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The omega-3 index, the percentage of EPA plus DHA in erythrocytes (measured by standardised analysis), represents a human body's status in EPA and DHA. An omega-3 index is measured in many laboratories around the world; however, even small differences in analytical methods entail large differences in results. Nevertheless, results are frequently related to the target range of 8–11 %, defined for the original and scientifically validated method (HS-Omega-3 Index ® ), raising ethical issues, and calling for standardisation. No human subject has an omega-3 index <2 %, indicating a vital minimum. Thus, the absence of EPA and DHA cannot be tested against presence. Moreover, clinical events correlate with levels, less with the dose of EPA and DHA, and the bioavailability of EPA and DHA varies inter-individually. Therefore, the effects of EPA and DHA are difficult to demonstrate using typical drug trial methods. Recent epidemiologic data further support the relevance of the omega-3 index in the cardiovascular field, since total mortality, cardiovascular mortality, cardiovascular events such as myocardial infarction or stroke, or blood pressure all correlate inversely with the omega-3 index. The omega-3 index directly correlates with complex brain functions. Compiling recent data supports the target range for the omega-3 index of 8–11 % in pregnancy. Many other potential applications have emerged. Some, but not all health issues mentioned have already been demonstrated to be improved by increasing intake of EPA and DHA. Increasing the omega-3 index into the target range of 8–11 % with individualised doses of toxin-free sources for EPA and DHA is tolerable and safe.
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The 13th European Nutrition Conference was held at the Convention Centre, Dublin on 1518 October 2019
Conference on Malnutrition in an obese world: European perspectives
Symposium 2: Assessment and novel technologies
Omega-3 index in 2018/19
Clemens von Schacky
Omegametrix, Martinsried, Germany and Preventive Cardiology, University of Munich, Germany
The omega-3 index, the percentage of EPA plus DHA in erythrocytes (measured by standar-
dised analysis), represents a human bodys status in EPA and DHA. An omega-3 index is
measured in many laboratories around the world; however, even small differences in analyt-
ical methods entail large differences in results. Nevertheless, results are frequently related to
the target range of 811 %, dened for the original and scientically validated method (HS-
Omega-3 Index
®
), raising ethical issues, and calling for standardisation. No human subject
has an omega-3 index <2 %, indicating a vital minimum. Thus, the absence of EPA and
DHA cannot be tested against presence. Moreover, clinical events correlate with levels,
less with the dose of EPA and DHA, and the bioavailability of EPA and DHA varies
inter-individually. Therefore, the effects of EPA and DHA are difcult to demonstrate
using typical drug trial methods. Recent epidemiologic data further support the relevance
of the omega-3 index in the cardiovascular eld, since total mortality, cardiovascular mor-
tality, cardiovascular events such as myocardial infarction or stroke, or blood pressure all
correlate inversely with the omega-3 index. The omega-3 index directly correlates with com-
plex brain functions. Compiling recent data supports the target range for the omega-3 index
of 811 % in pregnancy. Many other potential applications have emerged. Some, but not all
health issues mentioned have already been demonstrated to be improved by increasing
intake of EPA and DHA. Increasing the omega-3 index into the target range of 811 %
with individualised doses of toxin-free sources for EPA and DHA is tolerable and safe.
n-3 Fatty acids: EPA: DHA
The omega-3 index was dened as the percentage of EPA
and DHA in a total of twenty-six specic fatty acids in ery-
throcytes in 2004
(1)
.Anintegralpartofthedenition was
the highly standardised analytical procedure
(1,2)
. As dis-
cussed in more detail elsewhere, every step of the analytical
method impacts substantially on the result
(2)
.Moreover,
parameters such as time and vigour of shaking the sample
during lipid extraction, or time and agent used for trans-
methylation impacted on results
(2)
. Nevertheless, it was
possible to standardise the analytical method in three geo-
graphically distinct laboratories, with regular prociency
testing demonstrating the fruitfulness of the efforts
(2)
.
Many laboratories around the world have their own
methods to analyse erythrocyte fatty acids, and some
are using these methods to produce results they call
omega-3 index. However, quantitatively, the results dif-
fer from the results obtained with the standardised
method, i.e. are either higher or lower
(2)
. This is problem-
atic if the target range of 811 % of the standardised
method is used as a reference. This can lead to over sup-
plementation (overshooting the target range, potential
risk of bleeding) or under supplementation (not reaching
the target value, increased risk for total mortality and
other untoward clinical events)
(37)
. Either way, non-
Corresponding author: Clemens von Schacky, email c.vonschacky@omegametrix.eu
Proceedings of the Nutrition Society, Page 1 of 7 doi:10.1017/S0029665120006989
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standardised measurements create serious ethical issues;
standardising the omega-3 index methodology is needed.
Currently, the standardised analytical method can be
identied by the trademark HS-Omega-3 Index
®
.As
with all other laboratory parameters, standardisation of
the omega-3 index is one of the prerequisites for this par-
ameter entering clinical medicine.
The present review of scientic publications highlights
developments in the past two years.
Omega-3 index and human life
Using the standardised method to analyse erythrocytes,
and more than 20 000 samples from Omegametrix clin-
ical routine determinations, no sample was found with
an omega-3 index <2 % (Fig. 1). The same was true for
tens of thousands of samples from the Omegametrix
two sister laboratories called Omegaquant in Sioux
Falls, SD, USA and Seoul, South Korea (data not
shown). Thus, human life without a dened minimum
of EPA and DHA in erythrocytes remains to be found,
i.e. minimum levels of EPA and DHA seem to be needed
for human life. This puts the discussion, as to whether
EPA and DHA can be considered drugs, to rest. Life
without drugs is possible, whereas life without EPA
and DHA is not.
