Review

Journal of Parenteral and Enteral

Nutrition
Essential Fatty Acid Requirements and Intravenous Volume 00 Number 0
xxx 2019 1–11
Lipid Emulsions 
C 2019 American Society for

Parenteral and Enteral Nutrition

DOI: 10.1002/jpen.1537
wileyonlinelibrary.com

Leah Gramlich, MD1 ; Carol Ireton-Jones, PhD2 ; John M. Miles, MD3 ;

Maya Morrison, MSRD4 ; and Alessandro Pontes-Arruda, MD4

Abstract
Linoleic acid (LA) and α-linolenic acid (ALA) must be supplied to the human body and are therefore considered essential fatty
acids. This narrative review discusses the signs, symptoms, diagnosis, prevention, and treatment of essential fatty acid deficiency
(EFAD). EFAD may occur in patients with conditions that severely limit the intake, digestion, absorption, and/or metabolism of
fat. EFAD may be prevented in patients requiring parenteral nutrition by inclusion of an intravenous lipid emulsion (ILE) as a
source of LA and ALA. Early ILEs consisted solely of soybean oil (SO), a good source of LA and ALA, but being rich in LA
may promote the production of proinflammatory fatty acids. Subsequent ILE formulations replaced part of the SO with other fat
sources to decrease the amount of proinflammatory fatty acids. Although rare, EFAD is diagnosed by an elevated triene:tetraene
(T:T) ratio, which reflects increased metabolism of oleic acid to Mead acid in the absence of adequate LA and ALA. Assays for
measuring fatty acids have improved over the years, and therefore it is necessary to take into account the particular assay used
and its reference range when determining if the T:T ratio indicates EFAD. In patients with a high degree of suspicion for EFAD,
obtaining a fatty acid profile may provide additional useful information for making a diagnosis of EFAD. In patients receiving an
ILE, the T:T ratio and fatty acid profile should be interpreted in light of the fatty acid composition of the ILE to ensure accurate
diagnosis of EFAD. (JPEN J Parenter Enteral Nutr. 2019;00:1–11)

Keywords
essential fatty acids; essential fatty acid deficiency; essential fatty acid requirements; intravenous fat emulsion; intravenous lipid
emulsion; parenteral nutrition

Introduction bonds in the acyl chain) or saturated (ie, no double bonds

in the acyl chain).1 The human body is able to synthesize
Fatty acids are hydrocarbon chains of variable length, with most fatty acids or obtain them from the diet.1,2 However,
a methyl group at one end and a carboxyl group at the other 2 polyunsaturated fatty acids, linoleic acid (LA; 18:2n-6, an
end.1 Fatty acids can be unsaturated (ie, 1 or more double n-6 fatty acid) and α-linolenic acid (ALA; 18:3n-3, an n-3

From the 1 Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada; 2 Good Nutrition for Good Living, Dallas, Texas,
USA; 3 Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, Kansas, USA; and 4 Baxter Healthcare
Corporation, Deerfield, Illinois, USA.
Financial disclosure: This review was sponsored by Baxter Healthcare Corporation. Medical writing assistance was provided by Justine Southby,
PhD, CMPP, and Tania Dickson, PhD, CMPP, of ProScribe Envision Pharma Group and was funded by Baxter Healthcare Corporation.
ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).
Conflicts of interest: L. Gramlich has been on advisory boards for Shire, has received research funding from Baxter Healthcare Corporation,
Abbott Laboratories, and Fresenius Kabi, and has participated in Speaker’s Bureaus for Baxter Healthcare Corporation, Abbott Laboratories,
Fresenius Kabi, and Shire. C. Ireton-Jones has participated in a Speaker’s Bureau for Fresenius Kabi and is an employee of Nutrishare Inc (Elk
Grove, CA, USA). J. M. Miles has served as a consultant for Baxter Healthcare Corporation. M. Morrison and A. Pontes-Arruda are employees
of and own shares in Baxter International Inc, the corporate parent of Baxter Healthcare Corporation. Baxter Healthcare Corporation was
involved in the preparation of the manuscript.
Received for publication August 30, 2018; accepted for publication February 28, 2019.
This article originally appeared online on xxxx 0, 2019.
Corresponding author:
Maya Morrison, MSRD, Baxter Healthcare Corporation, 1 Baxter Parkway, Deerfield, IL 60015, USA.
Email: maya_dally@baxter.com
2 Journal of Parenteral and Enteral Nutrition 00(0)

Figure 1. Fatty acid structures and biosynthetic pathways. Adapted from Lee S, et al. Current clinical applications of Ω-6 and
Ω-3 fatty acids. Nutr Clin Pract. 2006;21:323-341. Copyright 2006 American Society for Parenteral and Enteral Nutrition, with
permission from John Wiley and Sons.

