SUPPLEMENT

Proceedings of the IUNS 20th International Congress of Nutrition (Part 2)

Developing Suitable Methods of Nutritional Status

Assessment: A Continuous Challenge1–3
Ibrahim Elmadfa* and Alexa L. Meyer
Department of Nutritional Sciences, University of Vienna, Vienna, Austria

ABSTRACT

Reliable information about the nutritional status is essential to identify potential critical nutrients and the population groups at risk of deficiency, as
well as to develop effective public health policies to counteract unfavorable nutrition patterns that contribute to morbidity and mortality. In
this review, the important role of biomarkers in the assessment of nutritional status is outlined, major strengths and limitations of established and
new biomarkers are described, and important criteria for biomarker selection and development are discussed. Indeed, biomarkers offer a
more objective assessment tool than pure dietary approaches that suffer from inadequate data reporting in particular, although biomarkers
are often only measured in subsamples because of the higher costs and proband burden they entail. However, biomarkers are subject to individual
variability and influences from other factors besides the nutrient of interest. Rapid turnover or tight control of nutrient concentrations in
blood (homeostasis) limits their sensitivity as biomarkers, as in the case of many trace elements. The existence of different forms of a micronutrient
in the body adds additional complexity. Functional biomarkers, such as enzyme activities, mirror long-term status better but are subject to
confounding factors, and some are influenced by several micronutrients, not specific for only 1, so using a combination of biomarkers is advisable.
Additionally, the applicability of a biomarker also depends on the existence of adequate reference values and cutoff points for the target
population. Therefore, a careful selection is warranted, especially when biomarkers are to be used in larger samples. Adv. Nutr. 5: 590S–598S, 2014.

Introduction a rough estimation of the true situation, particularly as a re-

Nutritional status assessment provides the data necessary to sult of misreporting by the study participants and errors in
study the effects of nutrition on health and disease, to iden- quantification (3). Therefore, the validity of nutritional sta-
tify critical nutrients in a specific population and the groups tus assessment is greatly improved by biochemical analyses
within this collective that are at risk of deficiency, and to using nutritional biomarkers. However, in light of the com-
develop effective public health policies to prevent and cure plex influences on nutrient metabolism, they have to be se-
nutrition-related diseases. Indeed, diet-related noncommu- lected carefully (4).
nicable diseases are the most common cause of death world- This review presents the current fields of application of
wide and are associated with obesity and excessive intakes of biomarkers in the assessment of nutritional status and how
SFAs and/or free sugars (1). Knowledge of the nutritional they can contribute to the improvement of epidemiologic ap-
status is also required for the formulation of recommenda- proaches. The strengths and limitations of some established
tions for nutrient intake (2). and new biomarkers are described, and important criteria
Data on nutritional status at the population level are mostly for biomarker selection and development are discussed.
obtained from epidemiologic surveys that often enable only
Current State of Knowledge
1
Published in a supplement to Advances in Nutrition. Presented at the International Union of Assessment of body weight and the importance of body
Nutritional Sciences (IUNS) 20th International Congress of Nutrition (ICN) held in Granada,
Spain, September 15–20, 2013. The IUNS and the 20th ICN wish to thank the California composition. Body weight and composition mirror the ad-
Walnut Commission and Mead Johnson Nutrition for generously providing educational equacy of energy intake. BMI is generally considered a ver-
grants to support the publication and distribution of proceedings from the 20th ICN. The satile tool to assess body weight, especially in light of its easy
contents of this supplement are solely the responsibility of the authors and do not
necessarily represent the official views of the IUNS. The supplement coordinators were applicability in the field. However, the use of self-reported
Angel Gil, Ibrahim Elmadfa, and Alfredo Martinez. The supplement coordinators had no data, although they facilitate the assessment of large samples,
conflicts of interest to disclose. are often associated with underestimation of body weight and over-
2
This work received no financial support.
3
Author disclosures: I. Elmadfa and A. L. Meyer, no conflicts of interest. estimation of height. Thus, data measured under standardized
* To whom correspondence should be addressed. E-mail: [email protected]. conditions should be given as much preference as possible (5).