How the human body maintains these minimum levels
is unclear. Individuals, such as vegans or vegetarians,
ingest minimal amounts EPA and DHA (e.g. in one
study the mean was 15(
SD 35) mg/d EPA and 28
(SD 101) mg DHA/d according to dietary recall), yet in
these individuals, the mean omega-3 index found was
37(
SD 10) %
(8)
. In vegans or vegetarians, the omega-3
index did not correlate with the intake of α-linolenic
acid
(8)
, which was also true for omnivores in a country,
such as Canada, with high intake of α-linolenic contain-
ing axseed
(9)
. As a general rule, no level is solely con-
trolled by the inux, i.e. amounts going into the pool,
but also by other factors, such as distribution volume
(pool size), and efux, i.e. amounts leaving the pool.
The pool size for EPA and DHA in human subjects
has not been determined, and what factors regulate the
catabolism of EPA and DHA have not yet been well
dened in quantitative terms. It is not yet clear whether
small amounts of α-linolenic acid are metabolised to
EPA or DHA, or whether catabolism of EPA and
DHA is shut off to maintain a minimum omega-3
index
(10,11)
. Correspondingly, EPA and DHA might be
essential because life without a minimum omega-3
index is not possible. Alternatively, this may not be the
case if a minimum omega-3 index arises from α-linoleic
acid metabolism to EPA and/or DHA. The question of
essentiality cannot be resolved by simply analysing the
levels of fatty acids, but only by detailed metabolic stud-
ies in appropriate populations.
Issues in trial design
Frequently, clinical research organisations are hired to
conduct a multi-centre trial. By default, clinical research
organisations ask trial participants to ingest their trial
medication in the morning, which was also the case in
many, but not all large trials with clinical endpoints in
the omega-3 eld
(12,13)
. Trial medication in such trials
frequently was one capsule containing 1 g fat containing
860 mg EPA and DHA
(12,13)
. In many countries, break-
fast is a low-fat meal, if eaten at all. Bioavailability of
EPA and DHA is minimal with a low-fat meal, since
fat absorption requires a number of steps that are acti-
vated by a high-fat, but not by a low-fat meal
(14,15)
.In
other words, the bioavailability of EPA and DHA was
minimised by asking participants to ingest EPA and
DHA in the morning.
Moreover, in all trials so far, participants were
recruited irrespective of their baseline omega-3
index
(12,13)
. Patients with congestive heart failure with
reduced ejection fraction or major depression are charac-
terised by a low omega-3 index, but in many other health
issues, such as coronary artery disease, this is not neces-
sarily the case
(12,13,16,17)
. In addition, uptake of EPA and
DHA has high inter-individual variability, e.g. by a fac-
tor 13 in one trial
(18)
. The consequence of both inhomo-
geneous baseline levels and high inter-individual
variability of uptake was that on-trial levels of EPA
and DHA largely overlapped among placebo and
verum groups
(19)
. Since clinical events correlate with
the levels rather than with the intake of omega-3s, this
made it impossible to discern an effect of the intervention
with EPA and DHA
(12,13)
. The issues mentioned here are
discussed in more detail elsewhere
(12,13)
. In the future,
recruitment of trial participants will have to depend on
a low baseline omega-3 index (room for improvement
needed), and doses of EPA and DHA will have to be
individualised, in order to separate the levels in the pla-
cebo and verum groups. Positive trial results in popula-
tions characterised by a low omega-3 index, such as
patients with major depression or congestive heart failure
with reduced ejection fraction, support this approach,
although the dose was not individualised in the pertinent
trials
(20,21)
. Individualising the dose is likely to increase
the effect, and thus reduce the sample size, as well as
reduce the untoward effects
(12)
. The latter is supported
by the results of trials using high doses of EPA and/or
DHA, as in the JELIS or REDUCE-It trials
(6,7)
.In
both cases, the cost of a positive trial result was a small
increase in bleeding episodes (01 %/year)
(6,7)
.
Unfortunately, perception of the effectiveness of EPA
and DHA in clinical medicine is frequently shaped by the
results of pertinent Cochrane-Analyses. Cochrane-Analyses
include trials based on standardised Cochrane-criteria
designed for drug trials. In areas in which EPA and
DHA have been tested in randomised controlled trials,
Cochrane-Analyses tend to demonstrate no or only small
effects
(22)
. This is because Cochrane-criteria do not allow
trials with the design issues just discussed to be excluded.
Cardiovascular effects
The magnitude of the potential effects of EPA and DHA
can be estimated by considering the results of
C. von Schacky2
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epidemiologic studies, e.g. the Framingham study, using
the original omega-3 index. With an omega-3 index >68
%, total mortality was 65 % of total mortality with an
omega-3 index <42%
(3)
,reecting very similar results
from earlier studies
(4,5)
. The respective numbers for
total CVD (63 %), total CHD (59 %) and total stroke
(47 %) were similar
(3)
. Interestingly, simultaneously mea-
sured cholesterol levels were no risk for any of the events
mentioned
(3)
. The risk for peripheral artery disease was
also substantially lower with a higher omega-3 index
than with a lower omega-3 index
(23)
. When dietary intake
was assessed, associations with the health issues men-
tioned were substantially smaller
(24,25,26)
. Together with
the positive results from large intervention trials, the
numbers mentioned support the use of the omega-3
index to maximise the benet and minimise the risk of
EPA and DHA in the prevention of mortality and
CVD. In keeping, the American Heart Association has
issued scientic advisories recommending EPA and
DHA for the secondary prevention of CVD but refrained
from mentioning a dose
(27,28)
.
