1-Martin-Delivering Lipids and Fatty Acids
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Transcript of 1-Martin-Delivering Lipids and Fatty Acids
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Nutrition & NutritionalPractices
LipidsEarly Nutritional & Postnatal
Intestinal DevelopmentImmunonutrients
Growth &
Long-Term Outcomes
Growth &
Short-Term Outcomes
1
2
3 4
Overview
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Objectives
Review current recommendations for lipid delivery
Discuss fatty acid requirements during fetal development
Demonstrate postnatal fatty acid alterations resulting from
current neonatal nutritional practices & its impact on health
and disease
Postulate potential strategies to optimize postnatal fatty acid
levels
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Lipid: Definition
Organic compound that is readily soluble in nonpolar
solvent but not in polar solvent (e.g water)
Major biological functions involve energy storage,structural component of cell membrane, and cell
signaling.
Examples: sterols, cholesterol, monoglycerides,diglycerides, triglycerides, and phospholipids
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Lipids
Preterm infants have very limited endogenous lipid stores
Essential component of parenteral nutrition
Serves as a source of Linoleic Acid
Necessary to prevent essential fatty acid deficiency (0.5 1.0
gm/k/day) Meets high energy needs: High caloric source at 9 kcal/gm
Important source for gluconeogenesis; which, ultimately may alsoreduce need for increased glucose infusion rates
Step-wise advancement starting at 1.0 gm/k/day to goal of 3.5gm/k/day
Monitor triglyceride levels
20% preparation recommended for neonates; improved toleranceover 10% solutions (decrease risk of hypertriglyceridemia,hypercholesterolemia, hyperphospholipidemia)
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Triglycerides & Phospholipids
Triglyceride Phospholipid
http://www.chemistryland.com/CHM151W/12-Final/triglyceride.jpg https://reader009.{domain}/reader009/html5/0407/5ac8
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Fatty acid metabolism in the preterm infant
Innis, Neoreviews 2002
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Fatty Acid: Definitions
Long hydrocarbon chain capped by a carboxyl group
(COOH)
Saturated: Saturated with
hydrogens, every carbon
links with the maximumnumber of hydrogens, thus
all single bonds
Unsaturated: Not every
carbon links with the
maximum number ofhydrogens, thus some
carbon-carbon links are
double bonds
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Fatty Acid: Nomenclature
18:3 (n-3)
1. Total number of carbons (c)
2. Total number of double bonds
3. Number of carbon from the terminal methyl end
with the first double bond
1 2
3
Terminal
Methyl
Carbon
Carboxyl
group
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Fatty Acid: Nomenclature, cont
1. Total number of carbons (c)
22
2. Total number of double bonds
6
3. Number of carbon from the
terminal methyl end with the
first double bond
3
22:6 (n-3)
DHA
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Inflammation
DHA and polyunsaturated fatty acids (PUFAs) are important in:
1. Maintaining the structure of the cell, and
2. Regulating the production of inflammatory proteins
Nucleus
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Cell Membrane: A Closer Look
A Intracellular space or cytosol
B Extracellular space or vesicle/Golgi apparatus lumen
1. Non-raft membrane
2. Lipid raft
3. Lipid raft associated transmembrane protein
4. Non-raft membrane protein
5. Glycosylation modifications (on glycoproteins and glycolipids)
6. GPI-anchored protein
7. Cholesterol8. Glycolipid http://en.wikipedia.org/wiki/File:Lipid_raft_organisation_scheme.svg
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LCFA :(1) cellular membranes fluidity and function (DHA
most predominant FA in brain)
(2) central role in inflammatory cascades
PUFA & Systemic Inflammation
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Placental Transport of Fatty Acids
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Biomagnification
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Fatty Acids & Fetal Organ Development
Lapillonne, et al, 2009
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Fatty Acids & In-Utero Accretion Rate
Lapillonne, et al, 2009
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Retinopathy of Prematurity: 40%
Long-term cognitive impairment: 35%
Chronic Lung Disease: 30-50% Infection: 20%
Necrotizing Enterocolitis: 5%
What is common to many of these disease?
1. DHA is critical in brain and eye development
2. DHA prevents excessive inflammation
Diseases of Extremely Premature Infants
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IV Fluids
No DHA
Optimal Growth &
Organ Development
DHA
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1. What happens to DHA levels
after premature birth?
