Phytosterols are plant-derived sterols that are structurally and functionally analogous to cholesterol in vertebrate animals. Phytosterols are found in many foods and are part of the normal human diet. However, absorption of phytosterols from the diet is minimal. Most lipid emulsions used for parenteral nutrition are based on vegetable oils. As a result, phytosterol administration occurs during intravenous administration of lipid. Levels of phytosterols in the blood and tissues may reach high levels during parenteral lipid administration and may be toxic to cells. Phytosterols are not fully metabolized by the human body and must be excreted through the hepatobiliary system. Accumulating scientific evidence suggests that administration of high doses of intravenous lipids that are high in phytosterols contributes to the development of parenteral nutrition–associated liver disease. In this review, mechanisms by which lipids and phytosterols may cause cholestasis are discussed. Human studies of the association of phytosterols with liver disease are reviewed. In addition, clinical studies of lipid/phytosterol reduction for reversing and/or preventing parenteral nutrition associated liver disease are discussed.
OstlundRE.Phytosterols in human nutrition. Annu Rev Nutr. 2002;22:533-549.
2.
TraunerMMeierPJBoyerJL. Molecular pathogenesis of cholestasis. N Engl J Med. 1998;339:1217-1227.
3.
IkonenE. Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev. 2006;86:1237-1261.
4.
DawsonPALanTRaoA. Bile acid transporters. J Lip Res. 2009;50:2340-2357.
5.
HazardSEPatelSB. Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols. Pflugers Arch. 2007;435:745-752.
6.
ElorantaJJKullak-UblickGA. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys. 2005;433:397-412.
7.
KurvinenANissinenMJAnderssonS. Parenteral plant sterols and intestinal failure-associated liver disease in neonates. J Pediatr Gastroenterol Nutr. 2012;54:803-811.
8.
KastHRGoodwinBTarrPT. Regulation of multidrug resistant associated protein 2 (ABCC2) by the nuclear pregame X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem. 2002;277:2908-2915.
9.
WangHChenJHollisterKSowersLCFormanBM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3:543-553.
10.
CarterBATaylorOAPrendergastDR. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of bile acid nuclear receptor FXR. Pediatr Res. 2007;62:301-306.
11.
ZhaoAYuJLewJLHuangLWrightSDCuiJ. Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. DNA Cell Biol. 2004;23:519-526.
12.
SinalCJTohkinMMiyataMWardJMLambertGGonzalezFJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731-744.
13.
LiuYBinzJNumerickMJ. Hepatoprotection by farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest. 2002;112:1678-1687.
RepaJJBergeKEPomajzlCRichardsonJAHobbsHMangelsdorfDJ. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by liver X receptors α and β. J Biol Chem. 2002;277:18793-18800.
16.
SchmitzGLangmannTHeimeslS. Role of ABCG1 and other ABCG family members in lipid metabolism. J Lip Res. 2001;42:1513-1520.
17.
JiaLBettersJLYuL. Niemann-Pick C1-like1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Ann Rev Physiol. 2011;73:239-259.
18.
KidambiSPatelSB. Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8, and NPC1L1. A review. Xenobiotica. 2008;38:1119-1139.
19.
HuffMWPollexRLHegeleRA. NPC1L1: evolution from pharmacological target to physiological sterol transporter. Arterioscler Thromb Vasc Biol. 2006;26:2433-2438.
20.
WittenburgHCareyMC. Biliary cholesterol secretion by the twinned sterol half-transporters ABCG5 and ABCG8. J Clin Invest. 2002;110:605-609.
21.
SabevaNSLiuJGrafGA. The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease. Curr Opin Endocrinol Diabetes Obes. 2009;16:172-177.
22.
YuLHammerRELi-HawkinsJ. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol transport. PNAS. 2002;99:16237-16242.
23.
El KasmiKCAndersonALDevereauxMW. Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med. 2013;5:206ra137.
24.
ClaytonPTWhitfieldPIyerK. The role of phytosterols in the pathogenesis of liver complications of pediatric parenteral nutrition. Nutrition. 1998;14:158-164.
25.
TazukeYKiristiogluIHeidelbergerKPEisenbraunMDTeitelbaumDH. Hepatic P-glycoprotein changes with total parenteral nutrition administration. JPEN J Parenter Enteral Nutr. 2004;28:1-6.
26.
TazukeYTeitelbaumDH. Alteration of canalicular transporters in a mouse model of total parenteral nutrition. J Pediatr Gastroenterol Nutr. 2009;48:193-202.