Low levels of EPA and DHA precede the development
of congestive heart failure, and a low omega-3 index can
be found in these patients
(16,29,30)
. A large intervention
trial with approximately 860 mg EPA and DHA daily
in patients with congestive heart failure with reduced
ejection fraction increased the omega-3 index in the
verum group from 475 (SD 168) to 673 (SD 193) %
after 3 months, whereas it remained constant about
477 (SD 160) in the placebo group
(30)
. The target range
was not reached, but, since omega-3 index levels in the
verum group were somewhat separated from omega-3
index levels in the placebo group, the primary endpoint,
a combination of total mortality and hospitalisations,
was signicantly reduced in the verum group
(21)
.
An association between the intake of sh and blood
pressure was not found
(31)
. However, the circulating
levels of EPA and DHA were inversely related to blood
pressure
(31)
. In a representative assessment of the entire
population of Liechtenstein, the omega-3 index corre-
lated inversely with blood pressure (both systolic and
diastolic), whether assessed over 24 h, during daytime
or night, or conventionally in the ofce. The inverse cor-
relation was independent of age and sex and other con-
founders such as BMI, smoking status, glycated
haemoglobin A1c, educational status, fruit and vegetable
consumption, physical activity and others
(32)
.
Endothelial function improved in intervention trials,
also depending on the omega-3 index
(33,34)
.
Meta-analyses of intervention trials demonstrated that
EPA and DHA lower blood pressure
(35)
.
Brain and the omega-3 index
As mentioned, in the Framingham study, an omega-3
index of 68 % was associated with a 53 % lower risk
for total stroke than an omega-3 index of 42%
(3)
.In
the Reduce-It trial, in the verum group, stroke occurred
in ninety-eight patients, whereas it occurred in 134
patients in the placebo group, a 28 % reduction (hazard
ratio 072, 95 % CI 55, 093, P=001)
(7)
. Therefore, n-3
fatty acids must be considered a powerful possibility
for preventing the stroke, a catastrophic event for brain
structure and thus brain function.
In an epidemiologic study in children with a mean age
of 4, the omega-3 index correlated with complex brain
functions, such as executive function, in this case assessed
as the dimensional change card sort task
(36)
, extending
similar ndings from study populations aged 31, 67
and 78 years
(3740)
. Recent intervention trials conrmed
that improvements in complex brain functions correlate
with omega-3 index, when measured
(41,42)
.
Pregnancy and lactation
Premature birth before week 34 of pregnancy is more likely
with low levels than with high levels of EPA and DHA in
plasma or erythrocytes, with the risk for preterm birth cor-
relating inversely with those levels
(43,44)
. Another publica-
tion found post-partum depression to strongly depend on
Fig. 1. Omega-3 index (y-axis) in 23 615 erythrocyte samples from Europe (x-axis), as
determined in the clinical routine of Omegametrix
(66)
.
Omega3 index in 2018/19 3
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the omega-3 index, i.e. with a higher omega-3 index, post-
partum depression was much less likely than with a lower
omega-3 index
(45)
. Unfortunately, however, the ndings
are not directly comparable to the results obtained with
the original omega-3 index, since different analytical proce-
dures were used
(44,45)
.
In 2018, a large Cochrane Meta-Analysis clearly found
premature birth to be reduced both before weeks 34 and
37, gestational age to be prolonged by 167 days (95 % CI
095, 239), based on forty-one randomised controlled
trials in 12 517 pregnant women, a lower incidence of
low birth weight 156v. 14 %; relative risk 090 (95 %
CI 082, 099), based on fteen randomised controlled
trials in 8 449 pregnant women, and relative risk for peri-
natal death of the child to be 075 (95 % CI 054, 103),
based on ten randomised controlled trials in 7 416 preg-
nant women, and more benets for mother and child
(all comparisons relative to placebo or control)
(46)
.In
the practical conclusion, the authors mentioned: A uni-
versal supplementation can make sense, although, with
better knowledge, it should be aimed for women bene-
tting the most
(46)
.
Already in 2016, the omega-3 index had been assessed
in an almost representative manner in pregnant and lactat-
ing women in Germany and was found to be between 249
and 1110 % regardless of timepoint (pregnancy v. lacta-
tion) and whether the woman supplemented EPA and
DHA
(47)
. Taken together, in this authors opinion, the
data to date make it necessary to determine the omega-3
index before or early in pregnancy, later in pregnancy
and in lactation to make a targeted supplementation feas-
ible, with a target range of 811 % for the omega-3 index.
Omega-3 index in sports medicine
In 2014, we had observed that 106 German world class
athletes had a mean omega-3 index of 497 (SD 119) %,
with only one athlete in the target range
(48)
. More recently,
similar data were found in 404 US national division I col-
lege football athletes with a mean omega-3 index of 44(
SD
08) %, again only one athlete in the target range
(49)
.
Interestingly, the more energy was burned throughout
the season, the lower the omega-3 index became
(50)
.This
has important implications for athletes, since a low
omega-3 index predisposes to delayed-onset muscle sore-
ness, and increasing the omega-3 index results in less creat-
inekinasereleasefrommuscle,lessinammatory reaction
(measured as muscle swelling and pro-inammatory cyto-
kines in plasma) and less loss of function
(51,52)
. Joint pain
was reduced with a higher omega-3 index, at least in
dogs
(53)
. Joint stability, e.g. in the case of the shoulder rota-
tor cuff, was higher with a higher omega-3 index
(54)
.Inan
intervention trial, it had been demonstrated that brain
damage, assessed as neurolament light (the pertinent bio-
marker), can be reduced with high doses of EPA and DHA
in professional players of American football
(55)
. Jointly,
these ndings point towards higher membrane stability
with a higher omega-3 index. Together with the aspects
of cognition that have been improved by EPA and DHA
in intervention trials in athletes, such as reaction time
and efciency
(56)
, current data indicate that an omega-3
index in the target range may be an important asset for
the athlete. This is supported by the fact that athletes are
at an increased risk for major depression, suicide and sud-
den cardiac death, all in keeping with a low omega-3 index,
and all seriously impacting on an athletes life
(48)
.