fatty acid), cannot be synthesized by humans because they
lack the desaturase enzymes capable of catalyzing double
bond formation at the n-6 or n-3 position of the hydrocar-
bon chain (counting from the methyl carbon), respectively.2
Thus, these 2 fatty acids can only be obtained from the diet
and are considered essential fatty acids (EFAs).1,2
The EFAs LA and ALA serve as parent n-6 and n-
3 fatty acids, respectively, giving rise to longer-chain fatty
acids through desaturation and elongation (Figure 1). For
example, LA is metabolized to arachidonic acid (AA;
20:4n-6), and ALA is metabolized to docosahexaenoic acid
(DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-
3) (Figure 1).1,3 These longer-chain fatty acids give rise
to bioactive lipid mediators in the form of eicosanoids
(prostaglandins, thromboxanes, and leukotrienes), which
are growth factors and inflammatory mediators, and influ-
ence gene expression.1,4 The n-6-derived eicosanoids (eg,
from AA) are considered proinflammatory, whereas the
n-3-derived eicosanoids (eg, from EPA) are considered
anti-inflammatory.5 As fatty acids are involved in so many
physiological processes, changes in fatty acid intake can have
major effects.1,2
Essential fatty acid deficiency (EFAD) is prevented
if 2%–4% of total energy comes from LA and 0.25%–
0.5% from ALA, and thus it is not difficult to meet these
requirements under usual circumstances.6,7 As a result,
EFAD is rare in healthy children and adults who have a
varied diet with an adequate intake of EFAs.5,8,9 In addition,
because adipose tissue contains LA, mobilization of EFAs
from adipose tissue may prevent EFAD when the supply of
exogenous fat is insufficient, provided that the individual has
adequate fat stores.8,10 However, patients with conditions
that severely limit the intake, digestion, absorption,
and/or metabolism of fat are at risk of developing EFAD,
especially if fat stores are depleted. This includes patients
with chronic fat malabsorption because of pancreatic
insufficiency, massive bowel resection or mucosal
disease,9,11,12 patients with cystic fibrosis,13 children
Gramlich et al
receiving parenteral nutrition (PN) who are subjected to
severe soybean oil (SO) lipid restriction,14 and preterm
infants.15 In preterm infants, the risk of EFAD is related
not only to their limited fat stores but also to their reduced
ability to synthesize AA and DHA, which are in high
demand during brain and retinal development, and are
therefore considered “conditionally essential.”16-19
Although EFAD is generally rare, it became a significant
concern for patients receiving the early formulations of
lipid-free PN.5,20 In the 1970s, there were many reports of
EFAD in infant and adult patients receiving PN.21-27 To
provide an adequate amount of energy, early PN formula-
tions consisted primarily of high concentrations of glucose
and amino acids and did not provide EFAs because lipid
emulsions for intravenous administration did not become
available in the United States until the 1970s.3,28 In addition,
in patients receiving PN with dextrose but no lipid, dextrose-
mediated insulin secretion has been found to suppress the
mobilization of EFAs from adipose tissue (depending on
the amount of dextrose given).6,10 After the risk of EFAD
in patients receiving prolonged fat-free PN was recognized,
intravenous lipid emulsions (ILEs; also referred to as IVLEs
or IVFEs [intravenous fat emulsions]) were added to PN
formulations to provide a source of LA and ALA.28-30
ILEs also provided a nonglucose source of energy, thereby
reducing the need for high glucose infusion rates.28 ILE-
containing formulations have been found to treat21,24,26,27
and prevent27,31,32 EFAD in adult, infant, and pediatric
patients receiving PN. Over the years, ILEs have become
a crucial component of PN, and they have evolved with
respect to lipid type and content.3,30,33
The advent of novel ILEs, which have variable concentra-
tions of EFAs, provides an opportunity to review the con-
dition of EFAD, including highlighting the circumstances
in which it might occur in patients receiving PN despite
the availability of ILEs and discussing the considerations
associated with the choice of ILE. The aim of this narrative
review (based on a search of the literature between 1974 and
September 2017) is to discuss the laboratory and clinical
signs and symptoms, diagnosis, and treatment of EFAD.
In addition, this review will discuss the role of ILEs in the
treatment, prevention, and diagnosis of EFAD in patients
receiving PN. With the introduction of ILEs with different
compositions, it is critical to understand the dosing of ILEs
and how their use affects EFA status.
Laboratory and Clinical Signs and Symptoms
of EFAD
Biochemical evidence of EFAD appears earlier than the
clinical signs and symptoms.9,26,34 Diagnostic biochemi-
cal manifestations of EFAD include decreased plasma
levels of LA and ALA, and an elevated triene:tetraene
(T:T) ratio (the significance of this ratio is described in
3
the Diagnostic Testing section).6,9 Other nonspecific bio-
chemical manifestations of EFAD include elevated liver
enzymes, hyperlipidemia, thrombocytopenia, and altered
platelet aggregation.9 Thus, in patients at risk of EFAD
and exhibiting these biochemical manifestations, assess-
ment of EFAD should be considered. It should be noted
that elevated liver enzymes, hyperlipidemia, and altered
platelet aggregation can also be a consequence of ILE
administration.35 Clinical manifestations of EFAD include
hair loss, impaired wound healing, increased susceptibility
to infection, reduced growth rate in infants and children,
and a dry scaly rash arising from increased transepidermal
water loss due to increased water permeability of the skin
(see Fleming et al25 for a photograph of the type of rash
associated with EFAD).6,9,21,25,36,37
ILEs and EFAD
SO-Based ILEs
Most of the early ILEs included in PN to provide a source of
EFAs consisted of 100% SO, for example, Intralipid (Baxter
Healthcare Corporation, Deerfield, IL, USA; Table 1), Nu-
trilipid (B. Braun, Bethlehem, PA, USA), and Lipovenoes
(Fresenius Kabi, Bad Homburg, Germany).1,30,33,38 SO-
based ILEs contain a large amount of LA and a moderate
amount of ALA (Table 2).1 Although SO ILE has been
used successfully to deliver lipid via PN, concerns have been
raised that this type of ILE, being rich in the n-6 fatty
acid LA, promotes the production of proinflammatory n-
6-derived eicosanoids, resulting in increased oxidative stress
and systemic inflammation.1,3,5,28 In addition, SO-based
ILEs have been associated with the development of intesti-
nal failure–associated liver disease (IFALD), particularly in
pediatric patients.19 However, multiple components of the
SO ILE have been implicated, including not only the high
ratio of n-6 to n-3 fatty acids but also the high phytosterol
levels and low vitamin E content compared with other types
of ILE.19 As a result, in subsequent ILE formulations,
the SO has been partially replaced with lipid sources that
provide less bioactive fatty acids, thereby decreasing the
amount of proinflammatory EFAs.1 These ILEs are widely
available in Europe and Canada but less so in the United
States.3,30,35
Medium-Chain Triglyceride–Based Intravenous
Emulsions
Medium-chain triglyceride (MCT)–based ILEs (for exam-
ple, Lipofundin-MCT [B. Braun, Melsungen, Germany]
and Lipovenoes MCT [Fresenius Kabi]) consist of mixtures
of SO and MCTs derived from coconut oils and other
tropical nut oils.1,30,33 MCTs are saturated fatty acids with
hydrocarbon chains of 6–10 carbon atoms esterified to
4 Journal of Parenteral and Enteral Nutrition 00(0)

