124 Food and Nutrition Bulletin, vol. 32, no.

2 © 2011, The United

Nations University.
Vitamin E deficiency in developing countries
Abstract
In addition to its role as a potent antioxidant, vitamin
E is involved in a wide range of physiological processes,
ranging from immune function and control of inflammation
to regulation of gene expression and cognitive
performance. Results from multiple studies suggest that
poor nutritional status and higher prevalence of other
oxidative stressors such as malaria and HIV infection
predispose populations in developing countries for vitamin
E deficiency. Although direct comparison between
study outcomes is complicated by varied definitions of
vitamin E deficiency, data trends indicate that children
and the elderly are more vulnerable age groups and that
men may be at higher risk for deficiency than women.
Public health initiatives aimed at improving the vitamin
E status of high-risk populations in developing countries
would be prudent to counteract oxidative stress, improve
immune function, and protect against neurologic and
cognitive deficits. Additional research is needed to establish
dose–response relationships of various interventions
and to develop cost-effective, culturally-appropriate, and
targeted programs.
Key words: Deficiency, developing country, oxidative
stress, vitamin E
Introduction
As the diverse roles of vitamin E in the maintenance
of health and the prevention of disease become elucidated,
the extensive implications of its deficiency are
increasingly evident. In addition to its role as a potent
antioxidant, vitamin E is involved in physiological
processes ranging from immune function and control
of inflammation to regulation of gene expression and
cognitive performance. Deficiency of vitamin E is
characterized by peripheral neuropathy, ataxia, and
anemia. Populations in developing countries may be
at greater risk for deficiency due to limited intake of
food sources of the vitamin and higher prevalence of
oxidative stressors such as malaria and HIV infection,
which accelerate its depletion. This review provides a
summary of vitamin E sources, functions, and requirements,
presents evidence for the health consequences
of vitamin E deficiency, considers risk factors for
deficiency in the developing country context, examines
prevalence estimates of deficiency reported in
developing countries, and provides recommendations
for public health initiatives to improve the vitamin E
status of vulnerable populations.
Background
Forms and bioavailability
The vitamin E family is composed of four tocopherols
(α, β, γ, and λ) and four tocotrienols (α, β, γ, and λ) that
differ from one another in the degree and site of methylation
in the chromanol ring and the configuration of
the methyl groups in the side chains [1]. The structures
of the eight isoforms are shown in figure 1 [2].
The most abundant form of vitamin E found in
human tissues is α-tocopherol. Naturally occurring
α-tocopherol in foods is the RRR- or d-stereoisomer,
while synthetic or all-rac-α-tocopherol is a mixture
of eight stereoisomers. Because only the four 2R-α-
tocopherol isomers are efficiently retained in the
human body [3], synthetic α-tocopherol is less biologically
active than the natural form. Several studies
conducted in humans with and without aberrations
in vitamin E metabolism have concluded that stereoisomers
and isoforms of vitamin E are equally absorbed
Daphna K. Dror and Lindsay H. Allen
The authors are affiliated with the US Department of
Agriculture, Agricultural Research Service, Western Human
Nutrition Research Center, Davis, California, USA.
Please direct queries to the corresponding author: Daphna
Dror, Allen Laboratory, USDA ARS WHNRC, 430 W. Health
Sciences Drive, Davis, CA 95616, USA; e-mail: dkdror@
ucdavis.edu.
Vitamin E deficiency in developing countries 125
and secreted in chylomicrons. However, verylow-
density lipoprotein (VLDL) is preferentially
enriched with RRR-α-tocopherol,
explaining the higher plasma concentrations
of this form [4–7]. Evidence from a kinetic
modeling study of radiolabeled RRR- and
all-rac-α-tocopherol administered to a single
subject in a crossover design showed that
peak plasma 14C concentration was 1.86 times
greater from RRR- than that from all-rac -
α-tocopherol [8].
The form of vitamin E present in the greatest
amounts in the human diet is γ-tocopherol;
however, the concentration of γ-tocopherol
in tissue is generally 10 times lower than that
of α-tocopherol. This discrepancy is related
to preferential retention of α-tocopherol
due to higher affinity for the α-tocopherol
transport protein (α-TTP) and preferential
catabolism of γ-tocopherol to its carboxy ethyl
hydroxyl chroman (CEHC) metabolite [9–10].
Despite its lower physiological concentrations,
research has indicated that γ-tocopherol may
serve an important functional role in the
human body. It surpasses α-tocopherol in
detoxifying lipophilic electrophiles, possesses
anti-inflammatory properties, generates the
metabolite γ-CEHC that facilitates natriuresis,
and may protect against cardiovascular disease
and prostate cancer [11].
Absorption and metabolism
All naturally occurring isoforms of vitamin
E are absorbed in the presence of dietary fat,
bile, and pancreatic secretions, with bioavailability
influenced by the amount of fat and
food matrix [12]. The proportion of ingested
vitamin E absorbed in humans is estimated
to range from 33% to 68% [9]. Bound in
micelles formed within the intestine, vitamin
E is passively absorbed into enterocytes and
incorporated into chylomicrons that are secreted into
the lymph [13–14]. Lipoprotein lipase (LPL) hydrolyzes
the chylomicrons to release vitamin E to tissues such
as muscles, adipocytes, and brain [1]. As chylomicron
remnants are formed, surface components including
some vitamin E are preferentially transferred to highdensity
lipoproteins (HDLs) and subsequently to other
lipoproteins in the circulation.
Vitamin E is taken up into the liver via lipoproteins
and chylomicron remnants. In the liver, the α-TTP
selectively salvages RRR-α-tocopherol and facilitates
its incorporation into VLDLs, possibly with assistance
from other transport proteins, including ATP-binding
cassette protein A1 (ABCA1) [15]. Following release of
VLDL from the liver, α-tocopherol is redistributed to
other lipoproteins for transport to the peripheral tissues.
Although adipocytes and skeletal muscle have the
capacity to accumulate vitamin E, mobilization from
these tissues to maintain plasma concentration is not
strongly influenced by dietary deficiency, exercise, or
weight loss [16–17].
Excess α-tocopherol and other vitamin E isoforms in
the liver are excreted into bile directly via a multidrugresistance
gene product (MDR2) or indirectly following
metabolism to CEHCs by a cytochrome P450-mediated
process. CEHCs are also excreted in urine. Because
release of vitamin E from tissue storage is a slow
process with poorly understood control mechanisms,
excretion is an important factor in the regulation of
circulating concentrations [9].
FIG. 1. Structures of the tocopherols (A) and tocotrienols (B).
Source: Food and Nutrition Board [2]
CH3
CH3
CH3
CH3
CH3
CH3
2R
_-Tocopherol
A.
4’R
phytyl tail
CH3 H
8’R
CH3 H
H3C
H3C
HO
O
CH3
CH3
CH3 CH3 CH3 CH3
_-Tocotrienol
B.
unsaturated tail
H3C
HO
O
CH3
CH3
CH3
_-Tocopherol phytyl tail
HO
O
CH3
CH3
_-Tocopherol phytyl tail
HO
O
CH3
CH3
_-Tocopherol phytyl tail
HO
O
H3C
CH3
CH3
CH3
_-Tocotrienol unsaturated tail
HO
O
CH3
CH3
_-Tocotrienol unsaturated tail
HO
O
CH3
CH3
_-Tocotrienol unsaturated tail
HO
O
126 D. K. Dror and L. H. Allen
Functions
Antioxidant
Vitamin E is a lipid-soluble chain-breaking antioxidant
that scavenges free radicals to protect cell membranes
and lipoproteins from oxidative damage. In the
presence of free metals such as iron or copper, lipid
hydroperoxides (ROOH) are oxidized to peroxyl radicals
(ROO·). Peroxyl radicals react 1,000 times faster
with α-tocopherol than with polyunsaturated fatty
acids (PUFAs), preventing further oxidation [18]. The
tocopheroxyl radical then reacts with hydrogen donors
such as vitamin C or glutathione to return vitamin E to
its reduced state [9].
Immune regulator
Evidence from animal and human studies suggests a
role of vitamin E in the immune system, with even
marginal deficiency impairing the immune response
[19]. Two randomized, controlled trials found that
supplementation with vitamin E improved immune
function in elderly nursing home residents [20–21].
