Parenteral nutrition–associated liver disease (PNALD) is a complex disease that is diagnosed by clinical presentation, biochemical markers of liver injury, concurrent use of parenteral nutrition (PN), and negative workup for other causes of liver disease. Since the first case of PNALD was reported more than 30 years ago, clinicians have had few effective treatments for PNALD, and when disease progressed to liver cirrhosis, it was historically associated with poor outcomes. Within the past 5 years, there has been much excitement about new treatments for PNALD, including use of both parenteral and enteral ω-3 polyunsaturated long-chain fatty acids (ω-3 PUFA) as well as restricting dosing of ω-6 PUFA. Scientists are also interested in uncovering the mechanisms associated with liver injury seen in PNALD. This article reviews the recent literature relating to the pathophysiology and treatment of PNALD.
BealeEFNelsonRMBucciarelliRLDonnellyWHEitzmanDV. Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics. 1979;64(3):342-347.
2.
SinatraFR. Cholestasis in infancy and childhood. Curr Probl Pediatr. 1982;12(12):1-54.
3.
WhitingtonPF. Cholestasis associated with total parenteral nutrition in infants. Hepatology. 1985;5(4):693-696.
4.
FishbeinTM. Intestinal transplantation. N Engl J Med. 2009;361(10):998-1008.
5.
JavidPJKimHBDugganCPJaksicT. Serial transverse enteroplasty is associated with successful short-term outcomes in infants with short bowel syndrome. J Pediatr Surg. 2005;40(6):1019-1023.
6.
WillisTCCarterBARogersSPHawthorneKMHicksPDAbramsSA. High rates of mortality and morbidity occur in infants with parenteral nutrition–associated cholestasis. JPEN J Parenter Enteral Nutr. 2010;34(1): 32-37.
7.
JavidPJCollierSRichardsonD. The role of enteral nutrition in the reversal of parenteral nutrition–associated liver dysfunction in infants. J Pediatr Surg. 2005;40(6):1015-1018.
8.
MerrittRJ. Cholestasis associated with total parenteral nutrition. J Pediatr Gastroenterol Nutr. 1986;5(1):9-22.
9.
MossRLDasJBRaffenspergerJG. Necrotizing enterocolitis and total parenteral nutrition–associated cholestasis. Nutrition. 1996;12(5):340-343.
10.
CarterBAShulmanRJ. Mechanisms of disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2007;4(5):277-287.
11.
CoppleBLJaeschkeHKlaassenCD. Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis. 2010;30(2):195-204.
12.
SpencerAUYuSTracyTF. Parenteral nutrition–associated cholestasis in neonates: multivariate analysis of the potential protective effect of taurine. JPEN J Parenter Enteral Nutr. 2005;29(5):337-343; discussion 343-344.
13.
ColombVJobert-GiraudALacailleFGouletOFournetJCRicourC. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children. JPEN J Parenter Enteral Nutr. 2000;24(6):345-350.
KearnsGLAbdel-RahmanSMAlanderSWBloweyDLLeederJSKauffmanRE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-1167.
AlemmariAMillerGGArnoldCJZelloGA. Parenteral aluminum induces liver injury in a newborn piglet model. J Pediatr Surg. 2011;46(5):883-887.
19.
GouletOJolyFCorriolOColomb-JungV. Some new insights in intestinal failure–associated liver disease. Curr Opin Organ Transplant. 2009;14(3):256-261.
20.
DriscollDFLingPRBistrianBR. Physical stability of 20% lipid injectable emulsions via simulated syringe infusion: effects of glass vs plastic product packaging. JPEN J Parenter Enteral Nutr. 2007;31(2):148-153.
21.
DriscollDFLingPRAnderssonCBistrianBR. 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. JPEN J Parenter Enteral Nutr. 2009;33(3):327-335.
22.
BalistreriWF. Bile acid therapy in pediatric hepatobiliary disease: the role of ursodeoxycholic acid. J Pediatr Gastroenterol Nutr. 1997;24(5):573-589.
23.
TeitelbaumDHTracyTFJrAouthmanyMM. Use of cholecystokinin-octapeptide for the prevention of parenteral nutrition–associated cholestasis. Pediatrics. 2005;115(5):1332-1340.
24.
KaufmanSS. Prevention of parenteral nutrition–associated liver disease in children. Pediatr Transplant. 2002;6(1):37-42.
25.
LambertJRThomasSM. Metronidazole prevention of serum liver enzyme abnormalities during total parenteral nutrition. JPEN J Parenter Enteral Nutr. 1985;9(4):501-503.
26.
JensenARGoldinABKoopmeinersJSStevensJWaldhausenJHKimSS. The association of cyclic parenteral nutrition and decreased incidence of cholestatic liver disease in patients with gastroschisis. J Pediatr Surg. 2009;44(1):183-189.
27.