2. If low, do they cause disease?
DHA
Optimal Nutrition
Fat
Sugars
Proteins
IV Fluids
No DHA
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Biorepository: All samples
collected & stored
Nutritional
Blood Fecal
Linked to all clinical information
Analyze fatty acids and
correlate with disease
Infant Health Research Program
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Similarly, LA and AA levels rapidly change
from blood levels discovered to be present
throughout the third trimester
Linoleic Acid (LA)
Arachidonic Acid (AA)
5
10
15
20
Median
LAandAAlevels,mol%
0 1 2 3 4Postnatal Week (Birth = Week 0)
LA levels observed in TERM infants
LA levels observed in PRETERM infants
Median LA levels present
throughout the 3rd trimester
Median AA levels present
throughout the 3rd trimester
Median AA levels at birth in PRETERM infants
Median AA levels at birth in TERM infants
Martin et al, Journal of Pediatrics, 2011
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*
+ CLD
No CLD
3
4
5
6
7
MeanDHAlevel,mol%
0 1 2 3 4
Postnatal week (birth = week 0)
* * *
Mean DHA levels for all infants
(n=54) (n=63) (n=56) (n=34) (n=35)
Low DHA Levels are Linked to the
Development of Chronic Lung Disease (CLD)
Martin et al, Journal of Pediatrics, 2011
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CLD OR (95% CI) p
LA 0.9 (0.7, 1.1) 0.4
AA 0.9 (0.6, 1.3) 0.6
DHA 2.5 (1.3, 5.0) 0.001
LA: DHA 8.6 (1.4, 53.1) 0.02
Late-onset sepsis Hazard ratio (95% CI) p
LA 0.8 (0.7, 0.96) 0.02
AA 1.4 (1.1, 1.7) 0.02
DHA 1.4 (1.0, 2.0) 0.08
LA: DHA 4.6 (1.5, 14.1) 0.007
Postnatal Alterations in Select Fatty Acids &
Ratios are Associated with an Increased Risk
of CLD & Late-Onset Sepsis
Models adjusted for gestational age, gender, growth restriction, severity of
illness, total Intralipid intakeMartin et al, Journal of Pediatrics, 2011
(1.3)
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DHA
Odds Ratio
Outcomes
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
ROP
LOS
CLD
AA
Odds Ratio
Outcomes
0.0 0.5 1.0 1.5 2.0
ROP
LOS
CLD
Martin et al, Journal of Pediatrics, 2011
Postnatal Alterations in Select Fatty Acids
Associated with an Increased Risk of CLD &
Late-Onset Sepsis
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Putting it All Together
3
4
5
6
7
8
Me
dianDHAlevel,m
ol%
0 1 2 3 4
Postnatal Week (Birth = Week 0)
Current delivery of nutrition failsto maintain DHA levels
Median DHA levels at birth in TERM
infants
Median DHA levels at birth in PRETERM
infants
Median DHA levels present
throughout the 3rd trimester
DHA
Deficit ?
Parenteral phase Enteral phase
Martin et al, Journal of Pediatrics, 2011
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Unique Developmental Needs
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Needs of the Premature Infant Unmet
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Defining the Needed Changes
Carbohydrates
Proteins
Fats
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Lapillonne 2010
Autopsy data, n-3 content in skeletal muscleGA< 28 weeks, n=40
Postnatal DHA Deficiency Inevitable
Consequence of Current Recommendations &
Practice in Preterm Infants
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Lapillonne 2010
Cumulative DHA deficit Correlation between birth weight &
cumulative DHA deficit
Postnatal DHA Deficiency Inevitable
Consequence of Current Recommendations &
Practice in Preterm Infants
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Early Alterations in Fatty Acids Occur During a
Critical Period of Immune & Organ Development
Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center
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Ollero, et al. J Cellular Physiology 2004;200:235244
Ileum Lung
PPAR is expressed in enterocytes &
bronchial epithelial cells
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1 2 3
PPARs 4
Microbiome
Influence the adhesion of Lactobacillus
Lactic acid bacteria dominate
Wahli W. Journal of Internal Medicine 2008;263:613-619Marion-Letellier, et al. Gut 2009;58:586-593
PPAR=Peroxisome proliferator-activated receptor
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BM & Infant FA Levels Associated With Infant
Cognitive Development
Sabel et al Prostaglandins, Leukotrienes and Essential Fatty Acids 2012
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Parenteral Phase of Lipid Delivery
Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center
3
4
5
6
7
MedianDHAlevel,mol%
0 1 2 3 4
Postnatal Week (Birth = Week 0)
Parenteral phase Enteral phase
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Enteral Phase of Lipid Delivery
Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center
3
4
5
6
7
MedianDHAlevel,mol%
0 1 2 3 4
Postnatal Week (Birth = Week 0)
Parenteral phase Enteral phase
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Prematurity
Low DHA
NEC(Rat Model)
ROP(Mouse Model)
Preterm
Infants
DHA
PUFA Supplementation and Disease in
Neonatal Disease Models
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Lu et al. Pediatric Research,
2007
AA+DHA Egg PL DHA Control
PUFAs and Necrotizing Enterocolitis
Decrease PAFR and TLR4 gene expression
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Omega-3 and Retinopathy of Prematurity
Connor et al. Nature Medicine, 2007 Mouse pups exposed to 75% O2 from P7 P12
Vasoobliteration / Neovascularization: 21.5 / 9 13.7 / 5.7
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Omega-3 and Retinopathy of Prematurity
21.9 / 8.3 11.9 / 4.3
- 3 PUFA suppressesTNF-
Connor et al. Nature Medicine, 2007
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PUFA Supplementation and Disease in
Neonatal Disease Models
Prematurity
Low DHA
NEC(Rat Model)
ROP(Mouse Model)
Preterm
Infants
DHA
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Cochrane Neonatal Group.