Although the mechanism has not been fully elucidated,
vitamin E appears to reduce age-associated defects in
T-cell function both directly and indirectly by moderating
production of the T-cell suppressive factor PGE2
by macrophages [22]. In relation to viral infections, it
has been proposed that antioxidant nutrient deficiency
may not only compromise the host immune system,
but also lead to enhanced viral mutation rate through
direct oxidative damage of viral genes [23].
Novel functions
More recently, vitamin E has been ascribed a diverse
range of functions. The novel roles of vitamin E include
regulation of signal transduction via membrane-bound
or recruited enzymes, regulation of gene expression,
activity as a redox sensor, participation in cellular
trafficking, and control of inflammation [24–25]. In
the domain of cardiovascular health, α-tocopherol has
been shown to inhibit smooth-muscle cell proliferation
[26], endothelial dysfunction [27], and platelet aggregation
[28] via protein kinase C-dependent mechanisms.
However, clinical trials of α-tocopherol for the prevention
of cardiovascular disease have yielded largely negative
results [1]. In the elderly, vitamin E status has been
positively associated with cognitive function, physical
performance, and longevity [29–34].
Vitamin E requirements
The Dietary Reference Intakes (DRIs) for vitamin E
were revised by the Food and Nutrition Board of the
Institute of Medicine in 2000. The Recommended Daily
Allowance (RDA) for vitamin E in each age group
was calculated as the Estimated Average Requirement
(EAR) plus twice the assumed coefficient of variation
of 10% due to lack of information on the standard
deviation of the requirement for vitamin E. In adults,
the EAR is set at 12 mg/day of RRR-α-tocopherol on
the basis of studies conducted in men demonstrating
that this intake limited hydrogen peroxide-induced
erythrocyte hemolysis to < 12%. Parallel data were not
available for women, but it was assumed that although
total body weight is lower in women than in men, the
larger percentage of body weight as fat mass would
lead to similar requirements for vitamin E. In children,
the EAR and RDA were extrapolated from adult data
accounting for lean body mass and needs for growth
[2]. The current DRIs by age group and physiological
state are listed in table 1. It is notable that these recommendations
are aimed at the prevention of symptomatic
deficiency rather than health promotion or disease prevention,
in part because of the paucity of evidence that
higher intakes of vitamin E reduce the risk of disease.
Dietary sources
Major dietary sources of α- and γ-tocopherols include
vegetable oils, nuts, whole grains, and green leafy vegetables.
All eight isoforms of vitamin E occur naturally
in foods but in differing amounts. The contents of
α- and γ-tocopherol found in major dietary sources,
as estimated by the US Department of Agriculture
(USDA) National Nutrient Database, are listed in
table 2 [35].
Although the USDA database reports both α- and
γ-tocopherol contents of many foods, food composition
tables from other countries often report total
vitamin E or α-tocopherol contents only. In some
countries, nutrient databases do not include estimates
of vitamin E from food sources. Table 3 summarizes
the vitamin E information provided by a variety of
national and regional food composition tables available
through the Food and Agriculture Organization
TABLE 1. Dietary Reference Intakes (mg/day) for RRR-α-
tocopherol
Group AI EAR RDA
Infants
0–6 mo 4
7–12 mo 5
Children
1–3 yr 5 6
4–8 yr 6 7
9–13 yr 9 11
14–18 yr 12 15
Adults ≥ 19 yr 12 15
Pregnant women
14–50 yr
12 15
Lactating women
14–50 yr
16 19
AI, Adequate Intake; EAR, Estimated Average Requirement; RDA,
Recommended Daily Allowance
Source: US Department of Agriculture [35].
Vitamin E deficiency in developing countries 127
(FAO) of the United Nations [36].
Assessment of status
Plasma or serum α-tocopherol is the
most widely used biomarker of vitamin
E status [37], partially because
of the practicality of its use in large
surveys and the field setting. However,
confounding factors, including
age, sex, plasma lipids, lipid-lowering
drugs, and smoking, affect the accuracy
of this indicator [38]. Circulating
α-tocopherol levels are highly
correlated with levels of blood lipids,
especially of cholesterol, so the ratios
of α-tocopherol to plasma lipids or
cholesterol alone are often considered
more meaningful indicators of
status in healthy individuals. Because
serum cholesterol was among the
strongest predictors of serum
α-tocopherol in the third National
Health and Nutrition Examination
Survey (NHANES III, 1988–1994),
the α-tocopherol:total cholesterol
ratio has been considered the preferred
measure of vitamin E status
[39–40]. In subjects with altered lipid
levels due to liver disease or other
health conditions, it is valuable to
present both absolute α-tocopherol
and the α-tocopherol:lipid ratio for
optimal assessment of status.
Despite its value as a biomarker,
plasma or serum α-tocopherol is not
well correlated with dietary intake
[2]. Platelet α-tocopherol concentration
is considered a more sensitive
indicator of dietary vitamin E intake
on the basis of a better dose–response
relationship and absence of influence
by plasma lipids [41], but it is not a
practical measurement for fieldwork.
Vitamin E deficiency
Defining deficiency
According to the Food and Nutrition Board of the
Institute of Medicine, vitamin E deficiency in normal,
healthy adults is defined by a plasma α-tocopherol
concentration < 12 μmol/L (0.5 mg/dL) based on the
association of greater concentrations with normal in
vitro hydrogen peroxide-induced erythrocyte hemolysis
[2]. However, studies of vitamin E status in diverse
populations have used cutoffs ranging from 2.8 to 24
μmol/L (0.1 to 1.0 mg/dL) to define deficiency and
insufficiency (table 4).
TABLE 2. α- and γ-Tocopherol contents of foods
Food Serving size
α-Tocopherol
(mg)
γ-Tocopherol
(mg)
Seeds and nuts 1 oz (28.5 g)
Sunflower seeds 7.4 0.0
Almonds 7.3 0.2
Hazelnuts 4.3 0.0
Mixed nuts 3.1 NA
Pine nuts 2.6 3.2
Peanuts 2.2 2.4
Brazil nuts 1.6 2.2
Oils 1 tbsp (13.5 g)
Sunflower 5.6 0.7
Cottonseed 4.8 NA
Safflower 4.6 0.1
Canola 2.4 3.8
Peanut 2.1 2.2
Corn 1.9 8.2
Olive 1.9 0.1
Soybean 1.1 8.7
Fruits and vegetables . cup
Tomato puree (canned) 2.5 0.3
Avocado puree (raw) 2.4 0.4
Spinach (cooked) 1.9 NA
Broccoli (cooked) 1.1 0.2
Pumpkin (cooked) 1.0 NA
Staples and grains (cooked) 100 g
Maize (cornmeal) 0.4 1.9
Plantain 0.1 NA
Wheat 0.0 0.2
Rice 0.0 0.0
Millet 0.0 NA
Other 2 tbsp
Peanut butter 2.9 3.0
Wheat germ 2.3 NA
Rice bran 0.7 NA
Wheat bran 0.1 NA
Oat bran 0.1 0.0
NA, not available
Source: US Department of Agriculture [35].
TABLE 3. Vitamin E information provided in national or
regional food composition tables
Nation or region Vitamin E information
Africa None
Australia and New Zealand Vitamin E
Canada α-Tocopherol
Denmark α-Tocopherol
East Asia None
Finland α-Tocopherol
Japan Vitamin E
Middle/Near East None
Switzerland α-Tocopherol
Tanzania Vitamin E
Uruguay None
Source: Food and Agriculture Organization [36].