590S ã2014 American Society for Nutrition. Adv. Nutr. 5: 590S–598S, 2014; doi:10.3945/an.113.005330.

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 Moreover, BMI provides no information on body com- (14). Besides, the International Diabetes Federation using
position and the relative amounts of lean and fat mass. WC as a diagnostic criterion for the metabolic syndrome
This can lead to misinterpretations in individuals with a gives separate values for Asians (90 cm in Asian men instead
high or low muscle mass, as well as in the general popula- of 94 cm in white men, but 80 cm is valid for both white and
tion, especially for those with intermediate BMI ranges in Asian women). Both entities acknowledge the possibility of
which fat mass is higher than average (6). an additional categorization for different Asian subpopula-
Thus, a study in the United States found that 30% of the tions, such as Japanese and East and South Asians (17).
male and 46% of the female participants were classified as Excessive adipose tissue in normal-weight individuals
obese according to their body fat content, although their was described previously, especially in women, and is asso-
BMI was <30 kg/m2 (7). ciated with an unfavorable metabolic profile comparable
The limits of the BMI to detect obesity were also evi- with classical obesity. Thus, assessment of body composition
denced by the Austrian Nutrition Report 2012 (8). The prev- is also important in light of the emerging role of visceral ad-
alence of obesity assessed by BMI ($30 kg/m2) was 9.7% in ipose tissue, in particular in the development of noncom-
adult women and 14.9% in men, whereas it was 14.9% and municable diseases such as type 2 diabetes mellitus (18,19).
39.7%, respectively, when taking measured body fat content Although WC allows a reasonable estimate of body fat con-
as a criterion. Similarly, among elderly adults (aged 65–80 y), tent, it suffers from a high individual variability. The problem
37.2% of women and 27.5% of men had a BMI considered with more accurate laboratory methods is their high technical,
overweight (24–29.99 kg/m2), whereas body fat content was operational, and financial expenses, as well as the participant
too high (i.e., >23% in men and >35% in women) in 62.4% burden. The latter is particularly true for hydrodensitometry
and 54.5%, respectively. In children, the discrepancy between or underwater weighing, which is still considered 1 of the
obesity prevalence assessed by BMI and fat content was partic- gold standards in the evaluation of body composition.
ularly seen in boys, in which increases in lean body mass A widely used technology is the biologic impedance analysis
contributed more to body weight increases than in girls. based on the differences in the electrical conductivity of differ-
A commonly used approach to estimate body fat mass is ent body tissues. The required equipment is inexpensive, easy to
the measurement of waist circumference (WC)4. Indeed, the use, and transportable, making it suitable for field applications.
positive correlation between WC and cardiovascular mortal- However, inaccuracies can arise from variations in body hydra-
ity, all-cause mortality, and the risk of cardiometabolic diseases tion and as a result of ethnic-, age-, and gender-related differ-