27.
WhitfieldPDClaytonPTMullerDPR. Effect of intravenous lipid emulsions on hepatic cholesterol metabolism. J Pediatr Gastroenterol Nutr. 2000;30:538-546.
28.
BobergKMAkerlundJEBjorkhemI. Effect of Sitosterol on the rate-limiting enzymes in cholesterol synthesis and degradation. Lipids. 1989;24:9-12.
29.
VlaardingerbroekHNgKStollB. New generation lipid emulsions prevent PNALD in chronic parenterally-fed preterm pigs. J Lip Res. 2014;55:466-477.
30.
SheferSSalenGNguyenL. Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. J Clin Invest. 1988;82:1833-1839.
31.
NguyenLBSheferSSalenGTintSGBattaAK. Competitive inhibition of hepatic sterol 27-hydroxylase by sitosterol: decreased activity in sitosterolemia. Proc Assoc Am Physicians. 1998;110:32-39.
32.
PedenVHWitzlebenCLSkeltonMA. Total parenteral nutrition. J Pediatr. 1971;78:180.
33.
FarrellMKBalistreriWF. Parenteral nutrition and hepatobiliary dysfunction. Clin Perinatol. 1986;13:197-212.
34.
TouloukianRJSeashoreJH. Hepatic secretory obstruction with total parenteral nutrition in the infant. J Pediatr Surg. 1975;10:353-360.
35.
BealeEFNelsonRMBucciarelliRLDonnellyWHEitzmanDV. Intahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics. 1979;64:342-347.
36.
NehraDFallonEMCarlsonSJ. The prevention and treatment of intestinal failure-associated liver disease in neonates and children. Surg Clin N Am. 2011;91:543-563.
37.
KellyDA. Preventing parenteral nutrition liver disease. Early Human Dev. 2010;86:683-687.
38.
CavicchiMBeauPCrennPDegottCMessingB. Prevelance of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. Ann Intern Med. 2000;132:525-532.
39.
DiamondIRde SilvaNTTomlinsonGE. The role of parenteral lipids in the development of advanced intestinal failure-associated liver disease in infants: a multiple-variable analysis. JPEN J Parenter Enteral Nutr. 2011;35:596-602.
40.
DuroDMitchellPDKalishLA. Risk factors for parenteral nutrition-associated liver disease following surgical therapy for necrotizing enterocolitis. J Pediatr Gastroenterol Nutr. 2011;52:595-600.
LumanWShafferJL. Prevalence, outcome and associated factors of deranged liver function tests in patients on home parenteral nutrition. Clin Nutr. 2002;21:337-343.
43.
TomerGAnanthanarayananMWeymannABalasubramanianNSuchyFJ. Differential developmental regulation of rat liver canalicular membrane transporters BSEP and MRP2. Pediatr Res. 2003;53:288-294.
44.
ChenHLChenHLLiuYJ. Developmental expression of canalicular transporter genes in human liver. J Hepatol. 2005;43:472-477.
45.
BeathSVDaviesPPapadopoulouA. Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. J Pediatr Surg. 1996;31:604-606.
46.
ChristensenRDHenryEWiedmeierSEBurnettJLambertDK. Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease. J Perinatol. 2007;27:284-290.
47.
ZimmermanTLThevanantherSGhoseRBurnsARKarpenSJ. Nuclear export of retinoid X receptor (alpha) in response to interleukin-1beta-mediated cell signaling: roles of JNK and SER260. J Biol Chem. 2006;281:15434-15440.
48.
MoseleyRHWangWTakedaH. Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis. Am J Physiol. 1996;271:G137-G146.
49.
AllardyceDB.Cholestasis caused by lipid emulsions. Surg Gynecol Obstet. 1982;154:641-647.
50.
NehraDFallonEMCarlsonSJ. Provision of a soy-based intravenous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates. JPEN J Parenter Enteral Nutr. 2013;37:498-505.
51.
PuderMValimCMeiselJA. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg. 2009;250:395-402.
52.
NayrouzMMAminSB. Cumulative amount of intravenous lipid intake and parenteral nutrition-associated cholestasis in neonates with gastrointestinal surgical disorders. Am J Perinatol. 2014;31:419-424.
53.
XuZHarveyKAPavlinaT. Steroidal compounds in commercial parenteral lipid emulsions. Nutrients. 2012;4:904-921.
54.
ForchielliMLBersaniGTalaSGrossiGPuggioliCMasiM. The spectrum of plant and animal sterols in different oil-derived intravenous emulsions. Lipids. 2010;45:63-71.