128 D. K. Dror and L. H. Allen
TABLE 4. Prevalence of vitamin E deficiency in developing countries
A. Children
Reference Location/ethnicity
No. and sex
of subjects Age Definition of deficiency % Deficient
Median (range)
or mean } SD
α-tocopherol
(μmol/L) Other findings
Monteiro et al.,
2009 [75]
Brazil, Argentina,
Mexico
336 1–3 yr Plasma α-tocopherol
< 18 μmol/L
89 12.42 (3.34–44.75),
11.38 (3.66–26.75)
in HIV-infected
and -exposed children.
respectively
No significant difference in prevalence
of low vitamin E status between HIVinfected
and HIV-exposed children
Khatib et al., 2009
[72]
North Badia,
Jordan (Bedouin
population)
262:
137 F
125 M
0.5–5.5 yr Serum α-tocopherol
< 11.6 μmol/L (I) OR
< 17.2 μmol/L (II)
17.1 (I)
89.2 (II)
15.8 (6.3–17.2) Stunted children had lower vitamin E
concentrations than normal children;
linear growth positively correlated with
vitamin E status
Allen et al.,
unpublished
data, 2009
Valley of Solis,
Mexico
128:
63 F
65 M
23 } 8 mo Serum α-tocopherol
< 11.6 μmol/L
46.9 NA Prevalence of vitamin E deficiency
35%–65% in 4 study groups at baseline
decreased to 5%–18% following 3 mo
intervention, although only 1 group
(n = 29) received α-tocopherol supplement
Giraud et al., 2008
[74]
Kwangju, Korea 131:
66 F
65 M
2–6 yr Plasma α-tocopherol
< 12 μmol/L
67 11.9 } 2.3 (2 yr)
10.5 } 2.1 (3 yr)
10.4 } 2.0 (4 yr)
10.9 } 1.7 (5 yr)
10.2 } 2.0 (6 yr)
67% had intakes < Korean AI and 77% <
US EAR according to intake observations
and 3 24-h recalls
Plasma α-tocopherol significantly higher
in 2-year-old group than other age
groups
Dancheck et al.,
2005 [95]
Blantyre, Malawi 173 1 yr Plasma α-tocopherol
< 11.6 μmol/L
19.1
(1.2 in
mothers)
16.1 } 4.9 Plasma α-tocopherol significantly associated
with BMI, weight-for-age z-score,
and weight-for-height z-score
Ta et al., 2003 [73] South Vietnam 284 F 7–9 yr Serum α-tocopherol
< 4.8
μmol/L (I) OR serum
α-tocopherol:total lipid
< 2.36 (II)
20.0 rural
27.1 urban (I)
100.0 (II)
7.4 } 4.6 (rural)
9.0 } 4.6 (urban)
α-Tocopherol:total
lipid 1.48 } 0.91
(rural), 1.63 } 0.83
(urban)
Low levels explained by inadequate
consumption of tocopherol-rich food
sources in both groups and vegetable oil
in the rural group
Arsenault et al.,
unpublished
data, 2003
Northern
Thailand
49 8.7 } 1.5 yr Plasma α-tocopherol
< 11.6 μmol/L
20.4 14.6 } 3.7
Vitamin E deficiency in developing countries 129
Barros et al., 2002
[96]
Northeast Brazil 81 Newborn Umbilical cord plasma
α-tocopherol < 4.6
μmol/L
23.2 5.8 (3.0–12.6) No significant differences in vitamin E
status by sex
Allen et al., 2000
[97]
Valley of Solis,
Mexico
219 18–36 mo Plasma α-tocopherol
< 11.6 μmol/L
70 7.8 } 5.2 Rural Mexico, poor communities. Low
dietary fat intakes. Maize-based diet
Fazio-Tirrozzo et
al., 1998 [76]
Shire Valley,
southern Malawi
118 nonpregnant
girls
10–19 yr Serum α-tocopherol ≤ 8.8
μmol/L (I) OR < 11.6
μmol/L (II) OR serum
α-tocopherol: cholesterol
< 2.2 μmol/mmol
(III)
40.7 (I)
59.3 (II)
23.9 (III)
10.2 } 5.6 Significant correlations between serum
tocopherol and retinol
Girls with low BMI (chronic energy depletion?)
had lower tocopherol:cholesterol
ratios
33.9% of girls were stunted, 15.9% had
positive blood smears for malaria, and
20% reported blood in urine (urinary
schistosomiasis)
Wetherilt et al.,
1992 [77]
Turkey (urban and
rural schools)
960 7–17 yr Plasma α-tocopherol
< 12 μmol/L (I) OR
≤ 15 μmol/L (II)
6.4 (I)
21.8 (II)
21.9 } 6.9 Significantly poorer vitamin E status in
rural than in urban children
No significant correlation between vitamin
E status and age
B. Elderly
Reference Location/ethnicity
No. and sex
of subjects Age Definition of deficiency % Deficient
Median (range)
or mean } SD
α-tocopherol
(μmol/L) Other findings
Oldewage-Theron
et al., 2009 [55]
Sharpeville, South
Africa
235:
196 F
39 M
60–93 yr Serum α-tocopherol
< 2.8 μmol/L (I) OR
< 3.7 μmol/L (II)
20.9 (I)
37.1 (II)
4.8 } 2.6 95% consumed less than EAR for vitamin
E according to 24-h recall
Obese women had significantly lower
levels of vitamin E than normal-weight
women
Assantachai et al.,
2007 [56]
Thailand 2,336 ≥ 60 yr Plasma α-tocopherol
< 14 μmol/L
55.5 NA Male sex significant risk factor
Deficient subjects had higher diastolic
blood pressure giving rise to more heart
disease
Vitamin E deficiency more likely in
presence of low vitamin C, β-carotene,
folate, and vitamin A, according to
authors due to inadequate intake of vegetables
and fruits
Shahar et al., 1999
[63]
Eastern Malaysia 350 ≥ 60 yr Plasma α-tocopherol
≤ 12 μmol/L
26.7 16.8 } 9.1 (men)
17.6 } 6.9 (women)
Men at higher risk for deficiency than
women
continued
130 D. K. Dror and L. H. Allen
TABLE 4. Prevalence of vitamin E deficiency in developing
countriesv (continued)
C. Mixed age or other
Reference Location/ethnicity
No. and sex
of subjects Age Definition of deficiency % Deficient
Median (range)
or mean } SD
α-tocopherol
(μmol/L) Other findings
Papathakis et al.,
2007 [98]
South Africa 144 F (24 wk
postpartum)
14–50 yr Serum α-tocopherol
< 11.6 μmol/L
70 11.35 } 1.68 (HIV+),
12.45 } 1.24 (HIV–)
No significant difference in vitamin E
concentration by HIV status
Obeid et al., 2006
[79]
Beirut, Lebanon 857 25–64 yr Plasma α-tocopherol
< 5.8 μmol/L (I) OR
< 11.6 (II) OR plasma
α-tocopherol:cholesterol
< 2.5 μmol/mmol (III)
0.7 (I)
4.4 (II)
4.1 (III)
24.5 } 11.4 Vitamin E and vitamin E:cholesterol
ratio both significantly correlated with
vitamin A
Vitamin E significantly correlated with
age, systolic and diastolic blood pressure,
blood glucose, cholesterol, and
triglycerides
Gouado et al., 2005
[78]
Northern
Cameroon
81:
41 F
40 M
3–61 yr Serum α-tocopherol
< 5.8 μmol/L (I) OR
< 11.6 μmol/L (II)
12.3 (I)
33.3 (II)
12.2 } 0.7 Nonsignificant positive trend between
vitamin E status and age
Vitamin A highly correlated with vitamin
E
Women had significantly lower vitamin
E: total triglycerides ratio than men
Wondmikun et al.,
2005 [99]
Gondar, Ethiopia 322 F (pregnant,
3rd
trimester)
≥ 16 yr Serum α-tocopherol
< 24 μmol/L
42 25.5 } 0.9
Mulokozi et al.,
2003 [100]
Tanzania 90 F (pregnant,
~6
mo)
18–45 yr Plasma α-tocopherol
< 11.6 μmol/L (I) OR
≤ 16.2 μmol/L (II)
11 (I)
61 (II)
15.4 (12.0–19.8) Significant positive relationship between
plasma α-tocopherol and retinol
concentrations
AI, Adequate Intake; BMI, body mass index; EAR, Estimated
Average Requirement
Vitamin E deficiency in developing countries 131
Notably, data from NHANES 1999/2000 showed that
although only 0.5 } 0.1% of adults over age 20 were
deficient according to the above definition (serum
α-tocopherol < 11.6 μmol/L [0.5 mg/dL]) [42], 89.8% of
men and 96.3% of women 19 years of age or older in the
same survey had usual α-tocopherol intakes under the
EAR [43]. This discrepancy urges caution in the interpretation
of circulating α-tocopherol as an indicator of
status and also draws attention to the limitations of the
evidence upon which intake requirements are based.