is scientifically well established and is a diagnostic variable ences. Recently, DXA and air displacement plethysmography
for the metabolic syndrome. However, there is a variety of gained popularity in body composition assessment. Despite
measurement protocols using different body sites (9). The their reliance on assumptions about the density of lean and
currently used values are based on an increasing cardiome- fat body tissues and tissue hydration, they show a good accur-
tabolic risk associated with a WC >80 cm in women and >94 acy, but they are not widely available because of the cost of the
cm in men and such a high risk of a WC >88 cm in women equipment and because it is not easily transportable (20,21).
and >102 cm in men found in a European population from Currently, there is still a need for accurate methods to as-
The Netherlands. WC was measured midway between the sess body composition that are at the same time inexpensive
lowest rib and the iliac crest (10–12). However, a meta-analysis and applicable with minimal effort on large samples in nu-
of 120 studies suggested that the relation with disease risk trition surveys.
appears to be given regardless of measurement site (13).
In turn, a strong ethnic effect on the amount and distribu- Assessing the intake of food and food components. Infor-
tion of body fat was observed. This is especially true for in- mation on the supply of food and nutrients and other food
dividuals of Asian descent who, at a given BMI and WC, components is commonly obtained through dietary assess-
have higher body fat contents and a higher cardiometabolic ment. At the population level, statistical databases, such as
risk than whites despite a certain variability between differ- the food balance sheets of the FAO or national household
ent Asian populations (14,15). budget survey data, provide a rough overview of nutritional
Conversely, in African Americans, visceral adipose tissue supply, but more detailed information on the actual food in-
is on average lower than in white and Hispanic individuals of take can only be gained from dietary surveys (22,23). These
the same BMI and WC, but to date, there is no clear evidence methods are used for the compilation of multinational re-
of an effect on cardiovascular risk (16). These findings stress ports describing the nutritional situation, thus providing a
the need for defining race-specific cutoff points for WC and basis for intervention policies, such as the European Nutrit-
BMI. Suggestions were already made for Asian populations. ion and Health Report 2004 and 2009 (23,24) and Compar-
Thus, the WHO defined BMI categories associated with an ative Analysis of Food and Nutrition Policies in WHO
increased cardiometabolic risk (23–27.5 kg/m2) and a high European Member States, 2003 (25).
cardiometabolic risk ($27.5 kg/m2) for Asian populations Comparable with self-reported anthropometric data, di-
etary reports are compromised by misreporting, whether in-
advertently or deliberately (26).
4
Abbreviations used: MTHFR, methylene tetrahydrofolate reductase; SR-BI, scavenger-receptor
class B type I; TEE, total energy expenditure; WC, waist circumference; 25(OH)D3, 25-hydroxy The heavy impact of misreporting on the validity of energy
vitamin D3. intake assessment in the frame of the NHANES was outlined