KimHBFauzaDGarzaJOhJTNurkoSJaksicT. Serial transverse enteroplasty (STEP): a novel bowel lengthening procedure. J Pediatr Surg. 2003;38(3):425-429.
28.
GuraKMParsonsSKBechardLJ. Use of a fish oil–based lipid emulsion to treat essential fatty acid deficiency in a soy allergic patient receiving parenteral nutrition. Clin Nutr. 2005;24(5):839-847.
29.
GuraKMDugganCPCollierSB. Reversal of parenteral nutrition–associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics. 2006;118(1):e197-e201.
30.
VanekVWSeidnerDLAllenP. A.S.P.E.N. position paper: clinical role for alternative intravenous fat emulsions. Nutr Clin Pract. 2012;27(2):150-192.
31.
SalvadorAJaneczkoMPoratRSekhonRMoewesASchutzmanD. Randomized controlled trial of early parenteral nutrition cycling to prevent cholestasis in very low birth weight infants. J Pediatr. 2012;161(2):229-233.
32.
AlwaynIPGuraKNoseV. Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res. 2005;57(3):445-452.
33.
LeeSKimSLeHD. Reduction of hepatocellular injury after common bile duct ligation using omega-3 fatty acids. J Pediatr Surg. 2008;43(11):2010-2015.
34.
KohlMWedelTEntenmannA. Influence of different intravenous lipid emulsions on hepatobiliary dysfunction in a rabbit model. J Pediatr Gastroenterol Nutr. 2007;44(2):237-244.
35.
GrimmHTibellANorrlindBBlecherCWilkerSSchwemmleK. Immunoregulation by parenteral lipids: impact of the n-3 to n-6 fatty acid ratio. JPEN J Parenter Enteral Nutr. 1994;18(5):417-421.
36.
FurstPKuhnKS. Fish oil emulsions: what benefits can they bring?Clin Nutr. 2000;19(1):7-14.
37.
GuraKMLeeSValimC. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition–associated liver disease. Pediatrics. 2008;121(3):e678-e686.
38.
PuderMValimCMeiselJA. Parenteral fish oil improves outcomes in patients with parenteral nutrition–associated liver injury. Ann Surg. 2009;250(3):395-402.
39.
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(6):1191-1195.
40.
CheungHMLamHSTamYHLeeKHNgPC. Rescue treatment of infants with intestinal failure and parenteral nutrition–associated cholestasis (PNAC) using a parenteral fish-oil-based lipid. Clin Nutr. 2009;28(2):209-212.
41.
CalhounAWSullivanJE. Omegaven for the treatment of parenteral nutrition associated liver disease: a case study. J Ky Med Assoc. 2009;107(2): 55-57.
42.
ChungPHWongKKWongRMTsoiNSChanKLTamPK. Clinical experience in managing pediatric patients with ultra-short bowel syndrome using omega-3 fatty acid. Eur J Pediatr Surg. 2010;20(2):139-142.
43.
DiamondIRSterescuAPencharzPBKimJHWalesPW. Changing the paradigm: Omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48(2):209-215.
44.
FitzgibbonsSCJonesBAHullMA. Relationship between biopsy-proven parenteral nutrition–associated liver fibrosis and biochemical cholestasis in children with short bowel syndrome. J Pediatr Surg.2010;45(1):95-99.
45.
SodenJSLovellMABrownKPartrickDASokolRJ. Failure of resolution of portal fibrosis during omega-3 fatty acid lipid emulsion therapy in two patients with irreversible intestinal failure. J Pediatr. 2010;156(2): 327-331.
46.
DimmittRALeadfordAIBartleD. Impact of omega-3 fatty acids on liver function test and liver histology in children with intestinal failure associated intestinal disease. Presented at: Pediatric Academic Society; April 30, 2012; Boston, MA.
47.
MossRLDasJBRaffenspergerJG. Total parenteral nutrition–associated cholestasis: clinical and histopathologic correlation. J Pediatr Surg. 1993;28(10):1270-1274; discussion 1274-1275.
48.
HammelPCouvelardAO’TooleD. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med. 2001;344(6):418-423.
49.
BurnsDLGillBM. Reversal of parenteral nutrition–associated liver disease with a fish oil-based lipid emulsion (Omegaven) in an adult dependent on home parenteral nutrition [published online Jun 8, 2012]. JPEN J Parenter Enteral Nutr.
50.
SeidaJCMagerDRHartlingLVandermeerBTurnerJM. Parenteral omega-3 fatty acid lipid emulsions for children with intestinal failure and other conditions: a systematic review [published online June 8, 2012]. JPEN J Parenter Enteral Nutr. doi:10.1177/0148607112450300.
51.
RollinsMDScaifeERJacksonWDMeyersRLMulroyCWBookLS. Elimination of soybean lipid emulsion in parenteral nutrition and supplementation with enteral fish oil improve cholestasis in infants with short bowel syndrome. Nutr Clin Pract. 2010;25(2):199-204.
52.