There is some evidence suggesting that normal
concentrations of plasma α-tocopherol are lower in
pediatric populations and higher during pregnancy [37,
44–46]. In a study of 39 healthy children aged 1 to 12
years and adults, the mean plasma α-tocopherol level
was 13.8 μmol/L (0.59 mg/dL) in children compared
with 18.3 μmol/L (0.79 mg/dL) in adults. Although
36% of the pediatric population studied had plasma
concentrations < 11.6 μmol/L (0.5 mg/dL), none of
these subjects had excessive in vitro hydrogen peroxideinduced
erythrocyte hemolysis. The authors concluded
that 7 to 21 μmol/L (0.3 to 0.9 mg/L) α-tocopherol is
a normal range for children [44]. During pregnancy,
blood α-tocopherol concentrations increase in association
with blood lipids [47]; however, an alternative
reference range of normalcy for different stages of
pregnancy has not been established.
In studies reporting the ratio of α-tocopherol to total
lipids (cholesterol and triglycerides) or cholesterol
alone, the lower limits of the normal range are 1.6
to 2.4 μmol of α-tocopherol:mmol lipid or 2.2 to 2.5
μmol α-tocopherol:mmol cholesterol. Although use of
these indices may prevent overestimation of vitamin E
deficiency in developing countries where serum lipid
levels can be low, their interpretation is complicated
by altered lipid metabolism of severe protein–energy
malnutrition (PEM). Unlike mild undernutrition, PEM
is characterized by elevated circulating triglycerides
and fatty liver, possibly related to an inability of tissue
or plasma triglycerides to undergo lipolysis due to
the unavailability of sufficient protein for synthesis of
lipolytic enzymes [48]. Furthermore, α-tocopherol may
become trapped in triglyceride-rich lipoproteins that
cannot be effectively catabolized. For these reasons, in
the developing country context it is valuable to consider
both absolute and adjusted circulating α-tocopherol
concentrations.
Symptoms of deficiency
While overt vitamin E deficiency in humans is rare,
causes include severe malnutrition, fat malabsorption
syndromes (cystic fibrosis, cholestatic liver disease, and
intestinal resection), genetic defects affecting α-TTP or
lipoprotein synthesis, and some hematologic disorders
(β-thalassemia major, sickle-cell anemia, and glucose-6
phosphate dehydrogenase deficiency) [1]. Severe malnutrition
may result in deficiency due to limited intakes
of dietary vitamin E and protein necessary for α-TTP
synthesis [9]. Symptomatic vitamin E deficiency has
not been reported in healthy individuals consuming
diets low in vitamin E [17].
In various species of animals depleted of vitamin E,
described symptoms of deficiency have included necrotizing
myopathy, fetal death and resorption, anemia,
and tissue accumulation of lipofuscin, a pigment associated
with aging [49]. In humans, clinical vitamin E
deficiency is characterized by progressive peripheral
neuropathy, ataxia, muscle weakness, retinal damage
leading to blindness (retinitis pigmentosa), infertility,
and dementia [1, 17, 50]. Individuals with autosomal
recessive mutations in the gene for α-TTP (ataxia with
vitamin E deficiency [AVED]) present with neurodegenerative
symptoms including cerebellar ataxia, loss
of deep tendon reflexes, vibratory-sense disturbances,
dysarthria, muscle weakness, head titubation, and
dystonia [51].
Acanthocytosis, a characteristic alteration of the
erythrocyte membrane morphology, is associated
with vitamin E deficiency and results in increased
erythrocyte hemolysis and anemia. It is likely that the
peripheral neuropathy and anemia seen in vitamin E
deficiency are caused by excessive free radical damage
to the large-caliber axons in sensory neurons and to
the erythrocyte membrane, respectively [18]. Plasma
α-tocopherol concentrations < 8 μmol/L are associated
with neurologic disease in humans [52–53], while concentrations
< 12 μmol/L are associated with increased
red blood cell fragility in vitro [2].
Risk factors for deficiency
In addition to dietary intake and conditions of oxidative
stress, the risk of vitamin E deficiency may
be influenced by age, obesity, and sex. Historically,
children have been the population in which vitamin
E deficiency due to underconsumption is most frequently
observed [18]. A study of dietary intake of
toddlers aged 18 to 30 months in Egypt, Kenya, and
Mexico estimated that the mean daily vitamin E intake
was inadequate in all groups [54]. In some elderly
populations, low dietary diversity and poor fruit and
vegetable intake may contribute to poor antioxidant
vitamin status [55–56]. The observation that vitamin
E deficiency is often accompanied by low circulating
levels of other antioxidants, including vitamin C and
β-carotene, supports the theory that deficiencies are
associated with poor intake and greater oxidative stress.
Among adolescents and adults, obesity and male sex
may predispose individuals to vitamin E deficiency. An
association between obesity and poor vitamin E status
has been demonstrated in multiple studies [55, 57–59],
possibly due to sequestration of α-tocopherol in adipose
tissue [60]. Many studies conducted in developing
and developed countries have shown a greater
risk of vitamin E deficiency in men than in women
132 D. K. Dror and L. H. Allen
[56, 61–63]. Although the cause of the discrepancy is
poorly understood, contributing factors may include
greater intake of PUFAs, more frequent smoking and
alcohol consumption, and higher prevalence of heart
disease in men. Alternatively, the discrepancy may be
explained in part as an artifact of using the same cutoffs
for deficiency in men and women.
Vitamin E deficiency in developing
countries
Additional influences on vitamin E status
In developing countries, prevalent conditions including
malnutrition, malaria, and HIV infection may compromise
vitamin E status and raise intake requirements. In
PEM, chronic underconsumption of vitamin E leads
to depletion of α-tocopherol in target tissues. Vitamin
E deficiency may be exacerbated by limited ingestion
of protein necessary for synthesis of hepatic α-TTP.
In a study that compared Indian children with PEM
according to weight-for-age criteria with age-matched
healthy controls, Kalra et al. found significantly lower
mean serum α-tocopherol concentrations (6.0 } 2.6
μmol/L compared with 9.5 } 2.1 μmol/L in controls)
and a significantly higher prevalence of neurologic
deficits in the children with PEM [52]. After 6 weeks of
supplementation with 100 mg/kg/day of α-tocopherol
in aqueous solution, children with PEM had a significant
increase in serum α-tocopherol and significant
improvement in a variety of neurologic tests [53].
Malaria is endemic in parts of Asia, Africa, and
Central and South America, causing an estimated
500 million episodes of infection annually [64]. Compromise
of vitamin E status during malarial infection
may be mediated by hepatic cell apoptosis caused by
increased oxidative stress. Besides depleting plasma
α-tocopherol and other plasma antioxidants directly,
subsequent hepatic dysfunction may reduce the secretion
of α-tocopherol from the liver [65]. A study of
Indian children aged 2 to 11 years comparing plasma
α-tocopherol concentrations in healthy controls with
the concentrations in children with mild or severe
malaria found significant differences in vitamin E
status according to the severity of malarial infection.
The median plasma α-tocopherol concentrations in
controls and in children with mild and severe infection
were 17.7, 11.5, and 7.3 μmol/L, respectively [66]. Mean
serum α-tocopherol was found to increase significantly
from 7.6 } 2.6 to 8.6 } 2.6 μmol/L in a group of Ugandan
children aged 1 to 10 years after 7 days of treatment
for acute malaria [67].
Like malaria, HIV is highly prevalent in developing
countries. Of the estimated 33 million people living
with HIV globally, approximately 67% are in sub-Saharan
Africa [68]. HIV-positive patients have increased
oxidative stress biomarkers and lower plasma antioxidants
compared with healthy volunteers. Allard et al.
found significantly lower mean plasma α-tocopherol
concentrations in Canadian HIV-positive patients
(22.5 } 1.2 μmol/L) than in seronegative controls
(26.6 } 2.6 μmol/L) [69]. Supplementation of HIVinfected
subjects with vitamin E was found to decrease
both oxidative stress and viral load [70–71].
Prevalence of vitamin E deficiency
Because of the wide variation in the biomarkers and
cutoffs used to define vitamin E deficiency, direct
comparison of the prevalence of inadequacy in studied
populations is not possible. Nevertheless, these data
provide an indication of the degree of deficiency as a
public health concern and illustrate its geographic, age,
and sex distribution. A summary of prevalence studies
of vitamin E deficiency in developing countries by age
group is presented in table 4.
