

Choline Protects Against Intestinal Failure–Associated Liver Disease in Parenteral Nutrition–Fed Immature Rats

Background: Deficiency of choline, a required nutrient, is related to intestinal failure–associated liver disease (IFALD). Therefore, we aimed to investigate the effects of choline supplementation on IFALD and the underlying mechanisms. Methods: Male Sprague‐Dawley rats (4 weeks old) were fed AIN‐93G chow and administered intravenous 0.9% saline (control), parenteral nutrition (PN), or PN plus intravenous choline (600 mg/kg) for 7 days. We evaluated body weight, hepatic histology, biochemical indicators, triglycerides, oxidative status, methylation levels of peroxisomal proliferator‐activated receptor alpha (PPARα) gene promoter, expression of PPARα and carnitine palmitoyltransferase 1 (CPT1), and levels of choline metabolites. Results: The PN + choline group exhibited improved body weight compared with the PN group. PN impaired hepatic function, increased hepatic triglycerides, induced dyslipidemia, enhanced reactive oxygen species and malondialdehyde, and reduced total antioxidant capacity. The PN group had higher pathologic scores than the control group. These results were prevented by choline administration. Compared with the control group, PN increased PPARα promoter methylation and hepatic betaine concentration, reduced hepatic choline and phosphatidylcholine (PC) levels, decreased plasma choline and betaine concentrations, and downregulated PPARα and CPT1 mRNA and protein expression. Choline supplementation elevated hepatic choline and PC levels and enhanced plasma choline, betaine, and PC concentrations but reduced hepatic betaine level, reversed PPARα promoter hypermethylation, and upregulated PPARα and CPT1 mRNA and protein expression in PN‐fed rats, compared with rats receiving PN alone. Conclusion: Choline addition to PN may prevent IFALD by reducing oxidative stress, enhancing hepatic fat export, and promoting fatty acid catabolism in immature rats receiving PN.     