55.
EllegardLSunessonABosaeusI. High serum phytosterol levels in short bowel patients on parenteral nutrition support. Clin Nutr. 2005;24:415-420.
56.
La ScalaGCLe CoultreCRocheBGBugmannPBelliDC. The addition of lipids increases the total parenteral nutrition-associated cholestasis in the rat. Eur J Pediatr Surg. 1993;3:224-227.
57.
PencoJMMBotejaraEMMartinezJS. Liver lipid composition and intravenous, intraperitoneal, and enteral administration of Intralipid. Nutrition. 1994;10:26-31.
58.
ChenWJYehSLHuangPC. Effects of fat emulsions with different fatty acid composition on plasma and hepatic lipids in rats receiving total parenteral nutrition. Clin Nutr. 1996;15:24-28.
59.
YehSLChenWJHuangPC. Effects of fish oil and safflower oil emulsions on diet-induced hepatic steatosis in rats receiving total parenteral nutrition. Clin Nutr. 1996;15:80-83.
60.
HydeMJAmusquivarELawsJ. Effects of lipid-supplemented total parenteral nutrition on fatty liver disease in a premature neonatal piglet model. Neonatology. 2008;93:77-86.
61.
KohlMWedelTEntenmannA. Influence of different intravenous lipid emulsions on hepatobiliary dysfunction in a rabbit model. J Pediatr Gastroenterol Nutr. 2007;44:237-244.
62.
TazukeYTeitelbaumDWasaMFukuzawaMLiboshiYFujimotoJ. Parenteral nutrition administration leads to specific alterations in the expression of adipocytokines and peroxisome proliferator-activated receptors in a rat model. JPEN J Parenter Enteral Nutr. 2011;35:329-336.
63.
JavidPJGreeneAKGarzaJ. The route of lipid administration affects parenteral nutrition-induced hepatic steatosis in a mouse model. J Pediatr Surg. 2005;40:1446-1453.
64.
AlwaynIPJGuraKNoseV. Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res. 2005;57:445-452.
65.
PrinceELazareFBTreemWR. ω-3 fatty acids prevent hepatic steatosis, independent of PPAR-α activity, in a murine model of parenteral nutrition associated liver disease. JPEN J Parenter Enteral Nutr. 2013;38:608-616.
66.
IyerKRSpitzLClaytonP. New insight into mechanisms of parenteral nutrition-associated cholestasis: Role of plant sterols. J Pediatr Surg. 1998;33:1-6.
67.
Van AerdeJEDuerksenDRGramlichL. Intravenous fish oil emulsion attenuates total parenteral nutrition-induced cholestasis in newborn piglets. Pediatr Res. 1999;45:202-208.
68.
MeiselJALeHDDe MeijerVE. Comparison of 5 intravenous lipid emulsions and their effects on hepatic steatosis in a murine model. J Pediatr Surg. 2011;46:666-673.
69.
ZhuXXiaoZChenX. Parenteral nutrition-associated liver injury and increased GRP94 expression prevented by ω-3 fish oil-based lipid emulsion supplementation. J Pediatr Gastroenterol Nutr. 2014;59:708-713.
70.
HarveyKXuZWalkerC. Parenteral lipid emulsions in guinea pigs differentially influence plasma and tissue levels of fatty acids, squalene, cholesterol, and phytosterols. Lipids. 2014;49:777-793.
71.
ClaytonPTBowronAMillsKAMassoudACasteelsMMillaPJ. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease. Gastroenterology. 1993;105:1806-1813.
72.
BindlLLutjohannDBuderusSLentzeMJBergmannKV. High plasma levels of phytosterols in patients on parenteral nutrition: a marker of liver dysfunction. J Pediatr Gastroenterol Nutr. 2000;31:313-316.
73.
LlopJMVirgiliNMoreno-VillaresJM. Phytosterolemia in parenteral nutrition patients: implications for liver disease development. Nutrition. 2008;24:1145-1152.
74.
PianesePSalviaGCampanozziA. Sterol profiling in red blood cell membranes and plasma of newborns receiving total parenteral nutrition. J Pediatr Gastroenterol Nutr. 2008;47:645-651.
75.
KurvinenANissinenMJGyllingH. Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure. J Pediatr Gastroenterol Nutr. 2011;53:440-446.
76.
DimakouKGuillotteCHillS. Phytosterols of HPN patients [abstract]. Clin Nutr. 2012;7(1):135.