Geographic distribution
Most population studies of vitamin E status in developing
countries have been undertaken in Asia and Africa,
with a limited number in Central and South America
and the Middle East. The reported prevalence of deficiency
has ranged from approximately 20% to 90%, in
large part due to variations in definitions of adequacy
as well as in study design and target populations. Several
studies have presented deficiency prevalence using
alternative cutoffs, resulting in substantially different
estimates.
Vitamin E deficiency prevalence estimates in children
in different parts of the world are heavily influenced
by the choice of cutoff. A study of 262 Bedouin
children aged 0.5 to 5.5 years in Jordan found 17.1%
and 89.2% of the study subjects to be vitamin E deficient
with the use of serum α-tocopherol < 11.6 μmol/L
and < 17.2 μmol/L as respective cutoffs [72]. On the
basis of work by Farrell et al. showing lower normal
levels of circulating α-tocopherol in children (7 to 21
μmol/L )[44], it can be argued that the prevalence of
deficiency in children was overestimated even with
the lower cutoff. A study of 284 schoolgirls aged 7 to 9
years in rural and urban communities of southern Vietnam
estimated the prevalence of vitamin E deficiency
to be 20.0% and 27.1% in rural and urban areas, respectively,
according to a cutoff of serum α-tocopherol < 4.8
μmol/L, but 100% in both areas according to a cutoff
of serum α-tocopherol:total lipid < 2.36 μmol/mmol.
Dietary intake was assessed by 24-hour recall; however,
tocopherol is not included in the Nutritive Composition
Table of Vietnamese Foods, and the estimated
intake was therefore not calculated [73]. It is likely that
the substantial differences in deficiency prevalence estimates
reported in this study were due to a relatively low
cutoff for serum α-tocopherol and a generous cutoff for
Vitamin E deficiency in developing countries 133
α-tocopherol:total lipid, revealing that such estimates
are heavily dependent on definitions.
Other studies conducted in children have used a
single definition of deficiency, although the choice of
cutoff similarly affected the estimated prevalence. In
Korea, the prevalence of vitamin E deficiency in 131
children aged 2 to 6 years was estimated at 67% with a
cutoff of plasma α-tocopherol < 12 μmol/L; however,
the authors noted that none of the subjects had concentrations
< 7 μmol/L [74]. In a multicenter study of
336 HIV-infected or HIV-exposed children aged 1 to
3 years in Brazil, Argentina, and Mexico, the choice of
plasma α-tocopherol < 18 μmol/L as a cutoff resulted
in a high estimated prevalence of deficiency (89%), in
concordance with the Jordanian study described previously.
The median plasma α-tocopherol concentrations
were 12.42 (range, 3.34 to 44.75) and 11.38 (range, 3.66
to 27.65) μmol/L in HIV-infected and HIV-exposed
groups, respectively, revealing that the estimated
prevalence would have been considerably lower with a
more conservative cutoff. The study failed to include a
control group without HIV infection or exposure [75].
The lack of a clear trend in severity of deficiency by
region, latitude, or climate, despite the variation in cutoffs
used, suggests that the prevalence is more strongly
influenced by culture, lifestyle, and presence of infectious
disease. Contributing factors may include overall
food availability, vitamin E contents of local dietary
staples, accessibility and cost of fruits and vegetables,
and prevalence of malaria and/or HIV infection.
Age distribution
The majority of studies of the prevalence of vitamin
E deficiency in developing countries have focused on
children (newborn to 19 years) and the elderly (≥ 60
years), the populations considered to be at higher risk
for deficiency. Only a few studies have investigated
vitamin E status in mixed-age populations, with some
being specific to pregnant or postpartum women.
Most investigations of vitamin E status in childhood
have included children within a specific age range,
precluding identification of periods of higher risk. The
studies involving the largest age ranges were conducted
by Fazio-Tirrozzo et al. among girls aged 10 to 19 years
in Malawi and by Wetherilt et al. among children aged
7 to 17 years in Turkey. The former investigators found
that the prevalence of deficiency was highest in girls
aged 14 to 16 years, although the prevalence in this
group did not differ significantly from the prevalence
in the older and younger age groups. Of the 118 girls
studied, 13.9% were wasted (body mass index below the
second centile for age) and 33.9% were stunted (heightfor-
age below the second centile), possibly indicating
chronic energy deficiency. None of the girls who were
wasted had an α-tocopherol:cholesterol ratio within
the normal range. Additionally, 15.9% of the girls had
positive blood smears for malaria and 20% reported
blood in the urine, indicative of urinary schistosomiasis,
which is endemic to the area [76]. Because the age
distributions of wasting, stunting, malaria, and bloody
urine were not reported, it is difficult to interpret
whether these factors contributed to the higher prevalence
of vitamin E deficiency (serum α-tocopherol
< 11.6 μmol/L) in girls aged 14 to 16 years. In Turkey,
the investigators failed to find an association between
vitamin E status and age among the children. In this
study, the nutritional status of children from different
regions of the country living in cities, small towns,
and villages was compared. Plasma α-tocopherol was
associated with level of urbanization and region, possibly
obscuring an effect of age [77]. Other investigators
have not reported prevalence rates within subgroups
of the age range studied. Although the use of cutoffs
equivalent to those in adult populations may have led to
overestimation of vitamin E deficiency in many studies
of children, on the basis of the available data vitamin E
deficiency is a significant concern among children of
all ages in the populations studied.
In a mixed-age population study, Gouado et al. demonstrated
a nonstatistically significant improvement in
vitamin E status with age from 3 to 61 years in a rural
population of northern Cameroon. The subjects in this
study were recruited from two neighboring villages.
Interestingly, the prevalence of severe vitamin E deficiency
(serum α-tocopherol < 5.8 μmol/L) differed significantly
between the study villages, with 10 subjects
(21.7%) severely deficient in one village and no subjects
severely deficient in the other. In contrast, the prevalence
of “low” status, defined as serum α-tocopherol
5.8 to 11.6 μmol/L, did not differ significantly by village
[78]. Obeid et al. found a significant positive correlation
between vitamin E status and age in a Lebanese
population aged 25 to 64 years. However, the correlation
was no longer present when vitamin E status was
expressed as the α-tocopherol:cholesterol ratio [79].
The overall prevalences of deficiency across age groups
were considerably higher in northern Cameroon than
in Lebanon with the use of either 5.8 or 11.6 μmol/L as
a cutoff for α-tocopherol; the difference is likely to be
related to differences in dietary intake, socioeconomic
status, and environmental stressors.
Although individuals over the age of 60 years are
theoretically at higher risk for deficiency, considerable
variability in definitions of deficiency in published
studies of the elderly in developing countries (< 2.8 to
< 14 μmol/L) makes comparison of the results challenging
[55–56, 63]. A study of 235 South Africans
aged 60 to 93 years used two alternative but highly
conservative cutoffs of < 2.8 and < 3.7 μmol/L of serum
α-tocopherol. Mean serum α-tocopherol measured by
HPLC in this study was 4.8 } 2.6 μmol/L, so that the
prevalence rates of deficiency were 20.9% and 37.1%
according to the respective cutoffs [55]. The considerably
lower circulating α-tocopherol concentrations
134 D. K. Dror and L. H. Allen
measured in this population as compared with other
populations may be attributable to poor dietary intake
and diversity. Analysis of two 24-hour dietary recalls
in a subset of study subjects (n = 139) found vitamin
E intakes below the DRI in 96% of women and 95%
of men [55]. In contrast, a large study of 2,336 older
Thai adults (≥ 60 years) found a prevalence of vitamin
E deficiency of 55.5% with the use of a liberal cutoff
(plasma α-tocopherol < 14 μmol/L) [56]. A study
in 350 rural elderly Malaysians (≥ 60 years) using a
more standard adult cutoff of < 12 μmol/L plasma
α-tocopherol found a 26.7% prevalence of deficiency
[63]. Dietary intakes were not estimated in the Thai
study, whereas in the Malaysian study limitations
in food composition tables precluded estimation of
vitamin E intake. As a result, comparison of the effect
of inadequate intake on vitamin E status in the elderly
is not possible. In summary, early and advanced age
appear to contribute to vitamin E deficiency in populations
where dietary intake is insufficient and/or other
risk factors exist.