Impact of New-Generation Parenteral Lipid Emulsions in Pediatric Nutrition

Advancements in the care of premature infants and infants with severe bowel disease have occurred in which long-term use of i.v. nutrition is a cornerstone of successful therapy. Concern about the role of i.v. lipid emulsions in causing severe liver damage to high-risk infants receiving long-term i.v. nutrition has led to a variety of intervention strategies. These have had relatively limited success until the recent introduction of omega-3 (n–3) fatty acid-containing forms of lipid emulsions in place of the current omega-6 fatty acid-predominant lipid emulsions currently exclusively used in the United States. Preliminary data based on nonrandomized trials performed using compassionate-use protocols in the United States suggest very high rates of resolution of cholestasis with the use of an omega-3 fatty acid-predominant lipid emulsion. This result is supported by animal models of liver disease that demonstrate decreased liver damage when animals are provided omega-3 fatty acid-containing lipid emulsions compared with those primarily omega-6 fatty acid based. However, human trials are limited at this time and further research is needed to establish the best approach to preventing liver damage in infants receiving i.v. nutrition and the optimal dose and timing of intervention with novel lipid emulsions.The introduction of i.v. nutrition, including the use of protein, carbohydrates, lipids, vitamins, and minerals, represented a major advancement in the care of high-risk infants during the 1970s and 1980s and remains a cornerstone of advanced neonatal care. It has allowed for the care of increasingly small preterm infants, prevention of malnutrition in surgical patients, and slow advancement of enteral feedings allowing for better tolerance and lower risk of complications.This introduction, however, has not been without negative consequences. It has been recognized that total parenteral nutrition (TPN) leads to damage to organ systems, which uncommonly occurs with enteral nutrition. Perhaps the most severe of these is damage to the liver, a condition often called parenteral nutrition-associated liver disease (PNALD), leading to jaundice and cholestasis. This condition can occur in both preterm and full-term infants and can be severe enough to cause clinical liver failure and death or the need for liver transplant. Although reports of its incidence and severity vary, it can be expected to occur in as many as 10–30% of infants, requiring prolonged TPN. Outcomes are variable, but ∼40–60% of neonates who have significant cholestasis with a conjugated bilirubin >2.0 mg/dL who cannot tolerate enteral nutrition will develop end-stage liver failure requiring transplant or will die (1). Exact numbers are difficult to ascertain, because many of these deaths will be due to sepsis, in part due to the liver failure, but are difficult to directly link to the cholestasis.Although many components of TPN have been implicated in both animal and human studies of PNALD, recent interest has focused on the lipid component of TPN as being a major factor in the development of cholestasis (2). In the United States, only one form of lipid is fully approved for use in infants and children. That product, referred to as Intralipid, is an omega-6 fatty acid-predominant emulsion derived from soybean oil, egg phospholipids, and glycerin. As widely used in neonatology, it provides 2 kcal/mL of product and is routinely provided to most infants weighing less than ∼1500 g birthweight beginning within 24 h of life and continues to be provided for a week or more until feeding volumes are achieved that typically represent more than one-half of the total fluid volume intake. Although this relatively short-term use is uncommonly a cause of liver disease, many preterm infants will have a complicated course. These infants, or others infants who are born with major abdominal wall defects or who develop diseases including necrotizing enterocolitis, may receive very long-term TPN involving 4 wk or more of therapy.The evidence for a harmful effect of Intralipid on the liver comes from both animal and human data and is based on the fact that phytosterols are toxic and lead to decreasing bile secretion (3) as well as possible proinflammatory characteristics of ω-6 fatty acids. Regardless of the mechanism, there is considerable interest in treating this condition using novel therapies. One therapy that has been increasingly used is to decrease the dose of Intralipid provided in infants who develop PNALD. This intervention, often referred to as a lipid-lowering strategy or similar names, appears to have benefit in some patients. The frequency with which it is successful, however, is not clear and there are infants who do not respond to this approach and have progressive cholestasis even when receiving only a low dose, such as 1 g/(kg · d) of Intralipid.Historically, there has been a strong emphasis on managing infants who have PNALD by advancing feeds and discontinuing TPN as rapidly as possible. This approach remains a hallmark of the management of this condition. However, it is recognized that there are a substantial number of infants in whom this is not feasible due to the severity of their bowel disease and inability to receive a completely enteral diet. Some infants may tolerate a full feeding volume but not grow adequately on such a diet. Use of human milk feedings, amino acid-based infant formulas, and similar dietary strategies are helpful but cannot be effective when there is a major loss of intestine or other severe bowel dysfunction.Other strategies that are employed include the use of choleretic agents such as ursodeoxycholic acid, cycling of TPN administration (meaning that it is not given 24 h each day), and limitation of potentially toxic minerals (primarily copper and manganese) in the TPN. Experience with these strategies is also highly variable but generally has not had a major clinical outcome effect for most infants and cannot be relied upon to resolve cholestasis in many infants receiving long-term TPN.Most recently, consideration has been given to newer lipid products containing fatty acids that might be both less toxic than Intralipid and might have a therapeutic benefit in cholestatic infants. In this regard, a lipid emulsion has been evaluated that is based on ω-3 fatty acids, not ω-6 fatty acids. This product, Omegaven, originally designed for postsurgical use in adults, has been used in place of Intralipid. Multiple reports describing case series of infants with PNALD treated with Omegaven exist. Omegaven has been provided to several hundred, possibly more than 1000, infants in the United States and an unknown number of infants in other countries throughout the world (4, 5).Available data suggest that at least 80% and probably 90% or more of infants who receive Omegaven will recover with a decrease in their conjugated bilirubin amount of <0.5 mg/dL. Nonresponders are usually older infants, infants who ultimately had a different disease rather than PNALD, or infants who have other conditions such as fistulas or immune deficiency associated with recurrent sepsis.Because of this response rate and the severity of the condition, there are no randomized controlled trials of Omegaven compared with Intralipid in a substantial number of patients anywhere in the world. This limitation and the remarkable effects seen in these case series reports have sparked ongoing interest in evaluating animal models of cholestasis and the effects of different lipid admixtures on liver damage. In addition to the effects on treatment of established PNALD, there is considerable interest in prevention of this condition using novel lipid emulsions or combinations of available products.Overall, the last few years have seen considerable progression of this field. This includes several centers at which >100 infants have been treated with Omegaven with good results and now nearly 10 y experience in the United States, where the first US PNALD patient started therapy in September 2004, demonstrating safety. At the present time, there is only a single case report of any toxic side effect occurring in any infant, and that was not severe and was readily resolved after stopping the Omegaven.Although a blinded controlled trial of Omegaven use in infants with PNALD would be optimal, many have recognized that this is not feasible in infants with established significant PNALD, given the large number of infants and centers that have compassionate use protocols in place and the currently available case series data. However, even without a controlled trial, many advances in our understanding of the role of different lipid emulsions are needed and can be pursued. These include evaluation of the optimal strategy for preventing cholestasis in high-risk infants, the timing and amount of ω-3 fatty acids to be provided i.v., and the role of other factors in lipid products or TPN that may be altered to decrease the incidence or severity of PNALD. It is expected that this will be a major area of investigation in neonatal and infant nutrition during the next decade or more (6).The goal of this symposium was to both review the past data about PNALD and its relationship to lipids and consider approaches to future management and research in this field. I provided a summary of our research group’s current data related to this topic. Dr. Mark Puder from Children’s Hospital, Boston described his research related to lipid emulsions in both animals and in children. Dr. Doug Burrin from the USDA/Agricultural Research Service Children’s Nutrition Research Center in Houston described his animal model of cholestasis and findings related to PNALD and different lipid emulsions. Dr. Paul Wales from The Hospital for Sick Children in Toronto discussed his research into several lipid emulsions and then described ideas and suggestions for future research and clinical interventions that would help resolve the many pending issues in this field. All presenters explained that evaluation of new products requires the use of a variety of investigational techniques, including careful basic science studies of lipid effects on the liver, animal models of multiple lipid emulsions, and a range of intervention studies, hopefully using controlled trials in infants and older children. All agreed that this is a critical and exciting area of nutrition that can directly lead to improved health outcomes for a highly vulnerable population.     