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 recently. Based on the ratio of the reported energy intake to the by Goldberg and colleagues. However, this requires knowl-
estimated basal metabolic rate and the comparison of the re- edge or at least a good estimate of the physical activity level
ported energy intake to the estimated total energy expenditure of the target population because TEE can vary widely (34).
(TEE), it was concluded that, across all NHANES survey pe- Moreover, defining misreporting based on energy intake
riods, less than half of the population provided plausible energy might not catch inaccuracies in the assessment of certain nu-
intake amounts. Part of this seems due to methodologic causes, trients, especially in the case of selective misreporting (30).
as supported by a temporary increase in plausible reports after The fact that especially large surveys often rely on FFQs
methodologic improvements. However, considering that un- to collect data on food consumption can further compro-
derreporting was more pronounced in women than in men mise the accuracy of epidemiologic data on food and nutrient
and in overweight and obese than in normal-weight individuals, intake considering the limited power of FFQs for quantitative
deliberate misreporting by the participants seriously weakens intake evaluation.
the validity of nutritional surveillance data (3). When an FFQ is used to assess the food and nutrient in-
In line with the previously cited report, in obese individ- take as part of the nutritional status assessment, it has to be
uals, a selective underreporting of fat intake was observed, validated against a more precise method. Dietary approaches
whereas normal-weight individuals also underreported to validation are less expensive and more widely applicable,
healthy diets and foods, such as fruit, vegetables, and unsat- which allows for larger subsample sizes. Although dietary
urated FAs (26,27). records, particularly weighed ones, and 24-h recalls are gen-
Misreporting was observed across all age groups and in erally more accurate than FFQs, the measurement errors of
both males and females. Especially in the elderly, it is impor- these assessment methods are not entirely independent from
tant to discern underreporters from true undereaters be- those of the FFQ, limiting their suitability as reference
cause food intake often declines with age. Thus, based on methods. Thus, 24-h recalls like the FFQ relies on the partic-
weight change, Shahar et al. (28) identified 14% of a sample ipant’s memory (35).
of 296 elderly individuals (aged 70–79 y) as undereaters This makes validation of an FFQ against established bio-
(13% of women, 16% of men). markers preferable to dietary methods (4,36,37). Ideally, die-
In children, especially at younger ages, overreporting is tary and biochemical reference methods should be combined
more common than in adults. Younger children are also less because biochemical methods are independent from dietary
prone to selective misreporting of foods with a special social ones, which allows for a more objective evaluation (38).
value, such as sugar- or fat-rich foods that are often underre- As an example, this was applied in the development of a
ported and fruits and vegetables that are overreported. In diet quality index in elderly adults based on an FFQ. In this
turn, reporting of food intake by the parents generally results study, higher plasma concentrations of carotenoids were sig-
in greater accuracy at least for children of normal weight (29). nificantly associated with a higher quality index mirroring a
The extent of underreporting varies between studies, most higher intake of fruits and vegetables (39).
often ranging from 10% to 20% for energy intake in adults Moreover, the FFQ has to be adapted for the target group
with a tendency toward slightly higher deviations among and the purpose of the study. This influences the choice and
women than men (30). In the OPEN (Observing Protein amount of food items included, as well as the frequency cat-
and Energy Nutrition) Study, 12–14% of male participants egories and the portion sizes to be selected by the respon-
underreported their energy intake in 24-h recalls compared dent. An existing FFQ can help in the design of a new one
with 16–20% of their female counterparts (31). Furthermore, but should be revised, updated, validated by using adequate
it is generally more pronounced among overweight and espe- biomarkers, and pretested on the target population (35).
cially obese individuals: in the OPEN Study, men and women An additional constraint arises from the scarcity of good
with a BMI $ 30 kg/m2 underreported their energy intake on biomarkers, especially for macronutrient and energy intake.
average by 16% and 20%, respectively, compared with 7% Again, comparing the reported or estimated intake with the TEE
and 8%, respectively, for nonobese participants (32). is an option. TEE, in turn, is optimally determined through the
Misreporting arising from inadvertent omission of food double-labeled water method, although the high costs and tech-
items and errors in portion size estimation can be minimized nical requirements of this method limit its applicability (40).
by the use of food models, pictures, or modern information Recently, urinary excretion of sucrose and fructose was pro-
and communication technologies, which allow a more direct posed as a biomarker for sugar intake based on the fact that
and easier recording of the food consumed. Examples in- small amounts of these saccharides escape metabolism (41).
clude computer-assisted recording of foods and the taking Dietary assessment also requires comprehensive food
of pictures of the meals with a mobile phone. However, these composition databases. Their improvement and harmoniza-
techniques do not prevent deliberate misreporting (33). tion is the aim of the International Network of Food Data
Energy and, to a lesser extent, protein intake are the most Systems initiated by the UN in 1984, under the coordination
versatile markers to identify misreporters. By comparing re- of the FAO of the UN since 1999 and a task force of the In-
ported energy intake to the individuals’ measured or esti- ternational Union of Nutritional Sciences (42). Particularly,
mated TEE, implausibly low or high intake amounts can be data on dietary fiber, trace elements, bioactive plant components,
discerned. A common approach is the use of the Goldberg and fortified foods, as well as the composition of traditional and
cutoffs set within the 95% CI of the TEE based on the formula indigenous foods, are still insufficient (43,44).