Sex distribution
Among adults, many studies have demonstrated a
higher prevalence of vitamin E deficiency in men than
in women [56, 61–63]. In the study of the elderly Thai
cohort described above, male sex had an adjusted odds
ratio for vitamin E deficiency (plasma α-tocopherol
< 14 μmol/L) of 1.279 (95% confidence interval, 1.001
to 1.636) compared with female sex [56]. In an analysis
of samples collected from 2,373 elderly Taiwanese individuals
during a national nutrition and health survey,
the odds ratios for women having α-tocopherol < 11.6
μmol/L or α-tocopherol:cholesterol < 2.8 μg/mg were
0.48 (95% CI, 0.36 to 0.65) and 0.56 (95% CI, 0.38 to
0.81), respectively, compared with men [61].
However, some studies have found no sex differences
in the risk of vitamin E deficiency. Oldewage-Theron et
al. found no significant difference between the vitamin
E status of men and women in an elderly South African
population [55], and Obeid et al. found that neither
mean α-tocopherol nor α-tocopherol:cholesterol differed
significantly by sex in a mixed-age Lebanese
population [79]. In contrast to results from other
studies, Gouado et al. demonstrated that women had
a significantly lower vitamin E:triglyceride ratio than
men in northern Cameroon [78]. It is possible that
this observation may have been due to poor dietary fat
content as well as higher nutritional requirements in
men than in women.
To date, studies comparing the vitamin E status
of men and women have used the same definition
of deficiency for both sexes. Whether this practice
is justified is unclear. Early studies used to establish
the plasma α-tocopherol concentration necessary to
limit in vitro hydrogen peroxide-induced erythrocyte
hemolysis were conducted in a small sample of men,
although the results were generalized to both sexes
[80–82]. Physiological differences in lipid absorption,
metabolism, and storage may affect the normal range
of α-tocopherol concentrations in women; however,
alternative reference values for females have not been
investigated. On the basis of the available data, it
appears that depressed α-tocopherol concentrations
are generally more prevalent in men than in women in
developing countries.
Vitamin E intervention studies
To improve the vitamin E status of populations at risk
for deficiency, food-based or supplemental interventions
must be identified whereby dietary consumption
of the vitamin can be augmented effectively. Various
forms of vitamin E fortification and supplementation
have been evaluated in adult subjects under experimental
conditions using both natural (RRR-) and synthetic
(all-rac-) α-tocopherol. Food vehicles used for fortification
have included milk, orange juice, margarine, and
breakfast cereals, with α-tocopherol added in either
fat- or water-miscible solutions. Alternatively, some
trials have administered capsules of supplemental
α-tocopherol in conjunction with low- or high-fat diets.
It is important to note that experimental studies of
vitamin E fortification or supplementation have been
conducted in developed countries among participants
with adequate baseline status (> 20 μmol/L of plasma
α-tocopherol); therefore, the results cannot be generalized
to developing-country populations. Furthermore,
many experimental studies have provided supplementation
in doses that exceed those potentially achievable
through public health intervention. Nevertheless, the
results of these studies provide valuable information
about the comparative efficacy of supplementation or
fortification modes. A limited number of studies have
evaluated plasma α-tocopherol response to vitamin
E–specific, multimicronutrient, or food-based interventions
in population-based settings in developed and
developing countries. Experimental and populationbased
studies of interventions with vitamin E are summarized
in table 5.
Of note, esterified forms of α-tocopherol
(α-tocopheryl acetate or α-tocopheryl succinate) are
routinely used in supplements and fortified foods
due to their enhanced stability. In healthy individuals,
these esters are hydrolyzed and absorbed as efficiently
as α-tocopherol [83]. As defined by the Food
and Nutrition Board, 1 mg of all-rac-α-tocopheryl
acetate is equivalent to 1 international unit (IU)
of vitamin E [2]. One milligram or IU of all-rac-
α-tocopheryl acetate contains 0.9 mg of all-rac-α-
tocopherol, of which 0.45 mg is present as biologically
active 2R-α-tocopherol. In contrast, 1 IU of natural
RRR-α-tocopheryl acetate is defined as 0.67 mg of
Vitamin E deficiency in developing countries 135
TABLE 5. Vitamin E intervention trials
A. Experimental trials
Reference
Location/
ethnicity
No. of
subjects Age Intervention Results/comments
Herrero-Barbudo et
al., 2006 [101]
Madrid, Spain 19 22 } 3 yr 3 consecutive treatments:
430 mL unfortified whole, MMN-fortified
whole, or MMN-fortified skim
milk (vitamin E as all-rac-α-tocopheryl
acetate in fortified milks; RRR-α-
tocopherol measured in quadruplicate
samples 0.1–0.2 mg, 3.6–7.0 mg, and
2.4–5.9 mg in respective milks)
No significant increase in plasma α-tocopherol during postprandial
period from baseline (24.4 } 4.1 μmol/L) following any of milks;
no significant differences between milks in 6.5-h AUC values for
α-tocopherol in triacylglycerol-rich lipoprotein fractions
Fortified milks also contained vitamin D, folic acid, calcium,
phosphorus,
and vitamin A
Jeanes et al., 2004
[102]
Surrey, UK 8 28 } 6 yr 4 consecutive treatments:
135 mg capsule 2H-labeled RRR-α-
tocopherol as RRR-α-tocopheryl acetate
with test meals containing: I and
II) 17.5 g, III) 2.7, IV) 0 g fat
Significant time and treatment effect (p < .001) in 2H-labeled α–
tocopherol in plasma and chylomicrons over 9 h
Significantly greater plasma α-tocopherol concentration after 9 h
when capsule was ingested with high-fat (17.5 g) vs. low-fat meal
(2.7 g). Plasma concentrations NA, p < .05
Leonard et al., 2004
[84]
Oregon, USA 5 32 } 7 yr 4 consecutive treatments (vitamin E as
d9-all-rac-α-tocopheryl acetate with
236 mL fat-free milk):
I) 180 mg RRR-α-tocopherol capsule, II)
41 g cereal fortified with 13.5 mg RRR-
α-tocopherol, III) 45 g cereal fortified
with 180 mg RRR-α-tocopherol, IV)
180 mg RRR-α-tocopherol capsule +
41 g unfortified cereal
Compared with 180 mg RRR-α-tocopherol capsule, 180 mg or 13.5
mg RRR-α-tocopherol from fortified cereal ~ 25-fold and ~ 5-fold
more bioavailable (72 h AUC for respective treatments 30 } 7, 765
} 164, and 153 } 43 μmol·h/L; p < .0001 for all comparisons)
Percent increase in total plasma α-tocopherol significantly greater
with treatment III compared with I and II (99 } 39%, 14 } 15%,
and 28 } 11%, respectively; p < .001)
Hayes et al., 2001
[85]
Massachusetts,
USA
I: 48
II: 24
III: 7
18–40 yr Interventions I and II 4 wk, III 2 wk
I: 45 mg RRR-α-tocopherol as all-rac-
α-tocopheryl acetate in capsules, skim
milk, and 1% fat milks containing soybean
oil, milk fat, or both (1:1)
II: 180 mg/day RRR-α-tocopherol as
RRR-α-tocopheryl acetate in milk or
90 mg/day RRR-α-tocopherol as allrac-
α-tocopheryl acetate in milk or
orange juice
III: 13.5 mg/day RRR-α-tocopherol as
all-rac-α-tocopheryl acetate in milk
with or without added vitamins A
and D
I: After 4 wk, plasma α-tocopherol was unchanged in the control
group, increased significantly from 20.3 } 4.9 to 28.0 } 8.9
μmol/L
in the capsule group, and increased significantly from 20.3–24.1 }
2.6–4.8 to 37.1–45.1 } 4.2–12.4 μmol/L in the various milk groups.