Other recent ndings
Conventionally, SFA are considered as a homogenous
group with an ominous effect on life expectancy. With
the determination of the original omega-3 index comes
the measurement of six individual SFA in erythrocytes
(1)
.
It was thus determined that palmitic acid (C16:0) was
associated with increased total mortality in a 10-year epi-
demiologic study of 3259 participants, while the other
erythrocyte SFA investigated (C14:0, C18:0, C20:0,
C22:0, C24:0) had no association with total mortality
(57)
.
In a meta-analysis, higher levels of palmitic acid were
associated with a higher risk for developing type 2 dia-
betes
(58)
. In a single study, this was also true for gesta-
tional diabetes
(59)
. Cell membrane levels of palmitic acid
are partly derived from ingested palmitic acid, and partly
produced endogenously, e.g. in reaction to energetic sur-
plus
(60)
. Together with other ndings of individual struc-
ture, metabolism, biologic effects and impacts on life
expectancy, our ndings question the conventional group-
wise nomenclature of fatty acids (e.g. SFA, PUFA and
others), as well as the conventional recommendation to
avoid all SFA. Whether high levels of palmitic acid
might be a biomarker for metabolically untoward body
fat, such as excess hepatic fat, remains to be investigated,
which is also true for the potential effects of actively redu-
cing levels of palmitic acid.
The ndings just discussed were mirrored in an epide-
miologic study in children with a median age of 11 years,
with palmitic acid correlating positively with waist cir-
cumference, TAG, fasting insulin and fatty liver index,
against the background of a low omega-3 index (47
(SD 08) %)
(61)
. Interestingly, the levels of arachidonic
acid correlated inversely with the parameters men-
tioned
(61)
. According to a recent meta-analysis, high
levels of EPA and DHA in plasma or erythrocytes
were associated with a low risk for the metabolic syn-
drome
(62)
. Thus, the omega-3 index makes it possible to
investigate the relations between metabolism and
non-n-3 fatty acids in more detail.
In patients with chronic fatigue syndrome/myalgic
encephalomyelitis, a low mean omega-3 index was
found
(63)
. Chronic fatigue syndrome/myalgic encephalo-
myelitis is a debilitating chronic medical condition with-
out a known aetiology, no clinically established
diagnostic test and no effective pharmacologic treat-
ment
(63)
. Our ndings add chronic fatigue syndrome/
myalgic encephalomyelitis to the list of chronic inam-
matory diseases where EPA and DHA should be tested
in intervention trials for potential therapeutic value
(63)
.
Some recent intervention trials with EPA and DHA
had neutral results. In one trial, it became clear by meas-
uring the omega-3 index that this was due to participants
C. von Schacky4
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non-compliance
(64)
. In another trial, effects on cognitive
parameters were smaller than expected within the
16-week trial period, demonstrating the difculties of
such trials
(65)
.
Conclusion
In the years 2018 and 2019, a perspective on EPA and
DHA levels has proven useful to generate new knowl-
edge on fatty acids, such as there is no human life with
an omega-3 index 2 % in erythrocytes. Decits in
EPA and DHA, i.e. an omega-3 index below the target
range of 811 %, have been found in many countries
and populations. A decit in EPA and DHA is asso-
ciated with increased total mortality, fatal and non-fatal
cardiovascular events, stroke, impaired cognition, pre-
mature birth, perinatal mortality and other health
issues
(35,8,9,16,17,30,32,3739,45,47,48,54,63,64)
.Adecit in
EPA and DHA in the population studied is required
for positive results of a randomised controlled interven-
tion trial. Reducing a decit in EPA and DHA prolongs
life, and reduces fatal and non-fatal cardiovascular
events, strokes, premature birth, perinatal mortality and
other health issues. In a trial, this can only be detected if
the levels in the verum group differ sufciently from the
levels in the placebo or control group. Increasing the
omega-3 index into the target range of 811 % with indi-
vidualised doses of toxin-free sources for EPA and DHA
is tolerable and safe.
Financial Support
The present work was not supported by any funding
agency or by industry.
Conict of Interest
C. v. S. operates Omegametrix, a laboratory for fatty
acid analyses. In the past 3 years, C. v. S. received hon-
oraria for speaking and consulting from BASF/Pronova,
EPAX, Huntsworth Medical, Abbott, DSM, Marine
Ingredients and Norsan.
Authorship
The author had sole responsibility for all aspects of
preparation of this paper.
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... Then, participants were randomized to receive either a fixed dose of EPA and DHA or a placebo, analogous to a drug trial, where the absence of a drug is compared to its presence [30,31]. However, all humans have blood levels of EPA and DHA that have a statistically normal distribution in all populations studied thus far [5]. Of course, no effect of EPA and DHA can be detected in individuals with optimal blood levels; rather, a deficit at baseline is a prerequisite for an effect to be demonstrated. ...
... Since absorption of EPA and DHA requires fat digestion, and fat digestion needs to be initiated with sufficient fat in a meal, bioavailability of EPA and DHA was thus minimized [30][31][32]. Moreover, inter-individual variability in bioavailability is large (factor 13), which, together with the statistically normal distribution of the baseline blood levels unaccounted for, leads to blood levels of EPA and DHA overlapping during a trial between Verum (i.e., EPA and DHA) and Placebo groups [5,[30][31][32][33]. Since clinical events correlate more closely with blood levels than with dietary intake of EPA and DHA, a sufficiently large overlap of blood levels of EPA and DHA between EPA and DHA and Placebo groups will make it impossible to discern a difference in number of clinical events between EPA and DHA and Placebo groups [5,[30][31][32]. ...