Publication status and date:2011Review content assessed as up-to-date: 27 December 2010
Schulzke SM, Patole SK, Simmer K. Longchain polyunsaturated fatty acid supplementation
in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.:
CD000375. DOI: 10.1002/14651858.CD000375.pub4.Copyright 2011 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
LCPUFAsin preterm infants: Cochran Review
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On pooling of results, no clear long-term benefits or harms (if growth the only
parameter) were demonstrated for preterm infants receiving LCPUFA-supplemented
formula.
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Mental Development & DHA Supplementation
Makrides JAMA 2009
Randomized, double-blind enteral supplementation
< 33 weeks of gestation High DHA (1% total FA) versus standard (0.3% of total FA)
Day 2-4 to term
Outcome: NDI at 18 months
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3
4
5
6
7
8
MedianDHAlevel,mol%
0 1 2 3 4
Postnatal Week (Birth = Week 0)
Current delivery of nutrition fails
to maintain DHA levels
Median DHA levels at birth in TERM infants
Median DHA levels at birth in PRETERM infants
Median DHA levels present
throughout the 3rd trimester
DHA
Deficit
Enteral phase may be too late
?
Parenteral phase Enteral phase
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Delayed Enteral Feeding
% of infants with any enteral feedings
0
1020
30
40
50
60
70
80
90
100
23 24 25 26 27
Gestational Age (weeks')
%i
nfants
DOL 0 DOL 3 DOL 5 DOL 7 DOL 14
d0
d3
d5
d7
d14
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What Dictates Adequate Enteral Replacement
of Fatty Acids?
1. Achieving Adequate Levels2. Targeting Critical Balance of n3:n6 Fatty Acids
3. Ensuring Effective Digestion
4. Optimizing Absorption
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Maldigestion/Malabsorption of DHA Occurs in
Premature Infants
Martin-Freedman Laboratory, Beth Israel Deaconess Medical CenterUnpublished data
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Lipid Emulsions
Deshpande and Simmer Current Opin in Clin Nutr and Met Care 2011
(linoleic)
(linolenic)
Omega-6
Omega-3
Omega-3 fatty acid
supplementation prevents hepatic
steatosis in a murine model of
nonalcoholic fatty liver disease.
Alwayn et al., Pediatr Res
2005;57:445-452.
Reversal of parenteral nutrition-
associated liver disease in two
infants with short bowel syndrome
using parenteral fish oil:
implications for future
management.
Gura KM et al., Pediatrics
2006;118(1):e197-201.
Innis. NeoReviews. 2002;3(3):e49
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2010 Patient population: n=40, BW< 1250g
Intervention: Composition/blend of Omegaven & Clinoleic
Control group: Historical - Clinoleic
Pawlick Pediatrics 2011
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Pawlick Pediatrics 2011
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Parenteral Nutrition of Preterm Infants with a
Lipid Emulsion Containing 10% Fish Oil:
Effect on Plasma Lipids and Long-ChainPolyunsaturated Fatty Acids
2011
Patient population: n=47, BW< 1250g
Intervention: Omegaven vs IntraLipid N=23, 10% fish oil (2.3% DHA) v n=24 MCT/soybean oil (trace amounts DHA)
Rita DAscenzo, et al. J Pediatrics 2011
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Study group
with LOWER
AA
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Conclusions
Lipids are an important source of energy and aids in gluconeogenesis
Goal: 3 3.5 g/kg/day
LCPUFAs are biomagnified from mother to fetus during the last trimester
Fatty acids (FA) are essential for organ growth and regulation ofinflammation
FA profiles are dramatically altered in the earlypostnatal period
Changes in postnatal FA profiles are linked to neonatal disease
New strategies, that include both the parenteral and enteral periods, need
to be developed to maintain birth levels of FA
New strategies need to consider the role and balance of all critical FA
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