II: After 4 wk, plasma α-tocopherol increased from 20.0 } 5.5 to
41.5
} 10.2 μmol/L in the RRR milk group, from 22.4 } 3.9 to 48.9 }
6.4
μmol/L in the all-rac milk group, and from 22.5 } 5.3 to 38.3 }
9.4
μmol/L in the all-rac orange juice group (p < .05 for time effect in
all groups). Vitamin E:cholesterol ratio increased by 122 } 26%,
137 } 45%, and 75 } 30% in 3 groups, with percent increase
significantly
greater in the milk groups than in the orange juice group
(p < .05)
III: Vitamins A and D did not affect vitamin E delivery by milk
(from baseline 24.6 } 4.6 and 24.1 } 3.1 μmol/L in respective
groups to 30.5 } 6.2 and 28.0 } 3.4 μmol/L after 2 wk; time effect
significant but no significant difference between groups)
Overall: microdispersion of vitamin E in milk was most effective in
raising plasma α-tocopherol
continued
136 D. K. Dror and L. H. Allen
Roodenburg, 2000
[103]
Vlaardingen,
Netherlands
14 46.4 } 13.4
yr
Two 7-day experimental periods with
50 mg/day RRR-α-tocopherol in 50 g
low-fat (3 g) or high-fat (36 g) spread
ingested with a low-fat meal
Plasma α-tocopherol increased by 5.0 } 0.8 and 5.5 } 1.2 μmol/L
following
low- and high-fat treatments from baseline 25.1 } 2.1 and
24.4 } 2.2 μmol/L. Effect was significantly different from controls
(p < .001) but not significantly different by type of supplement
Roxborough, 2000
[104]
London, UK 30 22–41 yr Subjects received capsule containing
75 mg d6-RRR-α-tocopherol acetate
followed by standard breakfast and
underwent venous blood drawing at 6,
9, 12, 27, and 51 h after ingestion
Total plasma α-tocopherol increased significantly from baseline
(24.1 } 5.1 μmol/L) to peak (26.7 } 6.2 μmol/L, p < .001) at 12 h
and returned to baseline (23.5 } 5.4 μmol/L, p = .15) by 51 h
AUC varied widely between individuals: 12.9–493.4 μmol·h/L, CV
61.7% vs. 21.3% for baseline plasma α-tocopherol
Van het Hof et al.,
1998 [86]
Vlaardingen,
Netherlands
31 18–57 yr Experimental: 15.5 mg RRR-α-
tocopherol as all-rac-α-tocopherol
in 15 g full-fat margarine also fortified
with vitamin C, α-carotene, and
β-carotene for 4 wk
Control: unfortified margarine
After 4 wk, fortified margarine significantly increased plasma levels
of α-tocopherol from 20.1 } 0.4 to 23.8 } 0.4 μmol/L in
experimental
group (p < .05 for time effect) compared with 18.7 } 0.4 to
19.3 } 0.4 μmol/L in control group. Difference and 95% CI: 3.16
(1.65, 4.66), p = .0002
Borel et al., 1997
[105]
Clermont-Ferrand,
France
16 25 } 1 yr
(n = 8),
68 } 1 yr
(n = 8)
Subjects received 2 test meals containing
194 } 5 or 422 } 8 mg RRR-α-
tocopherol as all-rac-α-tocopheryl
acetate in an emulsion of 40 g fat in
random order 7–30 days apart
Fasting plasma α-tocopherol was significantly higher in the elderly
group (33.28 } 1.79 vs. 22.07 } 1.62 μmol/L), also after correction
for total lipids (p < .005)
Plasma and chylomicron α-tocopherol 24-h AUCs were significantly
higher after 422 mg than after 194 mg test meal in both groups
(p < .0005 and p < 0.5 for plasma and chylomicron α-tocopherol,
respectively)
Plasma α-tocopherol 24-h AUC was significantly higher in elderly
group for both test meals (p < .0001), while chylomicron
α-tocopherol 24-h AUC was significantly lower in elderly group
(p < .05)
Dimitrov et al.,
1996 [87]
Michigan, USA 3 in singledose,
8 in
multipledose
study
26–64 yr Single dose and 28-day multiple doses of
268, 536, or 804 mg RRR-α-tocopherol
as RRR-α-tocopheryl glycol 1000 succinate
(TPGS) (water-miscible, given
in 150 mL solution) and 268, 536, or
804 mg RRR-α-tocopherol as RRR-α-
tocopheryl acetate (TA) (fat-soluble,
given with 100 mL whole milk)
Single dose: TA was more effective than TPGS at raising plasma
α-tocopherol at all doses. 24-h AUC in excess of baseline values
was 81, 103, and 216 μmol·h/L for TPGS and 172, 380, and 355
μmol·h/L for TA (baseline status and p-value NA).
28-day: Mean elevations in plasma α-tocopherol after TA treatments
significantly different from baseline and between 400 and 800 IU
or 1200 IU (12.1, 19.8, and 19.3 μmol/L increases in respective
treatment groups, p = .01). Plasma α-tocopherol elevations
significantly
higher in TA than TPGS formulations: differences 6.5
μmol/L after 400 IU (p < .03), 15.8 μmol/L after 800 IU (p < .01),
and 13.4 μmol/L after 1,200 IU (p < .01) treatment
TABLE 5. Vitamin E intervention trials (continued)
Vitamin E deficiency in developing countries 137
Dimitrov et al.,
1991 [88]
Michigan, USA 64 (as
stated; does
not match
total n per
intervention)
24–62 yr 3 interventions (as all-rac-α-tocopherol
with 150 mL whole milk):
I: Single dose 220, 440, or 660 mg RRR-
α-tocopherol (n = 3)
II: 28-day multiple dose 220, 440, or 660
mg RRR-α-tocopherol (n = 49)
III: 440 mg/day RRR-α-tocopherol for
5 days in presence of low- or high-fat
diet (n = 6)
I: Peak plasma α-tocopherol 1–24 h after ingestion, dose-related
response in 1 of 3 subjects (numeric data not provided)
II: Average increases in plasma α-tocopherol above baseline (17.2
μmol/L) from data on days 4–28 of intervention were 14.4, 14.6,
and 14.9 μmol/L for respective groups (p-values not reported);
return to baseline 12–20 days after treatment ceased
III: Greater 2- to 5-day average plasma α-tocopherol in response
to supplementation with high-fat diet (baseline and increases not
reported, one-sided p = .035)
B. Population-based trials
Reference
Location/
ethnicity
No. of
subjects Age Intervention Results/comments
Vinod Kumar et al.,
2006 [89]
Chennai, India 413 5–15 yr Experimental: 1 g/child/day MMN
supplement
powder including 13.5 mg
RRR-α-tocopherol added to cooked
food in residential schools for 9 mo
Control: no intervention
Vitamin E stability in supplement maintained after 30 min cooking
(99.5%) or 10 mo storage (100%)
Significant improvement in vitamin E status in both experimental
and control groups from baseline (21.1 } 6.2 and 22.6 } 7.3
μmol/L) to endpoint (45.5 } 9.3 and 44.9 } 13.4 μmol/L, p < .05),
with significantly greater increase in experimental than control
group (p < .05)
Smuts et al., 2005
[90]
Indonesia, Vietnam,
South
Africa, Peru
1,134 6–12 mo Chewable tablet (foodlet) with I)
daily MMN including 6 mg RRR-α-
tocopherol, II) weekly MMN (double
daily dose), III) iron and IV) placebo
for 6 mo
Significant improvement in plasma α-tocopherol from baseline only
in daily supplement group (+10% from baseline), from 22 to 24
μmol/L
McGavin et al., 2001
[91]
Dunedin, New
Zealand
82 22–72 yr Dietary modification (30–40 mg/day
RRR-α-tocopherol), supplementation
(133 mg/day RRR-α-tocopherol), or
placebo for 8 wk
Plasma α-tocopherol significantly greater in diet than in placebo
group at 6 wk (difference 3.4 μmol/L), α-tocopherol:cholesterol
ratio greater at 4 and 6 wk (difference 0.9 and 0.9 μmol/mmol)
Plasma α-tocopherol and α-tocopherol:cholesterol ratio greater in
supplement than placebo group at 2, 4, 6, and 8 wk (difference
14.9, 17.3, 13.6, and 16.0 μmol/L and 2.3, 3.1, 2.8, and 3.4 μmol/
mmol)
Supplementation more effective than diet at appreciably raising
plasma α-tocopherol
AUC, area under the curve; CI, confidence interval; CV, coefficient
of variation; MMN, multiple micronutrients; NA, not available
138 D. K. Dror and L. H. Allen
biologically active RRR-α-tocopherol on the basis of
the rat fetal resorption assay [2]. Vitamin E quantities
administered in the studies presented in table 5 have
been standardized to milligrams of RRR-α-tocopherol
for ease of comparison.