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 Moreover, the composition of natural foods shows a wide group in randomized controlled intervention trials. This leaves
variability related to geographical and weather conditions, testing the effects of supplementation with a nutrient on the
cultivation techniques, and crop varieties. In prepared foods, candidate biomarker as the approach of choice (51,52). How-
differences in recipes add additional complexity (45). ever, in many cases, effects are observed in depleted but much
With regards to assessing the nutritional status of individ- less in adequately supplied individuals, reducing the value of
uals, additional difficulties arise from the fact that the refer- the biomarker to detect marginal status.
ence values for nutrient intake do not necessarily correspond The choice of biomarker is strongly influenced by the study
to one’s individual nutritional needs. In fact, most of these objectives. For large-scale nutrition surveys, factors such as
values, such as the RDA for the U.S. population, the reference cost, technical and personnel requirements, feasibility, and
nutrient intake for the UK population, and the reference participants’ burden are more important determinants than
values for nutrient intake (Zufuhrempfehlungen) of the in clinical intervention studies with smaller sample sizes.
German-speaking countries, are based on the estimated me- Measuring nutrient concentrations in blood or urine is a
dian requirement (estimated average requirement) of a given widely used method for status assessment because these sam-
collective of healthy individuals to which the equivalent of 2 ples are easy obtained. However, blood concentrations of
SDs is added. For nutrients for which requirements are not many nutrients, especially those involved in regulatory mech-
normally distributed within a population, the SD is replaced anisms such as calcium, zinc, and retinol, are maintained
by a CV of 20–30%. In this way, the requirements of 97.5% of within narrow ranges regardless of body stores (53,54).
the population are covered, but an inadequate supply would Changes in blood concentrations of such nutrients only occur
be expected in 2.5% of the population (2,46,47). In this in progressed/severe deficiency states. In other cases, like for
case, but also at population level, more accurate results re- carotenoids, they can vary markedly because of a short half-
quire the use of biochemical markers of nutrient status. life and depending on recent intake (55). Moreover, conditions
such as acute infections or stress can influence serum concen-
Nutritional biomarkers: criteria for development and trations of some nutrients, such as zinc (56). Concentrations
selection. A nutritional biomarker is a biochemical indica- in other tissues, such as cell membranes, fat tissue, or bone,
tor of intake and/or status of a given nutrient or food com- fluctuate less, which gives a better view of long-term supply.
ponent. Status markers are direct markers of past exposure. Unfortunately, some of these samples are difficult to obtain.
In turn, functional markers reflect an effect of a nutrient or For the assessment of the status of long-chain PUFAs, the con-
its absence. As such, some of them can also act as interme- centration in membrane phospholipids measured in erythro-
diate markers for future disease risk (36,37). cytes or whole blood were identified as better biomarkers of
The development of a nutritional biomarker for a specific long-term exposure than plasma concentrations (57,58).
nutrient is in most cases based on what is known about the Moreover, suboptimal nutrient intake over a longer time
chemistry, absorption, distribution in the body, and metab- can affect specific physiologic functions, such as activities of
olism of the latter. enzymes with nutrients as cofactors, which can serve as
With recent advances in metabolomic techniques enabling functional biomarkers (49).
the simultaneous measurement of several analytes and large An overview of plasma concentrations and examples of
sample amounts, the search for biomarkers can also follow a functional biomarkers for some micronutrients is given in
more inductive approach in that metabolites found in the sam- Table 1.
ple are examined for their suitability as biomarkers (48).
The search for nutritional biomarkers requires well-controlled Biomarkers complement dietary assessment. In the Aus-
dietary intervention designs to minimize potential confounding trian Nutrition Report 2012 (59), activity of erythrocyte gluta-
factors and a careful validation of the candidate markers, espe- mic oxaloacetic transaminase, a functional marker of vitamin
cially regarding dose–response effects and their specificity, sensi- B-6 status, better reflected the intake of this nutrient than the
tivity, and suitability for various population subgroups (37). plasma concentration of pyridoxal phosphate, especially in
However, although biomarkers allow a more objective as- adults younger than 65 y. Plasma concentrations were adequate
sessment of nutrient status, the fact that the effects of dietary in >80% of adults and elderly and 99% of children, whereas in-
compounds on body functions are generally more subtle and take was below the recommended amounts in 18% of male and
less clearly delimitable than those seen after drug administra- 32% of female children, ~40% of adults, and approximately
tion makes them less efficient than biomarkers used in drug half of the elderly. In turn, erythrocyte glutamic oxaloacetic
trials. For instance, marginal deficiency states are generally transaminase activity suggested a deficient status in ~40%
not associated with manifest clinical symptoms, which makes of children and adult men, 55% of adult women, and 22%
their detection much more challenging than that of a single and 26% of elderly women and men, respectively.
drug effect. Indeed, the absence of severe deficiency signs The importance of biomarkers for status assessment was
does not exclude detrimental effects on the body, underscoring also seen for folate in the Austrian Nutrition Report 2012, a
the importance of early diagnosis (49,50). This hierarchy of ef- national nutrition survey conducted in a representative sample
fects of nutrient deficiency on the body is depicted in Figure 1. of 1002 individuals from various age groups (59). Although
Moreover, testing biomarkers for essential nutrients limits 94–100% of the participants across all age groups did not
the possibilities to include a nonexposed human control reach the then-recommended intake value of 400 mg/d,

