1-Martin-Delivering Lipids and Fatty Acids

7/28/2019 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


13/57Enke et al. Br J Nutr, 2008

LCFA :(1) cellular membranes fluidity and function (DHA

most predominant FA in brain)

(2) central role in inflammatory cascades

PUFA & Systemic Inflammation


14/57Haggarty, Ann Rev Nutr, 2010

Placental Transport of Fatty Acids


15/57Haggarty, Ann Rev Nutr, 2010

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


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)



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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


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


DHA

Deficit ?

Parenteral phase Enteral phase



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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


3

4

5

6

7

MedianDHAlevel,mol%

0 1 2 3 4




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Enteral Phase of Lipid Delivery


3

4

5

6

7

MedianDHAlevel,mol%

0 1 2 3 4




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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


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


DHA

Deficit

Enteral phase may be too late

?



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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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THANK YOU

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1-Martin-Delivering Lipids and Fatty Acids

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