77.
AllardyceDBSalvianAJQuenvilleNF. Cholestatic jaundice during total parenteral nutrition. Can J Surg. 1978;21:332-339.
78.
SalvianAJAllardyceDB. Impaired bilirubin secretion during total parenteral nutrition. J Surg Res. 1980;28:547-555.
79.
ColombVJobert-GiraudALacailleFGouletOFournetJCRicourC. Role of lipid emulsions in cholestasis associated with long term parenteral nutrition in children. JPEN J Parenter Enteral Nutr. 2000;24:345-350.
80.
ShinJINamgungRParkMSLeeC. Could lipid infusion be a risk for parenteral nutrition-associated cholestasis in low birth weight neonates?Eur J Pediatr. 2008;167:197-202.
81.
CoberMPKilluGBrattainAWelchKBKunisakeSMTeitelbaumDH. Intravenous fat emulsions reduction for patients with parenteral nutrition-associated liver disease. J Pediatr. 2012;160:421-427.
82.
CoberMPTeitelbaumDH. Prevention of parenteral nutrition-associated liver disease: lipid minimization. Curr Opin Organ Transplant. 2010;15:330-333.
83.
SanchezSEBraunLPMercerLDSherrillMStevensJJavidPJ. The effect of lipid restriction on the prevention of parenteral nutrition-associated cholestasis in surgical patients. J Pediatr Surg. 2013;48:573-578.
84.
ReimundJMArondelYJolyFMessingBDuclosBBaumannR. Potential usefulness of olive-oil based lipid emulsions in selected situations of home parenteral nutrition-associated liver disease. Clin Nutr. 2004;23:1418-1425.
85.
HallikainenMHuikkoLKontraK. Effect of parenteral serum plant sterols on liver enzymes and cholesterol metabolism in a patient with short bowel syndrome. Nutr Clin Pract. 2008;23:429-435.
86.
PalovaSCharvatJKvapilM. Comparison of soybean oil and olive oil-based lipid emulsions on hepatobiliary function and serum triacylglycerols level during realimentation. J Intern Med Res. 2008;36:587-593.
87.
PawlikDLauterbachRTurykE. Fish oil fat emulsion supplementation may reduce the risk of severe retinopathy in VLBW infants. Pediatrics. 2011;127:223-228.
88.
AngstenGFinkelYLucasSKassaAMPaulssonMLiljaHE. Improved outcome in neonatal short bowel syndrome using parenteral fish oil in combination with ω-6/9 lipid emusions. JPEN J Parenter Enteral Nutr. 2012;36:587-595.
89.
LiljaHEFinkelYPaulssonMLucasS. Prevention and reversal of intestinal failure-associated liver disease in premature infants with short bowel syndrome using intravenous fish oil in combination with omega-6/9 lipid emulsions. J Pediatr Surg. 2011;46:1361-1367.
90.
XuZLiYWangJWuBLiJ. Effect of omega-3 polyunsaturated fatty acids to reverse biopsy-proven parenteral nutrition-associated liver disease in adults. Clin Nutr. 2012;31:217-223.
91.
DiamondIRSterescuAPencharzPBKimJHWalesPW. Changing the paradigm: Omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48:209-215.
92.
DiamondIRSterescuAPencharzPBWalesPW. The rationale for the use of parenteral omega-3 lipids in children with short bowel syndrome and liver disease. Pediatr Surg Int. 2008;24:773-778.
93.
KlekSChambrierCSingerP. Four-week parenteral nutrition using a third generation lipid emulsion (SMOFlipid): a double-blind, randomized, multicenter study in adults. Clin Nutr. 2013;32:224-231.
94.
GouletOAntebiHWolfC. A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: A single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2010;34:485-495.
95.
MuhammedRBremnerRProtheroeSJohnsonTHoldenCMurphyMS. Resolution of parenteral nutrition-associated jaundice on changing from a soybean oil emulsion to a complex mixed-lipid emulsion. J Pediatr Gastroenterol Nutr. 2012;54:797-802.
96.
RayyanMDevliegerHJochumFAllegaertK. Short-term use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium-chain triglycerides, and fish oil: a randomized double-blind study in preterm infants. JPEN J Parenter Enteral Nutr. 2012;36:81S-94S.
97.
SkouroliakouMKonstantinouDAgakidisC. Cholestasis, bronchopulmonary dysplasia, and lipid profile in preterm infants receiving MCT/ω-3-PUFA-containing or soybean-based lipid emulsions. Nutr Clin Pract. 2012;27:817-824.