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 FIGURE 1 Hierarchy of biomarkers of the
nutrient status of the body. Ca, calcium; Fe,
iron; Zn, zinc.

70–80% of children and adults and almost 70% of the elderly and the risk of cardiovascular and other metabolic and auto-
had adequate plasma concentrations of this vitamin. Homo- immune diseases, benefits from higher concentrations in the
cysteine concentrations were higher in individuals with lower healthy general population were not shown unequivocally
folic acid plasma concentrations, confirming the suitability of (61,62). Furthermore, serum concentrations below the ref-
this metabolite as a biomarker for folate, although it is also erence range are not necessarily associated with deficiency.
associated with vitamin B-12 and vitamin B-6 (59). Thus, African Americans have on average lower serum
Comparable discrepancies between the status assessed 25(OH)D3 concentrations than their white counterparts,
from dietary intake and the biochemical status were also re- but the prevalence of osteoporosis and the occurrence of fra-
ported from other countries. Thus, although according to the gility fractures are also lower (63). To define optimal ranges
NHANES the majority of the U.S. population does not meet for serum 25(OH)D3 concentrations for different popula-
the estimated average requirement, the biochemical status tion groups, additional randomized controlled trials are
based on serum a-tocopherol was deficient in <1% in the warranted, taking into account ethnic differences and the in-
Second National Report on Biochemical Indicators of Diet fluence of age-, gender-, and disease-related aspects (61,62).
and Nutrition in the U.S. Population 2012 (60). As discussed Correct reference ranges and validated sensitive and spe-
above, a possible explanation lies in the selective underre- cific biomarkers also reduce the risk of measurement errors
porting of fat-rich food that is the major source of vitamin E. and misclassification that can negatively influence the inter-
pretation of a study outcome.

The Importance of Reference Ranges The influence of genetic variability and differences between
The correct interpretation of biomarkers requires well- nutrient forms. Not only in the case of vitamin D are bio-
defined reference values for the respective marker. However, markers of nutritional status influenced by an individual’s
in many cases, there is still a lack of consensus on the normal genetic makeup. Genes involved in the absorption and me-
range in healthy adequately supplied individuals. An example tabolism of nutrients and other food components determine
that received much attention recently is vitamin D. Although the concentrations of these compounds in various body tis-
serum concentration of 25-hydroxy vitamin D3 [25(OH)D3] sues. This was shown for single nucleotide polymorphisms
is widely acknowledged as a valid biomarker for vitamin D in genes involved in the absorption, transport, and metabo-
status that reflects dietary intake and endogenous synthesis, lism of fat-soluble vitamins, such as genes for apoA, apoB,
the optimal range of this variable is still the matter of debate. and apoE, as well as lipoprotein lipase, scavenger-receptor class
Cutoffs for deficiency are generally set between 25 and B type I (SR-BI), and carotene oxygenases that were related to
50 nmol/L (10–20 ng/dL) based on the effects on calcium and plasma concentrations of a- and g-tocopherol, a- and b-
phosphate metabolism and bone health. However, with the carotene, lycopene, and b-cryptoxanthin and the response
emergence of new physiologic roles for vitamin D, questions to their dietary intake (64,65).
about the optimal range arose. Although some evidence exists Genetic variations also cause differences in nutrient re-
for associations between 25(OH)D3 serum concentrations quirements, such as the C677T polymorphism in the methylene