Parenteral Nutrition–Associated Cholestasis in Premature Infants

Purpose: To evaluate whether intravenous lipid (IL) intake is associated with the development of parenteral nutrition–associated cholestasis (PNAC) in infants younger than 32 weeks gestational age (GA). Methods: A retrospective matched case‐control study (1:1) was performed including infants younger than 32 weeks GA admitted to the neonatal intensive care unit within 48 hours after birth. Infants with a chromosomal disorder, TORCH infection (toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes, human immunodeficiency virus, and parvovirus), metabolic disorder, and/or surgical abnormality of the hepatobiliary system were excluded. Infants with PNAC (direct bilirubin 2 mg/dL or higher) comprised the case group, while infants without PNAC comprised the control group. Duration of parenteral nutrition, intravenous fluid intake on the day of development of PNAC, and GA were used as matching criteria. Results: A total of 46 subjects were studied. Daily average intravenous dextrose (ID) intake was significantly higher in infants with PNAC compared with infants without PNAC (12.72 ± 2.5 g/kg/d and 10.64 ± 2.1 g/kg/d, respectively, P = .004). On comparison of receiver operating characteristic curves, the area under the curve for ID intake (0.74) was significantly higher (P = .01) compared with the area under the curve for IL intake (0.59) and intravenous protein (IP) intake (0.52). On logistic regression, daily ID intake was associated with PNAC (odds ratio 1.7; 95% CI, 1.04–2.9, P = .03) after controlling for daily IP and IL intake. Conclusions: ID intake may be associated with the development of PNAC in premature infants. Our findings suggest that limiting ID intake may be more useful than limiting IL intake in reducing the incidence of PNAC in premature infants.     