Table 1. Indications of Commercially Available ILEs in the United States and/or Europe.a

ILE Indication References

Intralipid Source of energy and EFAs for patients requiring
PN for extended periods of time (usually >5
days) and a source of EFAs for prevention of
EFAD
For use as part of a balanced intravenous feeding
regimen in patients who are unable to receive
sufficient amounts of nutrients enterally
Lipofundin-MCTb Source of energy and EFAs for patients requiring
PN
ClinOleic/ClinoLipid Source of energy and EFAs for PN in adults when
oral or enteral nutrition is not possible,
insufficient, or contraindicated
Source of energy and EFAs for patients requiring
PN
Omegaven Source of energy and fatty acids in pediatric
patients with PNAC with direct or conjugated
bilirubin levels ࣙ2 mg/dL
PN supplementation with long-chain n-3-fatty
acids, especially EPA and DHA, when oral or
enteral nutrition is impossible, insufficient, or
contraindicatedc
SMOFlipid Source of energy and EFAs for PN in adults when
oral or enteral nutrition is not possible,
insufficient, or contraindicated
Source of energy and EFAs and n-3 fatty acids for
PN in patients when oral or enteral nutrition is
impossible, insufficient, or contraindicated
Lipidem/Lipoplusb Source of energy and essential n-6 fatty acids and
n-3 fatty acids as a component of a PN regimen
for adults
Intralipid [prescribing information]: Deerfield, IL,
USA: Baxter Healthcare Corporation, 2015.
http://ecatalog.baxter.com/ecatalog/loadResour
ce.blob?bid=20000307
Intralipid [summary of product characteristics]:
Runcorn, Cheshire, UK: Fresenius Kabi
Limited, 2018. http://www.mhra.gov.uk/home/
groups/spcpil/documents/spcpil/con1539317317
991.pdf
Lipofundin-MCT [summary of product
characteristics]: Melsungen, Germany: B. Braun
Melsungen AG, 2018. http://www.mhra.gov.uk/
home/groups/spcpil/documents/spcpil/con15405
26906305.pdf
Clinolipid [prescribing information]: Deerfield, IL,
USA: Baxter Healthcare Corporation, 2013.
https://www.accessdata.fda.gov/drugsatfda_docs
/label/2013/204508s000lbl.pdf
ClinOleic [summary of product characteristics]:
Thetford, Norfolk, UK: Baxter Healthcare Ltd,
2015. https://ecatalog.baxter.com/ecatalog/
loadResource.blob?bid=64438
Omegaven [prescribing information]: Fresenius
Kabi USA, 2018. https://www.accessdata.fda.
gov/drugsatfda_docs/label/2018/0210589s000lbl
edt.pdf
Omegaven [summary of product characteristics]:
Bad Homburg, Germany: Fresenius AG, 2015:
http://www.mhra.gov.uk/home/groups/spcpil/do
cuments/spcpil/con1535688413229.pdf
SMOFlipid [prescribing information]: Fresenius
Kabi, 2016. https://www.accessdata.fda.gov/
drugsatfda_docs/label/2016/207648lbl.pdf
SMOFlipid [summary of product characteristics]:
Runcorn, Cheshire, UK: Fresenius Kabi
Limited, 2019. http://www.mhra.gov.uk/home/
groups/spcpil/documents/spcpil/con1548997873
854.pdf
Lipidem/Lipoplus [prescribing information]:
B. Braun, Melsungen, Germany. https://www.
bbraun.com.vn/content/dam/catalog/bb
raun/bbraunProductCatalog/S/AEM2015/en-vn
/b/lipoplus.pdf.bb-.41648313/lipoplus.pdf

