Parenteral Plant Sterols and Intestinal Failure–associated Liver Disease in Neonates

Kurvinen, Annika; Nissinen, Markku; Andersson, Sture; Korhonen, Päivi; Ruuska, Tarja; Taimisto, Mari; Kalliomäki, Marko; Lehtonen, Liisa; Sankilampi, Ulla; Arikoski, Pekka; Saarela, Timo; Miettinen, Tatu A.; Gylling, Helena; Pakarinen, Mikko P.

doi:10.1097/mpg.0b013e3182474118

Cited by 97 publications

(88 citation statements)

References 44 publications

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“…SL is a blend of lipids including soybean oil, MCTs, olive oil, and fi sh oil and thus contains phytosterols. The attention on phytosterols stems from their structural similarity with bile acids and earlier reports of phytosterolemia associated with PNALD in TPN-fed pediatric patients ( 4,26,28 ). After 2 weeks, the differences in phytosterol intake among the groups were directly refl ected in both the plasma and liver phytosterol concentrations, with the highest and lowest phytosterol levels in IL and OV pigs, respectively.…”

Section: Discussionmentioning

confidence: 99%

New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs

Vlaardingerbroek

Stoll

et al. 2014

Journal of Lipid Research

116

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Cholestatic liver disease is one of the most common metabolic problems associated with total parenteral nutrition (TPN) in preterm infants, and it is strongly related to the duration of TPN ( 1 ). The incidence of parenteral nutrition-associated liver disease (PNALD) in infants who Abstract Total parenteral nutrition (TPN) is associated with the development of parenteral nutrition-associated liver disease (PNALD) in infants. Fish oil-based lipid emulsions can reverse PNALD, yet it is unknown if they can prevent PNALD. We studied preterm pigs administered TPN for 14 days with either 100% soybean oil (IL), 100% fi sh oil (OV), or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fi sh oil (SL); a group was fed formula enterally (ENT). In TPN-fed pigs, serum direct bilirubin, gamma glutamyl transferase (GGT), and plasma bile acids increased after the 14 day treatment but were highest in IL pigs. All TPN pigs had suppressed hepatic expression of farnesoid X receptor (FXR), cholesterol 7-hydroxylase (CYP7A1), and plasma 7 ␣ -hydroxy-4-cholesten-3-one (C4) concentrations, yet hepatic CYP7A1 protein abundance was increased only in the IL versus ENT group. Organic solute transporter alpha (OST ␣ ) gene expression was the highest in the IL group and paralleled plasma bile acid levels. In cultured hepatocytes, bile acid-induced bile salt export pump (BSEP) expression was inhibited by phytosterol treatment. We show that TPN-fed pigs given soybean oil developed cholestasis and steatosis that was prevented with both This work was supported in part by federal funds from the USDA,, the American Society for Parenteral and Enteral Nutrition, Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSEP, bile salt export pump; CA, cholic acid; CDCA, chenodeoxycholic acid; C4, 7 ␣ -hydroxy-4-cholesten-3-one; CYP8B1, sterol 12-alpha-hydroxylase; CYP7A1, cholesterol 7-hydroxylase; CYP3A29, cytochrome P450 3A29; CYP27A1, sterol 27-hydroxylase; FGF, fi broblast growth factor; FXR, farnesoid X receptor; GGT, gamma glutamyl transferase; MCT, medium chain triglyceride; MRP3, multidrug resistant protein 3; NTCP, Na + / taurocholate cotransporter; OBCA, obeticholic acid; OST ␣ / ␤ , organic solute transporters alpha and beta; PNALD, parenteral nutrition-associated liver disease; TPN, total parenteral nutrition; UDCA, ursodeoxycholic acid . and immediately placed in cages housed at 31°C to 32°C, as described previously ( 12 ). Based on body weight, pigs delivered from each sow were randomly assigned to one of the three TPN treatment groups or to enteral nutrition (ENT). After delivery, pigs were surgically implanted with catheters into the jugular vein and umbilical artery. Pigs in the enteral group also were implanted with an orogastric feeding tube, whereas TPN groups received a sham puncture. Maternal plasma (16 ml/kg intravenously during the fi rst 24 h) was administered for passive immunological protection. During the 14 day study, pigs received antibiotics (enrofl oxacin 5 mg/kg) intrave...

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Section: Discussionmentioning

confidence: 99%

New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs

Vlaardingerbroek

Stoll

et al. 2014

Journal of Lipid Research

116

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“…Our findings have important implications both for future studies of the use of CRP and cytokines as biomarkers in the neonatal population and for clinical care. Neonates may be highly sensitive to the adverse effects of PN and, in particular, components such as plant sterols [10,11,12]. If PN triggers inflammation within a few weeks of exposure – even before the onset of cholestasis – then strategies to limit early PN exposure while maximizing growth might be critical for the long-term health of VLBW infants.…”

Section: Discussionmentioning

confidence: 99%

“…For example, soybean oil-based lipid emulsions have been demonstrated to play an important role in PN-associated cholestasis [10,11,12]. In response to inflammatory signals, Kupffer cells produce cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6; cholangiocytes produce IL-8, IL-12p70, and TNF-α; and hepatocytes produce both cytokines and acute phase proteins [13].…”