Randomized Clinical Trial of New Intravenous Lipid (SMOFlipid 20%) Versus Medium‐Chain Triglycerides/Long‐Chain Triglycerides in Adult Patients Undergoing Gastrointestinal Surgery

Background: SMOFlipid 20% is intravenous lipid emulsion (ILE) containing long‐chain triglycerides (LCT), medium‐chain triglycerides (MCT), olive oil, and fish oil as a mixed emulsion containing α‐tocopherol. The aim was to assess the efficacy of this new ILE in gastrointestinal surgery compared with MCT/LCT. Methods: In this prospective study, 40 patients were randomized to SMOFlipid 20% or MCT/LCT (Lipovenoes 20%) group. Clinical and biochemistry data were collected. Inflammatory markers (CRP, IL‐6, IL‐10, TNF‐α, TGF‐β1) and oxidative stress (ROS and superoxide) were measured. Results: Thirty‐five patients (17 males and 18 females) with a mean age of 57 years completed the study. The patients’ demographic characteristics (age, gender, height, body weight, and BMI) were similar without significant differences between groups. The increment of triglyceride on day 6 from baseline was significantly lower in SMOFlipid group than in Lipovenoes MCT/LCT group. Inflammatory markers, as well as superoxide radical and total oxygen radical were not different between groups. Conclusions: Despite the comparable effect on inflammatory response, because of its well‐balanced fatty acid pattern, relatively low n‐6:n‐3 ratio, and high vitamin E content, SMOFlipid had a better triglyceride‐lowering effect as compared with MCT/LCT in adult patients undergoing gastrointestinal surgery.     

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.     

Clinical Management of Patients With Parenteral Nutrition–Dependent Short Bowel Syndrome During Teduglutide Therapy

Background: Patients with intestinal failure, who are dependent on parenteral nutrition (PN) to supplement their limited absorption of dietary nutrients, are subject to complications associated with long‐term PN therapy. Medication therapy that results in improved dietary nutrient absorption may enable these patients to reduce or even become independent from PN therapy and its related complications. The glucagon‐like peptide 2 (GLP‐2) analogue teduglutide was approved for use in such patients by the U.S. Food and Drug Administration in 2012. Purpose: The purpose of this article is to describe the experience of 7 patients with PN‐dependent intestinal failure who were treated with teduglutide by a single center that had been involved in the teduglutide clinical trials. Results: Two patients who were treated during the clinical trials and 5 others who were treated since teduglutide came to market in the United States are described. Protocols used to prepare and monitor patients with this drug and PN weaning and adverse event outcomes are presented. Conclusions: While some patients had uncomplicated PN reduction, others experienced various complications. Careful monitoring of patients' clinical course is needed during drug therapy.     

Thiamin Deficiency as a Cause of Persistent Hyperlactatemia in a Parenteral Nutrition–Dependent Patient

Background: Despite the demonstrated dangers of inadequate supplies of injectable multivitamins, periodic shortages of these crucial pharmaceuticals continue to occur in the developed world. This case report provides a recent example of the potential danger of rationing parenteral multivitamins in chronically parenteral nutrition (PN)–dependent patients in the setting of national supply shortages. Method and Results: Case report describing a chronically PN‐dependent 21‐year‐old man who presented with signs and symptoms of septic shock to a pediatric intensive care unit at a university hospital. The patient demonstrated hyperlactatemia that persisted following hemodynamic stabilization, and he was determined to be severely deficient in thiamin despite thrice‐weekly home multivitamin infusions, instead of daily due to national supply shortages. The patient's hyperlactatemia rapidly resolved following thiamine supplementation. Conclusion: Physicians must be vigilant for potentially life‐threatening nutrition deficiencies, as illustrated in this case of thiamine insufficiency, in PN‐dependent children and adults in the setting of nationwide limitations in multivitamin supply.