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 TABLE 1 Overview of the plasma concentrations and examples of functional biomarkers (nonexhaustive) for selected micronutrients1
Plasma concentration cutoffs
for status assessment Functional biomarkers Clinical signs of deficiency
Vitamin A
.1.05 μmol/L, normal Retinol-binding protein Night blindness, xerophthalmia, anemia
,0.7 μmol/L, markedly deficient
Vitamin D [as 25(OH)D3]
.50 nmol/L, desirable Alkaline phosphatase activity; Decline of bone density, rickets in children, osteomalacia in
,25 nmol/L, deficient serum osteocalcin adults, disturbed immune function
Vitamin B-6 (as pyridoxal phosphate)
.30 nmol/L, normal a-EGOT activity Rare; neurologic symptoms, seborrhea, dermatitis, eczema,
,20 nmol/L, deficient cheilosis, anemia (microcytic, hypochromic)
Folate (as folic acid)
$13.4 nmol/L, normal HCys, urinary excretion of FIGLU Anemia (macrocytic, hyperchromic), cheilosis, glossitis,
,6.8 nmol/L, markedly deficient neurologic symptoms in elderly, higher risk of cardiovas-
In erythrocytes: cular diseases (through HCys)
$356 nmol/L, normal
,317 nmol/L, deficient
Vitamin B-12
$147 pmol/L, normal HCys, methylmalonic acid Anemia (macrocytic, hyperchromic), neurologic symptoms
,110 nmol/L, markedly deficient
Calcium
Excretion in urine, 2.5–6.0 mmol/d, normal Excretion of hydroxyproline in urine Decline of bone density, osteoporosis, rickets in children,
osteomalacia in adults
Iron
Ferritin $15 μg/L, normal Hemoglobin, hematocrit, total iron Anemia (microcytic, hypochromic)
$12 μg/L (in children aged ,5 y), normal binding capacity
Zinc
Adults Activity of zinc superoxide dismutase, Growth retardation in children, disturbed immune function
13–19 μmol/L, normal zinc binding capacity in thalassemia (especially cellular), reduced glucose tolerance, skin
,11.5 μmol/L, deficient lesions, impaired wound healing
Children
,10 y: ,9.9 μmol/L, deficient
Pregnant women
Trimester 1: ,8.6 μmol/L, deficient
Trimester 2: 7.6 μmol/L, deficient
1
Based on data from references 49,79. α-EGOT, erythrocyte α-glutamate oxaloacetate transferase; FIGLE, formiminoglutamic acid; HCy, homocysteine.

tetrahydrofolate reductase (MTHFR) gene, resulting in a less equivalents that comprise all vitamers as far as these are
active enzyme and an association with a higher risk of neural measured. With regards to the special properties of non-
tube defects and cardiovascular disease (66). Because MTHFR a-tocopherol forms, a better differentiation seems advisable.
provides 5-methyl tetrahydrofolate as a methyl donor for the
reconversion of homocysteine to methionine, the lower activ- New nutritional biomarkers: the potential role of immune
ity of the mutant MTHFR can be compensated by higher fo- functions and gene expression. Advances in molecular bi-
late intake (66). ology extended our insights in the physiology of nutrients,
Another aspect to consider is the fact that nutrients occur thus offering new potential biomarkers of their status. In-
in different forms in food and in the body. These isomers deed, vitamins and minerals, but also FAs, especially PUFAs,
generally differ in their biologic activity, calling for conver- and amino acids can influence gene expression and cell pro-
sion factors to define equivalents. Although a single form liferation, and this has a particular impact on highly prolifer-
may reflect total body stores adequately [such as 25(OH) ating cells such as those of the immune system. Thus, it was
D3 for vitamin D], isoforms can differ in their effects. An reported that deficiency of trace elements, especially zinc and
example of this is vitamin E, because special functions of copper, was associated with reduced secretion of mediators,
g-tocopherol and the tocotrienols are emerging that are such as IL-2, IL-1b, and TNF-a, after mitogenic stimulation.
not observed with a-tocopherol, the major bioactive form Notably, a decrease of IL-2 secretion was already observed af-
(67). In some studies, g-tocopherol proved to be a more po- ter marginal copper deficiency (56,69). In turn, supplemen-
tent anticancerogenic agent than a-tocopherol, an effect that tation with zinc increased the stimulated secretion of IL-1b,
may be due to its better ability to scavenge reactive nitrogen IFN-g, and TNF-a (70). However, although cytokines and other
species. Being more hydrophilic than a-tocopherol, it exerts immune function markers may be sensitive markers of nutrient
its antioxidant effects in a complimentary way in other cell deficiency, they are rather unspecific (70).
compartments (67). Although studies are less abundant than In the case of zinc, recent studies identified some potential
for a-tocopherol, tocotrienols also showed positive effects markers, such as changes in zinc absorption and expression
on health and the prevention of diseases (68). So far, vitamin of zinc transporters and the storage protein metallothionein
E status is generally assessed on the basis of a-tocopherol (70,71). It was reported that zinc absorption is more influenced