DHA, docosahexaenoic acid; EFA, essential fatty acid; EFAD, essential fatty acid deficiency; EPA, eicosapentaenoic acid; ILE, intravenous lipid
emulsion; MCT, medium-chain triglyceride; PN, parenteral nutrition; PNAC, parenteral nutrition–associated cholestasis.
a Note that this list is not exhaustive, and individuals should consult the prescribing information in their country for the appropriate use of these

products.
b Not approved/available in the United States.
c Note that the European Summary of Product Characteristics states that Omegaven should be administered simultaneously with other fat

emulsions.

the glycerol backbone.6 MCTs do not contribute to the
synthesis of eicosanoids and thus provide a source of fat
energy without additional systemic effects.3 However, as
MCTs do not provide EFAs, they are unsuitable for use as a
sole source of fat.30
Olive Oil–Based ILEs
Olive oil (OO) is rich in oleic acid, an n-9 monounsaturated
fatty acid that is considered immune neutral.30,32,33 This
type of ILE consists of 20% SO and 80% OO and has
Gramlich et al 5

Table 2. Oil Sources and Fatty Acid Composition of Commercially Available ILEs.a

Component Lipofundin- ClinOleic/ Lipidem/

(% by weight) Intralipid MCT ClinoLipid Omegaven SMOFlipid Lipoplus

Oil source
Soybean oil 100 50 20 0 30 40
Coconut oil 0 50 0 0 30 50
Olive oil 0 0 80 0 25 0
Fish oil 0 0 0 100 15 10
Fatty acid
LA 44–62 24–29 14–22 1.5c 14–25 24–29
ALA 4–11 2.5–5.5 0.5–4.2 1.1c 1.5–3.5 2.5–5.5
Oleic acid 19–30 11b 44–80 4–11 23–35 8b
AA 0 0 0 0.2–2 0 0
DHA 0 0 0 14–27 1–3.5 4.3–8.6d
EPA 0 0 0 13–26 1–3.5

AA, arachidonic acid; ALA, α-linolenic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ILE, intravenous lipid emulsion; LA,
linoleic acid; MCT, medium-chain triglyceride.
a From the current prescribing information or summary of product characteristics for each product (Table 1), except where otherwise indicated.

Note that the percentages of fatty acids in these ILEs are usually reported as a range rather than an absolute value.
b From Calder et al.28
c Mean value.
d Range for DHA and EPA combined.

approximately one-third of the LA of ILEs containing
100% SO (eg, 19% vs 53% for ClinOleic [Baxter Healthcare
Corporation; Table 1] vs Intralipid; Table 2).30,32 Investiga-
tion of the anti-inflammatory effects of 3 types of ILE using
a number of in vivo (murine models of inflammation) and
in vitro (endothelial adhesion assays) techniques showed
the anti-inflammatory superiority of ClinOleic to that of
an SO/MCT (50:50) ILE and a mixed ILE containing SO,
MCT, OO, and fish oil (FO).39
The development of ILEs containing lower levels of LA
and ALA raised concerns about their ability to prevent
EFAD.34 However, although the LA content of OO-based
ILE is lower than that of SO-based ILE, studies have shown
that this does not reduce the potential of OO-based ILE
to prevent EFAD.31,32 Vahedi et al31 found no biochemical
evidence (based on T:T ratio >0.2) of EFAD in 13 patients
with intestinal failure receiving OO-based ILE or SO-based
ILE in a 3-month, double-blind, randomized study. Olthof
et al32 found no biochemical (T:T ratio >0.2) or clinical
(skin rash) evidence of EFAD in 30 patients with intestinal
failure receiving long-term (>3 months) home PN (HPN)
with OO-based ILE. Appropriate dosing of the ILE to meet
LA and ALA requirements will avoid EFAD in patients
receiving an OO-based ILE.
based ILE Omegaven (Fresenius Kabi; Table 1) contains
much less LA (4.5% vs 53%) and ALA (1.8% vs 8%)
than the 100% SO-based ILE Intralipid, but it contains
their downstream metabolites, namely AA, DHA, and EPA
(Table 2).35 Following administration of a 100% FO ILE
to a patient who had developed EFAD (elevated T:T ratio,
skin rash) because a severe soy allergy precluded the use
of SO-based ILE, the patient’s T:T ratio improved, and
the rash disappeared.40 Other reports support the notion
that a 100% FO-based ILE may be an effective alternative
ILE for the treatment and prevention of EFAD.41-43 Murine
studies suggest that, although the parent fatty acids LA and
ALA have historically been considered EFAs, provision of
their metabolites AA and DHA may also be sufficient to
prevent EFAD.34 However, the manufacturer of the 100%
FO-based ILE does not recommend its use as the sole source
of fat energy because of concerns that the low levels of
LA and ALA could lead to EFAD43 (see Table 1 for its
indications). As a result, FO ILE may be administered in
conjunction with an SO ILE or as a component of a mixed
ILE formulation. For example, SMOFlipid (Fresenius Kabi;
Table 1) contains 30% SO, 30% MCT, 25% OO, and 15%
FO (Table 2), and Lipidem/Lipoplus (B. Braun; Table 1)
contains 50% MCT, 40% SO, and 10% FO (Table 2).3,28,30