98.
PichlerJSimchowitzVMacdonaldSHillS. Comparison of liver function with two new/mixed intravenous lipid emulsions in children with intestinal failure [published online June 25, 2014]. Eur J Clin Nutr.
99.
TomsitsEPatakiMTolgyesiAFeketeGRischakKSzollarL. Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil: a randomized, double-blind clinical trial in premature infants requiring parenteral nutrition. J Pediatr Gastroenterol Nutr. 2010;51:514-521.
100.
SkouroliakouMKonstantinouDKoutriK. A double-blind, randomized clinical trial of the effect of ω-3 fatty acids on the oxidative stress of preterm neonates fed through parenteral nutrition. Eur J Clin Nutr. 2010;64:940-947.
101.
SaviniSD’AscenzoRBiagettiC. The effect of 5 intravenous lipid emulsions on plasma phytosterols in preterm infants receiving parenteral nutrition: a randomized clinical trial. Am J Clin Nutr. 2013;98:312-318.
102.
D’AscenzoRSaviniSBiagettiC. Higher docosahexaenoic acid, lower arachidonic acid and reduced lipid tolerance with high doses of a lipid emulsion containing 15% fish oil: a randomized clinical trial. Clin Nutr. 2014;33:1002-1009.
103.
DeshpandeGSimmerKDeshmukhMMoriTACroftKDKristensenJ. Fish oil (SMOFlipid) and olive oil lipid (Clinoleic) in very premature neonates. J Pediatr Gastroenterol Nutr. 2014;58:177-182.
104.
VlaardingerbroekHVermeulenMJCarnielliVPVazFMvan den AkkerCHPvan GoudoeverJB. Growth and fatty acid profiles of VLBW infants receiving a multicomponent lipid emulsion from birth. J Pediatr Gastroenterol Nutr. 2014;58:417-427.
105.
BekenSDilliDFettahNDKabatasEUZencirogluAOkumusN. The influence of fish-oil emulsions on retinopathy of prematurity in very low birth weight infants: a randomized controlled trial. Early Hum Dev. 2014;90:27-31.
106.
GuraKMDugganCPCollierSB. Reversal of parenteral nutrition-associated liver disease in 2 infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics. 2006;118:e197-e201.
107.
EkemaGFalchettiDBoroniG. Reversal of severe parenteral nutrition-associated liver disease in an infant with short bowel syndrome using parenteral fish oil (omega-3 fatty acids). J Pediatr Surg. 2008;43:1191-1195.
108.
GuraKMLeeSValimC. Safety and efficacy of fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics. 2008;121:e678-e686.
109.
PremkumarMHCarterBAHawthorneKMKingKAbramsSA. Fish oil-based lipid emulsions in the treatment of parenteral nutrition-associated liver disease: an ongoing positive experience. Adv Nutr. 2014;5:65-70.
110.
PremkumarMHCarterBAHawthorneKMKingKAbramsSA. High rates of resolution of cholestasis in parenteral nutrition-associated liver disease with fish oil-based lipid emulsion monotherapy. J Pediatr. 2013;162:793-798.
111.
KhanFAFisherJGSparksEA. Preservation of biochemical liver function with low-dose soy-based lipids in children with intestinal failure-associated liver disease. J Pediatr Gastroenterol Nutr. 2015;60:375-377.
112.
LamHSTamYHPoonTCW. A double-blind randomized controlled trial of fish oil-based versus soybean oil-based lipid preparations in the treatment of infants with parenteral nutrition-associated cholestasis. Neonatology. 2014;105:290-296.
113.
Venecourt-JacksonEHillSJWalmsleyRS. Successful treatment of parenteral nutrition-associated liver disease in an adult by use of a fish oil-based lipid source. Nutrition. 2013;29:356-358.
114.
BurnsDLGillBM. Reversal of parenteral nutrition-associated liver disease with a fish oil-based lipid emulsion (Omegaven) in an adult dependent on home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2013;37:274-280.
115.
TorresCSudanDVanderhoofJ. Role of an intestinal rehabilitation program in the treatment of advanced intestinal failure. J Pediatr Gastroenterol Nutr. 2007;45:204-212.
116.
CowlesRAVenturaKAMartinezM. Reversal of intestinal failure-associated liver disease in infants and children on parenteral nutrition: experience with 93 patients at a referral center for intestinal rehabilitation. J Pediatr Surg. 2010;45:84-88.
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