Experimental trials
Despite relatively small sample sizes and interventions
limited to 4-week regimens at most, experimental
studies indicate that increases in plasma α-tocopherol
can be achieved through both food fortification and
supplementation, with fat-soluble superior to watersoluble
forms. Compared with vitamin E supplements
provided in capsules, fortification of food vehicles has
proven to be more effective in improving circulating
α-tocopherol. It has been hypothesized that physical
properties involved in RRR-α-tocopherol presentation
influence its bioavailability, with fine dispersal
in food being preferable to the globular form in capsules
[84]. Leonard et al. demonstrated that 400 IU of
α-tocopheryl acetate from fortified breakfast cereal
was approximately 25 times more bioavailable than the
same dose in capsular form [84]. Microdispersion of
200 to 300 IU of α-tocopheryl acetate in milk, regardless
of fat content (0.5% or 1%) or type (vegetable oil
or milk fat), raised plasma α-tocopherol concentrations
110% above baseline [85]. In a study using a smaller
dose of vitamin E in a multiantioxidant-fortified margarine,
31 IU/day raised circulating concentrations by
16% compared with controls [86].
In comparing various doses of vitamin E in watermiscible
(RRR-α-tocopheryl glycol 1,000 succinate)
or fat-soluble (RRR-α-tocopheryl acetate) forms,
Dimitrov et al. found both single-dose and 28-day
multiple-dose treatments with the fat-soluble form to
have a significantly more pronounced effect on circulating
α-tocopherol [87]. Supplementation with more
than 800 IU/day of vitamin E did not appear to further
elevate plasma α-tocopherol, although supplementation
at this dose was more effective in the presence of
a high-fat diet [87–88].
Population-based trials
A small number of population-based trials have found
a significant impact of vitamin E fortification, supplementation,
or dietary modification in raising circulating
α-tocopherol concentrations. In two trials
conducted in children in developing countries, vitamin
E included as part of a multimicronutrient powder or
chewable tablet (foodlet) administered daily for 6 to 9
months resulted in significant improvement in vitamin
E status compared with baseline values and with
respective control groups [89–90]. Vitamin E in the
multimicronutrient powder was found to remain stable
after 30 minutes of cooking or 10 months of storage
[89]. In a study of adults in New Zealand, supplementation
with 200 IU/day of RRR-α-tocopherol was more
effective at appreciably raising circulating concentrations
after 8 weeks than a dietary modification aimed
to achieve vitamin E intakes of 30 to 40 mg/day (45
to 60 IU/day), although both interventions led to a
significant improvement in plasma α-tocopherol and
α-tocopherol:cholesterol ratio by 6 weeks [91].
Public health implications
With an increasing number of recognized and proposed
functions in diverse aspects of physiology,
vitamin E is a nutrient essential for achieving and
maintaining optimal health. Although overt symptoms
of vitamin E deficiency generally do not result from
poor dietary intake alone, subclinical inadequacy, as
evidenced by low circulating plasma levels, is detrimental
to immune function, control of oxidative damage,
and cognitive function. To ensure vitamin E adequacy
in population groups with a demonstrated prevalence
of deficiency or an increased risk of deficiency due to
undernutrition, infectious disease, or monotonous diet,
public health interventions aimed to improve status
are indicated.
Optimal status
There is considerable inconsistency in the definitions
of vitamin E deficiency in the literature, suggesting that
any cutoff may be an unreliable measure of adequacy.
On the basis of available evidence, the expert committee
of the Institute of Medicine determined that plasma
α-tocopherol concentrations < 12 μmol/L (0.5 mg/dL)
indicate deficiency in normal, healthy adults [2]. There
is some evidence suggesting that normal circulating
α-tocopherol concentrations in children may be
lower, possibly related to a parallel lower cholesterol
concentration [44, 46, 62]. Additional studies are
needed to evaluate appropriate pediatric cutoffs using
functional outcomes. Because of the difficulty of using
the α-tocopherol:lipid ratio as a biomarker of vitamin
E status in malnourished populations of developing
countries, and the knowledge that plasma concentrations
that are normal in adults are acceptable in
children, it seems suitable that public health initiatives
target > 12 μmol/L as a goal in all individuals.
Programs and policy
As demonstrated in experimental and populationbased
trials, various types of intervention can be
effective in enhancing vitamin E status. Depending
on population needs and resources, programs may be
directed at improving vitamin E status, antioxidant
vitamin status, or overall nutritional status. Different
Vitamin E deficiency in developing countries 139
potential approaches, including their advantages and
disadvantages in developing-country settings, are
considered below.
Dietary modification
Dietary staples in most developing countries are
poor sources of vitamin E. To achieve better status by
dietary modification, other vitamin E–rich foods must
be introduced through local cultivation or targeted
distribution in conjunction with education about the
importance of dietary diversification. Seeds, nuts,
peanuts, and certain vegetable oils are good sources of
vitamin E that are indigenous or possible to grow in a
variety of developing-country settings. For example, in
western Africa peanut (groundnut) oil is a significant
dietary component with widespread cultivation in rural
communities [92]. Increased intake of fruits and vegetables
has been shown to improve plasma antioxidant
concentrations, including α-tocopherol, after 3 months
of consumption by healthy German adults [93]. To our
knowledge, no interventions aimed at dietary modification
to improve vitamin E status have been carried
out in developing countries to date. However, existing
evidence suggests that increasing intakes of dietary
sources of the vitamin improves vitamin E status [91,
93], and it is feasible that such an intervention could
be targeted at high-risk populations in developing
countries.
Fortification
In experimental trials, fortification of foods, including
milk, margarine, and breakfast cereals, has proven
effective in increasing circulating α-tocopherol concentrations
[84–86]. Microdispersion of α-tocopheryl
acetate in a fat emulsion appears to be especially
advantageous in terms of nutrient stability and impact
on plasma α-tocopherol [84]. While fortification of
familiar foods is more likely to be accepted by a target
population than either dietary modification or supplementation,
its implementation is most practical
and cost-effective if the fortificant is added during
centralized processing. Because milk, fats, and grains
are typically cultivated locally in developing countries,
fortification as a means of improving vitamin E status
would require evaluation of other food vehicles.
Supplementation
Supplementation of children in developing countries
with vitamin E contained in a multimicronutrient
powder, tablet, or spread has been piloted effectively
in several trials [89–90, 94]. Focus group discussions
conducted in Tamil Nadu, India, revealed that supplement
powder is preferred to tablets because the latter
are perceived as medicine [89]. Furthermore, vitamin
E appears to be less bioavailable when isolated in a
capsule than when ingested together with food [84–85,
88]. Because populations in developing countries with
a high prevalence of vitamin E deficiency often suffer
from other micronutrient deficiencies, multimicronutrient
supplementation is likely to be both beneficial
and cost-effective. One gram of multimicronutrient
powder containing 30 IU of vitamin E was estimated
to cost 0.5 US cents per person per day [89].
Conclusions
Although data on vitamin E intake in developing
countries are limited, results from multiple studies
suggest that poor overall nutritional status and higher
prevalence of other oxidative stressors, such as malaria
or HIV, predispose populations for deficiency. Direct
comparison between study outcomes is complicated
by widely varying definitions of vitamin E deficiency.
However, data trends indicate that children and the
elderly are more vulnerable age groups and that men
may be at higher risk for deficiency than women.
Public health initiatives aimed at improving the vitamin
E status of high-risk populations would be prudent to
counteract oxidative stress, improve immune function,
and protect against neurologic and cognitive deficits.
On the basis of available research, supplemental vitamin
E appears to be most highly bioavailable when
finely dispersed in a fortified food source or as a
powder. Although it has not been piloted in a developing
country, dietary modification to increase intake of
natural sources of vitamin E is an alternative to fortification
or supplementation that is likely to be effective
in improving vitamin E status. Additional research is
needed to establish dose–response relationships of various
interventions and to develop cost-effective and culturally
appropriate programs targeted at the population
groups within developing countries who are at greatest
risk for vitamin E deficiency. Furthermore, in order to
monitor progress, a consensus must be reached regarding
appropriate definitions of vitamin E sufficiency by
age, sex, and physiological state.
Acknowledgments
Financial support for this review was provided by
HarvestPlus (www.HarvestPlus.org), a global alliance
of agriculture and nutrition institutions working to
increase the micronutrient contents of staple food crops
through biofortification. The views expressed do not
necessarily reflect those of HarvestPlus.
140 D. K. Dror and L. H. Allen