FO-Based ILEs Comparison of ILEs

FO is considered anti-inflammatory because it contains Available evidence suggests that mixed ILEs, which combine
a higher proportion of n-3 than n-6 fatty acids, with n- MCT, OO, and/or FO, offer some advantages over the use
3-derived eicosanoids being considered anti-inflammatory of SO alone. A recent systematic review assessed the effects
compared with n-6-derived eicosanoids.5 The 100% FO- of currently available ILEs in adult patients receiving HPN
6 Journal of Parenteral and Enteral Nutrition 00(0)
Table 3. Doses of Intravenous Lipid Emulsion Required to Meet Essential Fatty Acid Requirements in Adults.
Parameter Intralipid 20% Lipofundin-MCT 20%
kcal/L 2000
kcal/mL 2 1.9
% LAa 53
kcal from LA, kcal/mL 1.06
Volume required to obtain 75.5
80 kcal from LA, mL
LA, linoleic acid; MCT, medium-chain triglyceride.
a From Calder et al.28
and found that mixed ILEs may exert long-term clinical
benefit as indicated by improved fatty acid profiles and
antioxidant status.44 However, only 3 studies met the criteria
for the systematic review, and no randomized controlled
trials comparing mixed ILEs were identified. The authors
therefore recommend prospective studies over a number of
years to give a better indication of the long-term effects
of the different ILEs.44 A systematic review conducted to
assess the safety and efficacy of mixed ILEs compared
with 100% SO-based ILEs in preterm infants found no
statistically significant differences in clinically important
safety outcomes and insufficient evidence to recommend
any mixed ILE over a 100% SO-based ILE or vice versa
in preterm infants.45 The authors of this analysis also
recommended larger randomized studies to evaluate the
effectiveness of mixed ILEs compared with 100% SO-
based ILEs in preterm infants.45 Further investigation is
important because both SO-based and FO-containing ILEs
have been found to affect DHA levels in preterm infants.
Within the first postnatal week, there is a decline in DHA
and AA and an excess of LA in preterm infants receiving the
100% SO-based ILE Intralipid; prolonged use contributes
to a prolonged lower DHA status, even after establishment
of full enteral feedings.46 Although FO-containing ILEs
raise DHA and EPA levels, the early postnatal deficit in
DHA is not eliminated and there is a decline in AA, even
greater than that observed with Intralipid.46 Thus, there is
concern that current ILEs do not provide adequate amounts
of DHA essential for neurodevelopment in preterm infants.
Dosing of ILEs
An LA intake of 2%–4% of total energy, and an ALA
intake of 0.25%–0.5% of total energy, are recommended to
prevent EFAD.6,7,47 As it is the SO component of the ILE
that provides clinically significant amounts of LA and ALA,
the amount of ILE required to provide sufficient energy
from LA and ALA depends on its SO content, which varies
between the different types of ILE (Table 2). Table 3 shows
examples of dosing of 4 different types of ILE to provide
4% of total energy as LA to an adult weighing 80 kg, based
on the LA content of the ILE. Table 4 shows examples
ClinOleic 20% SMOFlipid 20%
1908 2000 2000
2 2
29 19 20
0.55 0.38 0.40
144.6 210.5 200.0
of dosing of 4 different types of ILE to provide sufficient
LA to a term infant weighing 3 kg (0.1 g/kg/d)48 and a
preterm infant weighing 1.5 kg (0.25 g/kg/d).48 Tables 3
and 4 show the minimum volumes of ILE to prevent
EFAD, rather than total lipid dosing. The ideal ILE dose
in relation to energy needs is not known. For example,
the amount of ILE required to provide minimal amounts
of EFAs in infants and children may not be sufficient to
provide the recommended lipid doses (up to 4 g/kg/d in
term and preterm infants and up to 3 g/kg/d in children).48
Lipid provision in children varies depending on the clinical
situation and is generally somewhere in the range of 25%–
50% of nonprotein energy, depending on age, growth, and
developmental stage.48
Diagnosis of EFAD
Diagnostic Testing
An elevated T:T ratio is considered biochemical evidence
of EFAD, in which a triene is a hydrocarbon with 3
double bonds between carbon atoms and a tetraene is a
hydrocarbon with 4 double bonds between carbon atoms.
Under normal circumstances, desaturases (which insert
double bonds between adjacent carbon atoms) and elon-
gases (which lengthen hydrocarbon chains) act on LA to
produce AA and on ALA to produce DHA and EPA
(Figure 1).1,3,8 In the absence of adequate LA and ALA,
these enzymes instead act on the nonessential n-9 fatty acid
oleic acid (18:1n-9), resulting in increased production of
Mead acid (20:3n-9, a triene; Figure 1), which, in combina-
tion with the reduced production of AA (a tetraene) from
LA, leads to an elevated T:T ratio.3,8,9
The use of different methods to extract and quantify
fatty acids has led to a number of different threshold
values for the T:T ratio being proposed to indicate EFAD
(Table 5).42,49-53 Based on the polyunsaturated fatty acid
patterns of heart tissue, erythrocytes, and plasma from
rats that developed severe symptoms of EFAD after being
fed a fat-free diet, Holman49 suggested that a plasma T:T
ratio of <0.4 indicated that the minimum dietary require-
ment for LA has been met. Subsequently, Holman et al,50
Gramlich et al 7

Table 4. Doses of ILE Required to Meet Essential Fatty Acid Requirements in Term and Preterm Infants.