TillmanEMCrillCMBlackDD. Enteral fish oil for treatment of parenteral nutrition–associated liver disease in six infants with short-bowel syndrome. Pharmacotherapy. 2011;31(5):503-509.
53.
SharmaAA. Supplementing enteral feeds with fish oil improves or reverses the total parenteral nutrition induced cholestasis in 4 infants in neonatal/pediatric intensive care units [abstract]. JPEN J Parenter Enteral Nutr. 2010;34(2):231.
54.
CoberMPKilluGBrattainAWelchKBKunisakiSMTeitelbaumDH. Intravenous fat emulsions reduction for patients with parenteral nutrition–associated liver disease. J Pediatr. 2012;160(3):421-427.
55.
NehraDFallonEMCarlsonSJ. Provision of a soy-based intravenous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates [published online July 5, 2012]. JPEN J Parenter Enteral Nutr.
56.
PiperSNSchadeIBeschmannRBMaleckWHBoldtJRohmKD. Hepatocellular integrity after parenteral nutrition: comparison of a fish-oil-containing lipid emulsion with an olive–soybean oil–based lipid emulsion. Eur J Anaesthesiol. 2009;26(12):1076-1082.
57.
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(6):797-802.
58.
de MeijerVELeHDMeiselJA. Parenteral fish oil as monotherapy prevents essential fatty acid deficiency in parenteral nutrition-dependent patients. J Pediatr Gastroenterol Nutr2010;50:212–218.
59.
StrijboschRALeeSArsenaultDA. Fish oil prevents essential fatty acid deficiency and enhances growth: clinical and biochemical implications. Metabolism2008;57:698–707.
60.
MallahHSBrownMRRossiTMBlockRC. Parenteral fish oil-associated burr cell anemia. J Pediatr2010;156:324–326e321.
61.
Omegaven [package insert]. Bad Homburg v.d.h., Germany: Fresenius Kabi AG; 2001.
62.
BaysHE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol2007;99:35C–43C.
63.
HarrisWS. Expert opinion: omega-3 fatty acids and bleeding-cause for concern?Am J Cardiol2007;99:44C–46C.
64.
BaysHE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C-43C.
65.
El-BadryAMGrafRClavienPA. Omega 3–omega 6: what is right for the liver?J Hepatol. 2007;47(5):718-725.
66.
De ViziaBRaiaVSpanoCPavlidisCCoruzzoAAlessioM. Effect of an 8-month treatment with omega-3 fatty acids (eicosapentaenoic and docosahexaenoic) in patients with cystic fibrosis. JPEN J Parenter Enteral Nutr. 2003;27(1):52-57.
67.
ThienprasertASamuhaseneetooSPopplestoneKWestALMilesEACalderPC. Fish oil n-3 polyunsaturated fatty acids selectively affect plasma cytokines and decrease illness in Thai schoolchildren: a randomized, double-blind, placebo-controlled intervention trial. J Pediatr. 2009;154(3):391-395.
68.
VaismanNKaysarNZaruk-AdashaY. Correlation between changes in blood fatty acid composition and visual sustained attention performance in children with inattention: effect of dietary n-3 fatty acids containing phospholipids. Am J Clin Nutr. May2008;87(5):1170-1180.
69.
SmithersLGGibsonRAMcPheeAMakridesM. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials. Am J Clin Nutr. 2008;87(4):912-920.
70.
SchmockerCWeylandtKHKahlkeL. Omega-3 fatty acids alleviate chemically induced acute hepatitis by suppression of cytokines. Hepatology. 2007;45(4):864-869.
71.
NovakTEBabcockTAJhoDHHeltonWSEspatNJ. NF-kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol Lung Cell Mol Physiol. 2003; 284(1):L84-L89.
72.
MalhiHGoresGJ. Cellular and molecular mechanisms of liver injury. Gastroenterology. 2008;134(6):1641-1654.
CarterBATaylorOAPrendergastDR. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res. 2007;62(3):301-306.
75.
KurvinenANissinenMJAnderssonS. Parenteral plant sterols and intestinal failure–associated liver disease in neonates. J Pediatr Gastroenterol Nutr. 2012;54(6):803-811.
76.
SigaletDBoctorDRobertsonM. Improved outcomes in paediatric intestinal failure with aggressive prevention of liver disease. Eur J Pediatr Surg. 2009;19(6):348-353.
77.
de MeijerVEGuraKMLeHDMeiselJAPuderM. Fish oil–based lipid emulsions prevent and reverse parenteral nutrition–associated liver disease: the Boston experience. JPEN J Parenter Enteral Nutr. 2009;33(5):541-547.
78.
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(5):485-495.
79.
AngstenGFinkelYLucasSKassaAMPaulssonMLiljaHE. Improved outcome in neonatal short bowel syndrome using parenteral fish oil in combination with omega-6/9 lipid emulsions. JPEN J Parenter Enteral Nutr. 2012;36(5):587-595.
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