... Moreover, inter-individual variability in bioavailability is large (factor 13), which, together with the statistically normal distribution of the baseline blood levels unaccounted for, leads to blood levels of EPA and DHA overlapping during a trial between Verum (i.e., EPA and DHA) and Placebo groups [5,[30][31][32][33]. Since clinical events correlate more closely with blood levels than with dietary intake of EPA and DHA, a sufficiently large overlap of blood levels of EPA and DHA between EPA and DHA and Placebo groups will make it impossible to discern a difference in number of clinical events between EPA and DHA and Placebo groups [5,[30][31][32]. As many systematic reviews and meta-analyses disregarded the methodological issues just discussed, and included trials based on other criteria, misleading results were and are being provided. ...
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Brain structure and function depend on a constant and sufficient supply with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by blood. Blood levels of EPA and DHA reflect dietary intake and other variables and are preferably assessed as percentage in erythrocytes with a well-documented and standardized analytical method (HS-Omega-3 Index®). Every human being has an Omega-3 Index between 2 and 20%, with an optimum of 8–11%. Compared to an optimal Omega-3 Index, a lower Omega-3 Index was associated with increased risk for total mortality and ischemic stroke, reduced brain volume, impaired cognition, accelerated progression to dementia, psychiatric diseases, compromises of complex brain functions, and other brain issues in epidemiologic studies. Most intervention trials, and their meta-analyses considered EPA and DHA as drugs with good bioavailability, a design tending to produce meaningful results in populations characterized by low baseline blood levels (e.g., in major depression), but otherwise responsible for many neutral results and substantial confusion. When trial results were evaluated using blood levels of EPA and DHA measured, effects were larger than comparing EPA and DHA to placebo groups, and paralleled epidemiologic findings. This indicates future trial design, and suggests a targeted use EPA and DHA, based on the Omega-3 Index.
... Variable baseline nutritional and/or metabolic status is a plausible and commonly cited explanation for the inconsistency between studies in the reported impact of protein and LC n-3 PUFA supplementation in older adults. 23,32 Counter to this notion however, despite a wide between-participant range in PRE-intervention protein intake (0.4 to 2.2 g/kg/day, 37% of the cohort had a dietary protein intake <1 g/kg/day) and LC n-3 PUFA status (erythrocyte EPA + DHA content 4.4% to 17.0% of total membrane fatty acids), we observed no association between these nutritional status measures, or numerous other dietary, phenotypic, or behavioural variables, and the responses to LEU-PRO and LEU-PRO+n-3 supplementation. Thus, our analyses imply that the phenotype and nutritional status of our participants are unlikely to explain the lack of observed group-level effect of the LEU-PRO and LEU-PRO+n-3 supplementation interventions, and further research will be required to untangle the reasons for the inconsistency regarding the impact of LEU-PRO and LC n-3 PUFA reported in the literature. ...
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Background: Precision nutrition is highly topical. However, no studies have explored the interindividual variability in response to nutrition interventions for sarcopenia. The purpose of this study was to determine the magnitude of interindividual variability in response to two nutrition supplementation interventions for sarcopenia and metabolic health, after accounting for sources of variability not attributable to supplementation. Methods: A 24 week, randomized, double-blind, placebo-controlled trial tested the impact of leucine-enriched protein (LEU-PRO), LEU-PRO plus long-chain n-3 PUFA (LEU-PRO+n-3) or control (CON) supplementation in older adults (n = 83, 71 ± 6 years) at risk of sarcopenia. To estimate the true interindividual variability in response to supplementation (free of the variability due to measurement error and within-subject variation), the standard deviation of individual responses (SDR ) was computed and compared with the minimally clinically important difference (MCID) for appendicular lean mass (ALM), leg strength, timed up-and-go (TUG), and serum triacylglycerol (TG) concentration. Clinically meaningful interindividual variability in response to supplementation was deemed to be present when the SDR positively exceeded the MCID. The probability that individual responses were clinically meaningful, and the phenotypic, dietary, and behavioural determinants of response to supplementation were examined. Results: The SDR was below the MCID for ALM (LEU-PRO: -0.12 kg [90% CI: -0.38, 0.35], LEU-PRO+n-3: -0.32 kg [-0.45, 0.03], MCID: 0.21 kg), TUG (LEU-PRO: 0.58 s [0.18, 0.80], LEU-PRO+n-3: 0.73 s [0.41, 0.95], MCID: 0.9 s) and TG (LEU-PRO: -0.38 mmol/L [-0.80, 0.25], LEU-PRO+n-3: -0.44 mmol/L [-0.63, 0.06], MCID: 0.1 mmol/L), indicating no meaningful interindividual variability in response to either supplement. The SDR exceeded the MCID (19 Nm) for strength in response to LEU-PRO (25 Nm [-29, 45]) and LEU-PRO+n-3 (23 Nm [-29, 43]) supplementation but the effect was uncertain, evidenced by wide confidence intervals. In the next stage of analysis, similar proportions of participant responses were identified as very likely, likely, possibly, unlikely, and very unlikely to represent clinically meaningful improvements across the LEU-PRO, LEU-PRO+n-3, and CON groups (P > 0.05). Baseline LC n-3 PUFA status, habitual protein intake, and numerous other phenotypic and behavioural factors were not determinants of response to LEU-PRO or LEU-PRO+n-3 supplementation. Conclusions: Applying a novel, robust methodological approach to precision nutrition, we show that there was minimal interindividual variability in changes in ALM, muscle function, and TG in response to LEU-PRO and LEU-PRO+n-3 supplementation in older adults at risk of sarcopenia.
... These fatty acids have neuroprotective properties and modulate synaptic membrane depolarization. A meta-analysis reveals low levels of omega-3 in the serum of patients with ASD [4]. ...