LA per Day
Total Energy Required to Lipofundin-MCT SMOFlipid
Weight per Day Prevent EFAD Intralipid 20% 20% ClinOleic 20% 20%

Term infant
3 kg 300 kcal 0.3 g 2.83 mL 5.17 mL 7.89 mL 7.50 mL
(100 kcal/kg) (0.1 g/kga )
Preterm infant
1.5 kg 180 kcal 0.375 g 3.54 mL 6.47 mL 9.87 mL 9.38 mL
(120 kcal/kg) (0.25 g/kgb )

EFAD, essential fatty acid deficiency; ESPGHAN, European Society of Paediatric Gastroenterology, Hepatology and Nutrition; ILE,
intravenous lipid emulsion; LA, linoleic acid; MCT, medium-chain triglyceride.
a ESPGHAN guidelines recommend that term infants receive 0.1 g/kg/d of LA to prevent EFAD.48 Note that the ESPGHAN guidelines also

recommend that children receive 0.1 g/kg/d of LA to prevent EFAD. Therefore, the ILE dosing for children can be determined in a similar manner
as for term infants, based on the weight of the child.
b ESPGHAN guidelines recommend that preterm infants receive 0.25 g/kg/d of LA to prevent EFAD.48

using packed-column gas-liquid chromatography to mea-
sure fatty acids in the plasma from individuals unlikely
to have derangements in EFA metabolism, suggested that
a plasma T:T ratio of 0.2 is the upper limit of normal
with respect to EFA status. Siguel et al,51 using capillary-
column gas-liquid chromatography to measure fatty acids in
plasma from reference subjects and patients with intestinal
fat malabsorption and suspected EFAD, suggested that
a plasma T:T ratio of >0.025 is indicative of EFAD.
Lagerstadt et al,52 using a capillary gas chromatography-
electron-capture negative-ion mass spectrometry method to
measure fatty acids in plasma from healthy adult donors
or pediatric patients with no apparent metabolic/nutrition
abnormalities, established reference ranges for the T:T ratio
for 4 age groups (Table 5), with a reference range of 0.010–
0.038 established for adults. These reference ranges for the
T:T ratio are currently used by the Mayo Medical Labora-
tories at the Mayo Clinic (Mayo Clinic Fatty Acid Profile,
Essential, Serum).54 More recently, Kish-Trier et al,53 using
a gas chromatography-negative chemical ionization-mass
spectrometry method modified from that of Lagerstadt et
al52 to measure fatty acids in plasma/serum samples that
were normal on routine biochemical genetic tests or col-
lected from healthy children and adults, reported reference
ranges for the T:T ratio for 3 age groups (Table 5), with a
reference range of 0.004–0.051 established for adults.
It should be noted that the newer methods of mea-
suring fatty acids described above51-53 established thresh-
olds/reference ranges for the T:T ratio that are an order of
magnitude lower than the previously reported threshold of
0.2.50 Siguel et al51 ascribed the differences between a T:T
ratio of >0.025 indicating EFAD as determined by their
assay (capillary-column gas-liquid chromatography) and a
T:T ratio of >0.2 indicating EFAD as determined by Hol-
man et al50 (packed-column gas-liquid chromatography) to
capillary columns being able to separate and quantify small
quantities of Mead acid (a triene) more accurately than
packed columns. The improved measurement of 1 compo-
nent of the T:T ratio (but not both) led to the lower T:T
ratios observed with the newer methods. It should also be
noted that the more recent assays provide reference ranges
for the T:T ratio rather than a threshold value indicative
of EFAD. Reference ranges represent values typically seen
in a given population and depend on the fatty acid dietary
intake of that population. Thus, when evaluating whether
a T:T ratio is indicative of EFAD, the method used to
measure fatty acids and the reference range established for
that method need to be taken into account.
Interpreting Fatty Acid Profiles
Although the T:T ratio is diagnostic of EFAD, it does not
take into account the n-3 fatty acid status19 and may be
affected by the fatty acid profile of the ILE the patient
is receiving. Vahedi et al31 found a significant increase in
oleic acid content in plasma phospholipids in patients re-
ceiving OO-based ILE, which is rich in oleic acid, compared
with patients receiving SO-based ILE after 3 months of
treatment. Importantly, oleic acid is metabolized into Mead
acid (Figure 1); thus, the T:T ratio would be expected to
be higher in these patients and may potentially exceed the
normal range, leading to an erroneous diagnosis of EFAD.
Similarly, de Meijer et al43 found that patients who were
receiving SO-based ILE at baseline had fatty acid profiles
reflective of the 100% SO-based ILE, that is, high levels
of LA and AA and low levels of EPA and DHA. When
these patients were switched to 100% FO ILE, their fatty
acid profiles gradually changed over the course of 6 weeks,
with decreasing levels of LA and AA and increasing levels
of EPA and DHA. In this situation, the T:T ratio would also
be expected to be higher as the tetraene levels are reduced.
Gramlich et al8 evaluated the fatty acid profiles (obtained
from the Mayo Clinic) of 3 patients receiving PN with
ILE and reported the patients’ T:T ratios, LA, ALA, and
8 Journal of Parenteral and Enteral Nutrition 00(0)

Table 5. Fatty Acid Assays and Their Associated T:T Ratio Threshold/Reference Range.