Section: Introductionmentioning

confidence: 99%

Early Inflammatory Markers for Prediction of Cholestasis in Very-Low-Birth-Weight Infants

et al. 2012

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Background: Neonatal cholestasis is associated with increased mortality and other adverse outcomes. There are no tools for prediction of infants at risk for cholestasis. Objective: To determine if cholestasis in very-low-birth-weight (VLBW) infants is associated with alterations in cytokines or C-reactive protein (CRP) and, if so, whether inflammatory markers predict which infants will develop cholestasis. Methods: VLBW infants expected to be on parenteral nutrition for >7 days were enrolled in this prospective cohort study. Infants with direct bilirubin ≥1.0 mg/dl were considered to have a high risk for cholestasis and were compared to infants who never developed direct bilirubin ≥1.0 mg/dl. Standard descriptive statistics were used to compare biomarkers over time. Multivariable models were used to estimate associations between early inflammatory markers and cholestasis. Results: Of 63 infants enrolled, 29 were at risk for cholestasis. CRP was highly correlated with direct bilirubin. Infants in the high-risk group had significantly higher IL-1β, IL-6, IL-8, and IL-10 at 2, 4, and 6 weeks and CRP at 2 and 6 weeks. In logistic models, CRP (OR = 4.97, p = 0.02) or IL-1β (OR = 1.11, p = 0.008) at 2 weeks of age was predictive of cholestasis. In linear mixed-effects models, CRP (p < 0.001) or IL-6 (p = 0.02) and IL-8 (p < 0.001) were predictive of cholestasis. Conclusion: Elevated CRP and cytokines are associated with cholestasis in VLBW infants. These inflammatory markers are candidates for further research into the pathogenesis, prediction, and prevention of cholestasis.

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“…In newborn infants, phytosterol contents in some IVLE have been implicated in IFALD by inducing inflammation and antagonizing hepatic farnesoid X receptor (FXR) function in bile-acid homeostasis [1,8]. Significantly higher ratios of serum phytosterols (stigmasterol, sitosterol, and avenasterol) were found associated with direct bilirubin in infants with IFALD, compared with those without IFALD [9]. The factors associated with IFALD in patients receiving high intakes of n-6 polyunsaturated fatty acids (n-6 PUFA) with soybean oil-based IVLE are the formation of n-6 arachidonic acid, a proinflammatory mediator, the high provision of phytosterols, and the limited supply of alpha tocopherol relative to PUFA supply [1,8,10].…”

Section: Introductionmentioning

confidence: 99%

Parenteral nutrition-associated cholestasis and triglyceridemia in surgical term and near-term neonates: A pilot randomized controlled trial of two mixed intravenous lipid emulsions

Pereira‐da‐Silva

Nóbrega

Rosa

et al. 2017

Clinical Nutrition ESPEN

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s u m m a r yBackground: Cholestasis is a common complication in infants receiving prolonged parenteral nutrition (PN). We studied the effects of two intravenous lipid emulsions composed with either 30% soybean oil, 30% medium-chain triglycerides (MCT), 25% olive oil, and 15% fish oil (SMOF) or with 50% MCT and 50% soybean oil n-6 (MCT/SOY) on the incidence of cholestasis in surgical term and near-term neonates. Methods: A single-center, double-blinded, randomized controlled trial compared the incidence of cholestasis using either SMOF or MCT/SOY in neonates born at gestational age !34 weeks undergoing major surgery. The primary outcome was the incidence of conjugated serum bilirubin >1 mg/dL. Other liver enzymes were assessed as secondary outcomes. A post-hoc analysis assessed serum triglycerides levels. Odds ratios were estimated by mixed-effects regression models. Results: Enrollment was prematurely interrupted because the MCT/SOY became unavailable, thus 49 infants (SMOF 22, MCT/SOY 27) completed the study. The exposure (time on PN, cumulative dose of lipids) was similar in both groups. Similar cumulative incidence rates were found for elevated conjugated bilirubinemia and other liver enzymes. Hypertriglyceridemia >250 mg/dL (12/49) was more frequent in MCT/SOY (37.0%, 95% CI 21.53e55.77) than in SMOF (9.1%, 95% CI 2.53e27.81, p ¼ 0.024). Triglyceridemia at the first assessment (median 8 postnatal days) was significantly higher with MCT/SOY than with SMOF (181 vs. 134 mg/dL, p ¼ 0.006). Over the whole study period, mean triglyceride concentration was 36.5 mg/dL higher with MCT/SOY compared with SMOF (p ¼ 0.013). Conclusion: Both emulsions had similar effects on the incidence of cholestasis and markers of liver integrity, but MCT/SOY induced higher serum triglyceride concentrations. Trial registration: ClinicalTrials.gov, NCT02633384

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Parenteral Plant Sterols and Intestinal Failure–associated Liver Disease in Neonates

Abstract: Frequent occurrence of IFALD among neonates on PN displays an association to duration of PN and markedly increased serum PS, especially stigmasterol, in comparison to healthy neonates and children on PN. Striking accumulation of parenteral PS may contribute to IFALD among neonates.

Cited by 97 publications

References 44 publications

New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs

New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs

Early Inflammatory Markers for Prediction of Cholestasis in Very-Low-Birth-Weight Infants

Parenteral nutrition-associated cholestasis and triglyceridemia in surgical term and near-term neonates: A pilot randomized controlled trial of two mixed intravenous lipid emulsions

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