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Background: Research suggests that a low omega-3 index may contribute to the low heart rate variability and the increased risk of cardiovascular morbidity and mortality in bipolar disorders. However, so far, no intervention trial with EPA and DHA has been conducted in bipolar patients attempting to increase their heart rate variability. Methods: 119 patients with bipolar disorder according to DSM-IV were screened, with 55 euthymic bipolar patients-owing to inclusion criteria (e.g. low omega-3 index (< 6%), SDNN < 60 ms.)-being enrolled in a randomized, double-blind, 12-week parallel study design with omega-3 fatty acids (4 capsules of 530 mg EPA, 150 mg DHA) or corn oil as a placebo, in addition to usual treatment. Heart rate variability as well as the omega-3 index were measured at baseline and at the endpoint of the study. Results: A total of 42 patients (omega-3: n = 23, corn oil: n = 19) successfully completed the study after 12 weeks. There was a significant increase in the omega-3 index (value at endpoint minus value at baseline) in the omega-3 group compared to the corn oil group (p < 0.0001). However, there was no significant difference in the change of the SDNN (value at endpoint minus value at baseline) between the treatment groups (p = 0.22). In addition, no correlation between changes in SDNN and change in the omega-3 index could be detected in the omega-3 group (correlation coefficient = 0.02, p = 0.94) or the corn oil group (correlation coefficient = - 0.11, p = 0.91). Similarly, no significant differences between corn oil and omega-3 group regarding the change of LF (p = 0.19), HF (p = 0.34) and LF/HF ratio (p = 0.84) could be demonstrated. Conclusions: In our randomized, controlled intervention trial in euthymic bipolar patients with a low omega-3 index and reduced heart rate variability no significant effect of omega-3 fatty acids on SDNN or frequency-domain measures HF, LF and LF/HF ratio could be detected. Possible reasons include, among others, the effect of psychotropic medication present in our trial and/or the genetics of bipolar disorder itself. Further research is needed to test these hypotheses. Trial registration ClinicalTrials.gov, NCT00891826. Registered 01 May 2009-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT00891826.
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Background Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide. This study aimed to investigate whether supplementation of n-3 polyunsaturated fatty acids (n-3 PUFAs) in parenteral nutrition may have beneficial effects on ROP in preterm infants. Methods A total of 89 preterm infants, admitted to Neonatal Intensive Care Unit (NICU) in Anhui Provincial Children’s Hospital from September 2017 to August 2020, were recruited in the study. Based on the medical documents, the subjects were categorised into two groups: administration of the fish oil emulsion (n=43) containing soy oil, medium-chain-triglycerides (MCT), olive oil and fish oil (6g/dL, 6g/dL, 5g/dL and 3g/dL respectively), and the soy oil emulsion (n=46) containing 10g/dL of soy oil and MCT each. At 4 weeks of hospitalization, ROP was screened and diagnosed. Fatty acids in erythrocytes were determined using gas chromatography. Results The averaged birth weight and gestational age were 1594±296 g and 31.9±2.3 wk, 1596±263 g and 31.6±2.3 wk respectively for preterm infants in the fish oil group and soy oil group. After 4 to 6 weeks of hospitalization, among all the preterm infants, 52 developed ROP (all stages) indicating an incidence of ROP at 58.43%. Although the incidence of ROP with any stages showed no differences between the two groups, the severe ROP incidence in the group with fish oil emulsions (2.33%) was significantly lower than that in the group with soy oil emulsions (23.91%) (P<0.05). After 14 days of nutrition support, the preterm infants administered fish oil emulsions had an increase in erythrocyte DHA content, with a reduction in ratio of arachidonic acid (AA) to DHA and an increase of n-3 index. Conclusion Supplementation of n-3 PUFAs through parenteral fish oil containing lipid emulsions resulted in an increase in erythrocyte DHA, and this might have beneficial effects on prevention of severe ROP in preterm infants.
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Omega-3 (n-3) fatty acids offer a plethora of health benefits with the majority of evidence showing beneficial effects from marine sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Emerging research examines the effects of n-3 dietary intakes on blood markers of vegetarians and vegans, but official guidance for plant based marine alternatives is yet to reach consensus. This scoping review provides an overview of trials investigating bioavailability of plant n-3 oils including EPA and DHA conversion. Searches of MEDLINE, PubMed, CINAHL and clinical trial registers identified randomized controlled trials from January 2010 to September 2020. The 'Omega-3 index' (EPA + DHA (O3I)), was used to compare n-3 status, metabolic conversion and bioavailability. Two reviewers independently screened articles and extracted data on outcomes. From 639 identified articles, screening and eligibility checks gave 13 articles. High dose flaxseed or echium seed oil supplements, provided no increases to O3I and some studies showed reductions. However, microalgal oil supplementation increased O3I levels for all studies. Findings indicate preliminary advice for vegetarians and vegans is regular consumption of preformed EPA and DHA supplements may help maintain optimal O3I. Further studies should establish optimum EPA and DHA ratios and dosages in vegetarian and vegan populations.
Article
Several countries have issued dietary recommendations about total and specific fatty acids (FAs) intake for the prevention of coronary heart disease (CHD). For many years until today, controversies have existed especially about the deleterious effect or not of saturated FAs, and the protective effect or not of n-3 polyunsaturated FAs, so that some authors have criticized these recommendations. There are many reasons for these controversies, including the different conclusions of prospective cohorts compared to randomized clinical trials (RCTs), the contradictory conclusions of meta-analyses depending on the quality, number, and type of studies included. The interrelationships between different FAs in the diet make it difficult to analyse the specific effect of a particular class of FAs on CHD. Furthermore, based on clinical practice and effectiveness of population-based prevention, it is very difficult at the individual level to assess in personal dietary intake the actual percentage and/or amount of SFAs contained in each meal or consumed daily/weekly. In this critical narrative review, we try to answer the question of whether it would not be more relevant, in 2020, to promote dietary patterns, rather than FAs intake recommendations. We critically analyze past and recent data on the association of FAs with CHD, then propose that Mediterranean diet and Japanese Diet should be revitalized for Westerners and Asian populations respectively. This does not exclude the usefulness of continuing research about effects of FAs towards CHD, and accepting that what seems true today might be revised, at least partially tomorrow.