Study Subjects/Diagnosis Assay Threshold/Reference Range

Holman 196049
Holman et al 197950
Siguel et al 198751
Lagerstadt et al
200152
Kish-Trier et al
201653
Rats with severe symptoms of
EFAD after being fed a
fat-free diet
Hospital patients without a
diagnosis of a disease in
which EFA metabolism may
be deranged plus 14 healthy
adult donors
Approximately 10
individuals of each sex and
aged from each decade
between 0 and 90 years
56 reference subjects and
10 patients with intestinal fat
malabsorption and
suspected EFAD
196 plasma specimens from
healthy adult donors or
pediatric patients with no
apparent metabolic or
nutrition abnormalities
306 plasma/serum samples
found to be normal on
routine biochemical genetic
tests or collected from
healthy children and adults
Fatty acids measured in heart
tissue, plasma, and
erythrocytes by alkaline
isomerization of the
ethanol-ether extract
Fatty acids measured in plasma
by packed-column gas-liquid
chromatography
Fatty acids measured in plasma
by capillary-column
gas-liquid chromatography
Fatty acids measured in plasma
by capillary gas
chromatography-electron-
capture negative-ion mass
spectrometry
Fatty acids measured in
plasma/serum by capillary
gas
chromatography-negative
chemical ionization-mass
spectrometry (modified from
the method of Lagerstadt et
al 200152 )
A plasma T:T ratio <0.4
indicates that the minimum
dietary requirement for LA
has been met
A plasma T:T ratio of 0.2 is the
upper limit of normalcy with
respect to EFA status
A plasma T:T ratio of >0.025
is indicative of EFAD
Reference ranges established
for the T:T ratio:
<1 month: 0.017–0.083
1–12 months: 0.013–0.050
1–17 years: 0.013–0.050
>17 years: 0.010–0.038
Reference ranges established
for the T:T ratio:
<1 month: 0.006–0.052
1 month to ࣘ12 months:
0.002–0.046
>1 year: 0.004–0.051

EFA, essential fatty acid; EFAD, essential fatty acid deficiency; LA, linoleic acid; T:T, triene:tetraene.