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 by current zinc intake than by long-term intake. In fact, al- a promising marker of fruit and vegetable consumption.
though total absorption increases with higher intakes, the op- However, the high costs of some of these markers, such as
posite is seen for percentage absorption rate (72,73). This the double-labeled water method, limit their use, so that there
makes nutrient transporters and storage proteins promising is a need for biomarkers applicable to large sample sizes that
candidate biomarkers. are not overly expensive while still offering a high sensitivity
Because sufficient micronutrient supply, especially of anti- and specificity. Although the determination in plasma or
oxidants and compounds involved in DNA synthesis, is neces- spot urine samples has a high practicability, the concentrations
sary for DNA stability, maintenance, and repair, chromosomal of many nutrients in these media show a high variability.
damage may also serve as a biomarker of nutritional status. In- This underscores the interest in markers from other tis-
deed, oxidative stress is a major cause of DNA damage, whereas sues or functional biomarkers showing less fluctuation.
folate provides methyl groups for the conversion of uracil to The fact that functional markers of nutrient status are of-
thymine and the maintenance of CpG methylation in DNA. ten also indicators of a higher risk of certain diseases, such as
In turn, minerals such as zinc, iron, and magnesium are cofac- hyperhomocysteinemia and cardiovascular risk or DNA
tors or components of DNA repair enzymes. Correlations be- damage and cancer risk, adds to their value. New analytical
tween markers of DNA damage, such as the formation of techniques, especially at the molecular level, offer a multi-
micronuclei and micronutrient status (folate, vitamin B-12, tude of potential biomarkers from the fields of immunology
iron), were shown in humans (74,75). and gene expression. However, although these markers are
Another relation between nutrients and the genome is very sensitive, they often lack specificity, so that a combina-
through epigenetic mechanisms, especially with the avail- tion of several biomarkers is advisable to differentiate be-
ability of nutrients that provide C1 units, needed for meth- tween micronutrients.
ylation. This was shown by Wolff et al. (76) who reported There is also a need to optimize the use of existing bio-
overexpression of the agouti gene and development of obe- markers especially by taking biologic/genetic variability into
sity, hyperinsulinemia, higher cancer susceptibility, and re- account. This also applies to reference ranges that can differ
duced life expectancy in mice exposed to methyl-deficient depending on age, gender, and ethnic background. In partic-
diets in utero. These changes were associated with altered ular, there is a lack of specific reference values for children
methylation of the agouti gene (77). The Dutch Hunger and the elderly.
Winter Study revealed epigenetic effects of nutrient status Advances in analytical procedures especially at the molec-
in humans as well: individuals whose mothers were exposed ular level will help in the development of new accurate and
to famine during pregnancy had altered methylation pat- precise biomarkers that are inexpensive and easily applicable
terns of regulative loci of candidate genes associated with even on large samples at the population level.
metabolic and cardiovascular diseases compared with their
siblings that developed under normal conditions (78). Acknowledgments
With all these potential biomarkers, difficulties arise from Both authors read and approved the final manuscript.
the fact that immune functions and gene and protein expres-
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