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To examine the association between maternal erythrocyte long-chain omega-3 PUFA (n-3 LCPUFA), measured in early pregnancy, and pregnancy and birth outcomes. One hundred and eight healthy women with a singleton pregnancy were included. Erythrocyte fatty acids were analyzed using gas chromatography. Gestational length, birth anthropometric measures, and pregnancy-associated complications were collected from hospital medical records. We observed significant positive associations between maternal docosahexaenoic acid (DHA) levels (p = 0.024) and omega-3 index values (p = 0.021) and gestational length in adjusted linear regression models. Each point in maternal DHA level was associated with 2.19 days longer gestational duration (β = 2.19; 95% CI 0.29–4.09). No consistent associations were found between n-3 PUFA levels and composite pregnancy outcome. These findings suggest that the gestational length is positively affected by maternal n-3 LCPUFA status as soon as the early stages of pregnancy.
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Background Confusion reigns about omega‑3 fatty acids and their effects. Scientific investigations did not appear to clarify the issue. Guidelines and regulatory authorities contradict each other. Objective This article provides clarity by considering not intake but levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocytes as a percentage of all fatty acids measured (omega‑3 index). Current data The largest database of all methods of fatty acid analyses has been generated with the standardized HS-Omega‑3 Index® (Omegametrix, Martinsried, Deutschland). The omega‑3 index assesses the in EPA+DHA status of a person, has a minimum of 2%, a maximum of 20%, and is optimal between 8% and 11%. In many western countries but not in Japan or South Korea, mean levels are suboptimal. Suboptimal levels correlate with increased total mortality, sudden cardiac death, fatal and non-fatal myocardial infarction, other cardiovascular diseases, cognitive impairment, major depression, premature birth and other health issues. Interventional studies on surrogate and intermediary parameters demonstrated many positive effects, correlating with the omega‑3 index when measured. Due to issues in methodology that became apparent from the perspective of the omega‑3 index many, even large interventional trials with clinical endpoints were not positive, which is reflected in pertinent meta-analyses. In contrast, interventional trials without issues in methodology the clinical endpoints mentioned were reduced. Conclusion All humans have levels of EPA+DHA that if methodologically correctly assessed in erythrocytes, are optimal between 8% and 11%. Deficits can cause serious health issues that can be prevented by optimal levels.
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Long-chain polyunsaturated fatty acids (LCPUFA) are important for brain development and function, maybe especially during adolescence. Observational studies have demonstrated an association between fish consumption (a source of LCPUFA) and cognition in adolescents, but intervention trials are lacking. The goal of the current study was to investigate the effect of one year of krill oil (a source of LCPUFA) supplementation on the cognitive performance of adolescents with a low Omega-3 Index (O3I ≤ 5%). A double-blind, randomized, and placebo-controlled supplementation trial with repeated measurements (baseline (T0), three months (T1), six months (T2), and 12 months (T3)) in adolescents (267 randomized) was executed. Participants were randomized to 400 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day in Cohort I or placebo and 800 mg EPA + DHA per day in Cohort II or placebo. O3I was monitored by a finger prick at all time points. At T0, T2, and T3, participants executed a neurocognitive test battery. Covariate corrected mixed models were run with either condition (krill or placebo) or O3I as predictors. Krill oil supplementation led to a small but significant increase in mean O3I, but few participants increased to the intended O3I range (8–11%). There was no significant effect of supplementation on the neurocognitive tests, nor a relationship between O3I and neurocognitive test scores. The increase in O3I was small in most participants, probably due to non-compliance. Possibly the increase in O3I was too small to demonstrate an effect. More research on the influence of LCPUFAs on cognition in adolescents is needed.
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Background: Omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3)), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) may benefit cardiovascular health. Guidelines recommend increasing omega-3-rich foods, and sometimes supplementation, but recent trials have not confirmed this. Objectives: To assess the effects of increased intake of fish- and plant-based omega-3 fats for all-cause mortality, cardiovascular events, adiposity and lipids. Search methods: We searched CENTRAL, MEDLINE and Embase to February 2019, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to August 2019, with no language restrictions. We handsearched systematic review references and bibliographies and contacted trial authors. Selection criteria: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation or advice to increase LCn3 or ALA intake, or both, versus usual or lower intake. Data collection and analysis: Two review authors independently assessed trials for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. Main results: We included 86 RCTs (162,796 participants) in this review update and found that 28 were at low summary risk of bias. Trials were of 12 to 88 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most trials assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5 g a day to more than 5 g a day (19 RCTs gave at least 3 g LCn3 daily). Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.93 to 1.01; 143,693 participants; 11,297 deaths in 45 RCTs; high-certainty evidence), cardiovascular mortality (RR 0.92, 95% CI 0.86 to 0.99; 117,837 participants; 5658 deaths in 29 RCTs; moderate-certainty evidence), cardiovascular events (RR 0.96, 95% CI 0.92 to 1.01; 140,482 participants; 17,619 people experienced events in 43 RCTs; high-certainty evidence), stroke (RR 1.02, 95% CI 0.94 to 1.12; 138,888 participants; 2850 strokes in 31 RCTs; moderate-certainty evidence) or arrhythmia (RR 0.99, 95% CI 0.92 to 1.06; 77,990 participants; 4586 people experienced arrhythmia in 30 RCTs; low-certainty evidence). Increasing LCn3 may slightly reduce coronary heart disease mortality (number needed to treat for an additional beneficial outcome (NNTB) 334, RR 0.90, 95% CI 0.81 to 1.00; 127,378 participants; 3598 coronary heart disease deaths in 24 RCTs, low-certainty evidence) and coronary heart disease events (NNTB 167, RR 0.91, 95% CI 0.85 to 0.97; 134,116 participants; 8791 people experienced coronary heart disease events in 32 RCTs, low-certainty evidence). Overall, effects did not differ by trial duration or LCn3 dose in pre-planned subgrouping or meta-regression. There is little evidence of effects of eating fish. Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20; 19,327 participants; 459 deaths in 5 RCTs, moderate-certainty evidence),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25; 18,619 participants; 219 cardiovascular deaths in 4 RCTs; moderate-certainty evidence), coronary heart disease mortality (RR 0.95, 95% CI 0.72 to 1.26; 18,353 participants; 193 coronary heart disease deaths in 3 RCTs; moderate-certainty evidence) and coronary heart disease events (RR 1.00, 95% CI 0.82 to 1.22; 19,061 participants; 397 coronary heart disease events in 4 RCTs; low-certainty evidence). However, increased ALA may slightly reduce risk of cardiovascular disease events (NNTB 500, RR 0.95, 95% CI 0.83 to 1.07; but RR 0.91, 95% CI 0.79 to 1.04 in RCTs at low summary risk of bias; 19,327 participants; 884 cardiovascular disease events in 5 RCTs; low-certainty evidence), and probably slightly reduces risk of arrhythmia (NNTB 91, RR 0.73, 95% CI 0.55 to 0.97; 4912 participants; 173 events in 2 RCTs; moderate-certainty evidence). Effects on stroke are unclear. Increasing LCn3 and ALA had little or no effect on serious adverse events, adiposity, lipids and blood pressure, except increasing LCn3 reduced triglycerides by ˜15% in a dose-dependent way (high-certainty evidence). Authors' conclusions: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and low-certainty evidence suggests that increasing LCn3 slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia.
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Background & aims: Previous studies suggest that polyunsaturated fatty acids (PUFAs) may reduce the risk of metabolic diseases, but some have shown ambiguous results. The aim of this study was to systematically evaluate and summarize available evidence on the association between omega-3 and omega-6 PUFA levels and risk of metabolic syndrome (MetS). Methods: A systematic literature search of articles published until December 2017 was conducted in PubMed, Web of Science, and Cochrane Library databases. Meta-analyses of the highest vs. lowest categories of omega-3 and omega-6 PUFAs were conducted using the random effects models. Results: Thirteen studies (2 case-control, 9 cross-sectional, 1 nested case-control, and 1 prospective cohort) with 36,542 individuals were included. Higher omega-3 PUFA levels in diets or blood were associated with a 26% reduction in the risk of MetS (odds ratio (OR)/relative risk (RR) 0.74, 95% confidence interval (CI) 0.62-0.89). This inverse association was evident among studies with Asian populations (OR/RR 0.69, 95% CI 0.54-0.87), but not among those with American/European populations (OR/RR 0.84, 95% CI 0.55-1.28). Null results were found regarding the association between circulating/dietary omega-6 PUFAs and MetS. Conclusion: The present meta-analysis indicates that higher intakes of omega-3 PUFAs, but not omega-6 PUFAs, was associated with lower MetS risk; adding to the current body of evidence on the metabolic health effects of circulating/dietary omega-3 PUFAs.
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N-3 polyunsaturated fatty acids (PUFA) and the numerous families of lipid mediators derived from them collectively regulate numerous biological processes. The mechanisms by which n-3 PUFA regulate biological processes begins with an understanding of the n-3 biosynthetic pathway that starts with alpha-linolenic acid (18:3n-3) and is commonly thought to end with the production of docosahexaenoic acid (DHA, 22:6n-3). However, our understanding of this pathway is not as complete as previously believed. In the current review we provide a background of the evidence supporting the pathway as currently understood and provide updates from recent studies challenging three central dogma of n-3 PUFA metabolism. By building on nearly three decades of research primarily in cell culture and oral dosing studies, recent evidence presented focuses on in vivo kinetic modelling and compound-specific isotope abundance studies in rodents and humans that have been instrumental in expanding our knowledge of the pathway. Specifically, we highlight three main updates to the n-3 PUFA biosynthesis pathway: (1) DHA synthesis rates cannot be as low as previously believed, (2) DHA is both a product and a precursor to tetracosahexaenoic acid (24:6n-3) and (3) increases in EPA in response to DHA supplementation are not the result of increased retroconversion.
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Background The etiology of degenerative rotator cuff tears is multifactorial but chronic inflammation plays an important role in the pathogenesis. Some polyunsaturated fatty acids (PUFA) can modulate inflammation and marine n-3 (Omega-3) PUFA have anti- inflammatory effects. We hypothesized that the Omega-3 Index is lower in patients with degenerative rotator cuff tears when compared to controls without rotator cuff tendinopathy. Methods From 684 consecutive patients with full thickness rotator cuff tears 655 were excluded because of possible bias. In the remaining 29 patients (22 m, 7 f; 53,9 y) with degenerative full thickness rotator-cuff tears, erythrocyte fatty acids were analyzed using the HS-Omega-3 Index® methodology. 15 healthy volunteers (10 m, 5 f; 52.5y) served as a control. Results The Omega-3 Index (% EPA + DHA) was 5.01% (95% CI: 3.81–4.66) in patients and 6.01% (95% CI: 4.48–5.72) in controls (p = 0.028) Conclusions Patients with full thickness degenerative rotator cuff tears had a significantly lower Omega-3 Index than controls without rotator cuff tendinopathy. Whether a lower Omega-3 Index represents an independent risk factor for degenerative rotator cuff tears should be further investigated, e.g. in a longitudinal study.