Mead acid levels plus the oleic acid and AA levels. Each
of the patients was receiving OO-based ILE at the time of
obtaining the fatty acid profile, with patients 1 and 2 having
switched from SO-based ILE. Patient 1 had low LA levels
and a T:T ratio (0.032) within the Mayo Clinic reference
range (0.010–0.038); patient 2 had LA levels within the
reference range, elevated Mead acid and oleic acid levels,
and an elevated T:T ratio (0.042); and patient 3 had low
LA levels, elevated Mead acid and oleic acid levels, and
an elevated T:T ratio (0.051).8 Based on the elevated T:T
ratios according to the assay reference range, it might be
concluded that patients 2 and 3 had biochemical evidence
of EFAD. However, the authors suggested that the low LA
levels and/or elevated Mead acid levels observed in these
2 patients may be reflective of the composition of the OO-
based ILE (ie, lower LA and significantly more oleic acid
than SO-based ILE).8 In support of this interpretation,
all 3 patients had AA levels within the reference range,
whereas in EFAD, elevated Mead acid levels are observed
in conjunction with reduced AA levels.5,9,24,55 A correct
diagnosis of EFAD requires that the T:T ratio is elevated
because LA levels are low enough to result in an increased
production of Mead acid as well as a decreased production
of AA, that is, both the numerator (triene/Mead acid) is high
and the denominator (tetraene/AA) is low. Changes in the
numerator only or the denominator only are most likely to
reflect dietary changes.
It has therefore been suggested that the fatty acid profile
as a whole should be considered when assessing whether a
patient has EFAD, especially in patients receiving PN with
one of the mixed ILEs.8,34,53 Kish-Trier et al53 recommended
that the levels of individual n-6 and n-3 fatty acids be taken
into account as well as the T:T ratio when assessing EFAD,
with a pattern of increased T:T ratio, decreased levels of
LA and ALA, and increased levels of Mead acid being
indicative of EFAD.
Although the fatty acid profile is valuable in assessing
whether a patient has EFAD, we recommend that patients
Gramlich et al
are not routinely tested for fatty acid status when receiving
an enteral or oral diet or adequate ILE. The risk of clinically
significant EFAD is extremely remote in patients receiving
PN who have adequate fat stores and are receiving PN for a
relatively brief period of time. In addition, the risk of EFAD
is very low in patients receiving PN who are on an enteral
or oral diet. On the other hand, we recommend screening
for EFAD in selected patients who have depleted fat stores
or who are receiving fat-free PN for >4 weeks, including
HPN patients. We also recommend screening for EFAD
in patients (particularly children) receiving fat-free PN or
inadequate ILE, intravenous SO lipid–restricted diets (<1
g/kg/d of SO), or doses of alternative ILEs less than the
recommended dose for age (eg, a preterm infant receiving
1.5 g/kg/d of SMOFlipid or a child with IFALD receiving
0.5 g/kg/d of FO monotherapy). On the other hand, we note
that, for example, a preterm infant receiving 1.5 g/kg/d of
SMOFlipid is not necessarily at risk of EFAD if enteral
feeding is also provided or this dosage is used in the short
term only. Ultimately, there are no set criteria for screening
for EFAD. Preterm infants receiving limited ILE dosing
may be at a higher risk of EFAD and need more frequent
monitoring until enteral nutrition is established. Adults,
however, may need less frequent monitoring as they have
greater fat stores, unless they are malnourished, in which
case the risk of EFAD is increased. These considerations
are negated by enteral or oral nutrition, and therefore the
decision of when to screen for EFAD requires clinical
judgment.
Treatment of EFAD
As described above, patients with EFAD may be treated
with PN formulations containing LA and ALA. For PN-
dependent patients who cannot receive ILE (for example,
patients with severe hypertriglyceridemia or an allergy to
ILE), oral and topical preparations containing EFAs may be
treatment options. There is some evidence that oral prepa-
rations containing EFAs may treat EFAD. Richardson and
Sgoutas23 reported EFAD in 4 patients receiving fat-free
PN; 2 patients received supplementation with oral LA in the
form of safflower oil, which reversed the EFAD. Unless a
patient’s intestinal absorption is completely impaired, oral
EFA preparations would be expected to be of some benefit
in treating EFAD. However, many HPN patients with short
bowel syndrome have some intestinal absorptive capacity
but cannot sustain themselves solely with enteral energy and
hence require delivery of nutrients, including lipids, via PN.
Studies of topical application of oils containing EFAs
have reported mixed results. One study reported that topical
application of sunflower seed oil in 2 infants receiving fat-
free PN resulted in rapid reversal of both the biochemical
and clinical manifestation of EFAD.56 One study reported
that topical application of safflower oil in 3 infants with
9
EFAD who were receiving fat-free PN alleviated their scaly
skin rash but did not correct their abnormal T:T ratios.26
One study reported that topical application of sunflower oil
partly corrected EFAD in 1 infant and prevented EFAD
in another infant.27 However, other studies have found
no effect of topical applications of oils or LA on EFAD
symptoms in infant or adult patients.9
Ongoing Knowledge Gaps
Several knowledge gaps exist, and numerous research ques-
tions need to be addressed. There is a need to determine
the contemporary incidence of EFAD in the setting of the
newer ILEs. Additionally, clarity regarding whether at-risk
patients should be screened for EFAD, as well as the cri-
teria for determining the appropriate timing for when such
screening should occur, is needed. Currently unanswered
questions in the setting of the newer ILEs include how
quickly EFAD occurs and for how long does the body need
to be depleted of EFAs? Is there a safe period for how
long enteral feeding can be withheld before patients develop
EFAD, and does short-term EFA depletion have short-
term or long-term consequences? This last question may
be very important in the preterm and infant population,
as long-term consequences of depletion of AA and DHA
(“conditionally essential” EFAs) have been reported,17,57
raising concerns about the potential impact of depletion of
LA or ALA. Lastly, the key question yet to be addressed is
whether the current cutoffs for the T:T ratio remain relevant
in the setting of the newer ILEs.
Conclusions
Although EFAD is uncommon in the general population,
certain populations of patients are at risk of developing
EFAD, including patients receiving PN. The inclusion of
ILEs in PN formulations, as a source of EFAs, was found
to prevent EFAD in infant and adult patients. An elevated
T:T ratio has traditionally been considered biochemical
evidence of EFAD. As the assays for measuring fatty acids
have improved over the years, the particular assay used and
its reference range need to be kept in mind when assessing
whether a patient has EFAD, as well as when evaluating the
T:T ratios published in the literature. The fatty acid profile
as a whole may provide additional information, especially
in patients receiving newer ILE formulations, as the fatty
acid composition, including the proportion of EFAs, varies
between the different types of ILE. The optimal balance
of fatty acids in ILEs that delivers clinical benefit while
reducing adverse effects remains to be determined.
Diagnosis of EFAD is multifactorial, and abnormal lab-
oratory values can occur in the absence of clinical symptoms
and physical findings. Therefore, in patients receiving ILE,
the following factors need to be considered when interpret-
ing the fatty acid profile (T:T) and suggesting the diagnosis
10
of EFAD: (1) the fatty acid composition of the ILE, (2) the
fatty acid profile levels of the downstream metabolites of
LA and ALA (AA, DHA, and EPA) as well as the levels
of LA and ALA themselves; (3) the patient’s oral intake
and absorption of fatty acids, and (4) the patient’s fatty acid
stores.
Statement of Authorship
L. Gramlich, C. Ireton-Jones, J. M. Miles, M. Morrison, and
A. Pontes-Arruda contributed to the conception and design
of the research; M. Morrison contributed to the acquisition
and analysis of the data; L. Gramlich, C. Ireton-Jones, J. M.
Miles, M. Morrison, and A. Pontes-Arruda contributed to the
interpretation of the data; and L. Gramlich, C. Ireton-Jones,
J. M. Miles, M. Morrison, and A. Pontes-Arruda contributed
to drafting the manuscript. All authors critically revised the
manuscript, agree to be fully accountable for ensuring the
integrity and accuracy of the work, and read and approved the
final manuscript.
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