Micronutrients in Neurology and Disease

Clinical Nutrition 43 (2024) 268e283
Contents lists available at ScienceDirect
Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu
ESPEN Endorsed Recommendation
The science of micronutrients in clinical practice e Report on the

ESPEN symposium*
Mette M. Berger a, *, Karin Amrein b, Rocco Barazzoni c, Laure Bindels d, Irene Breto n e,
Philip C. Calder f, Stefano Cappa g, Cristina Cuerda h, Patrizia D'Amelio i,
Angelique de Man j, Nathalie M. Delzenne k, Alastair Forbes l, Laurence Genton m,
Adrian F. Gombart n, Francisca Joly o, Alessandro Laviano p, Christophe Matthys q,
Pyi Pyi Phyo r, Paula Ravasco s, Mireille J. Serlie t, Alan Shenkin u, Nicole U. Stoffel v, w,
Dinesh Talwar x, Arthur R.H. van Zanten y
a
Lausanne University, Faculty of Biology & Medicine, 1005 Lausanne, Switzerland
b
Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
c
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
d
Faculty of Pharmacy and Biomedical Sciences, Louvain Drug Research Institute, Universit e Catholique de Louvain, Brussels, Belgium
e
Nutrition Unit, Hospital General Universitario Gregorio Maran ~o
n, Madrid, Spain
f
School of Human Development and Health, Faculty of Medicine, University of Southampton and NIHR Southampton Biomedical Research Centre,
University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
g
IUSS Cognitive Neuroscience (ICoN) Center, University School for Advanced Studies (IUSS-Pavia), 27100 Pavia, Italy
h
Departamento de Medicina, Universidad Complutense de Madrid, Nutrition Unit, Hospital General Universitario Gregorio Maran ~on, Madrid, Spain
i
Service de g eriatrie et r
eadaptation g
eriatrique, D
epartement de M edecine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
j
Department of Intensive Care Medicine, Research VUMC Intensive Care, Amsterdam Cardiovascular Science, Amsterdam Infection and Immunity Institute,
Amsterdam, the Netherlands
k
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Universit e Catholique de Louvain, Brussels, Belgium
l
Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
m
Clinical Nutrition Unit, Department of Endocrinology, Geneva University Hospitals, Geneva, Switzerland
n
Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
o
Beaujon Hospital, APHP, Clichy, University of Paris VII, France
p
Department of Translational and Precision Medicine, University La Sapienza, Rome, Italy
q
Human Nutrition, KU Leuven, Leuven, Belgium
r
WHO European Office for the Prevention and Control of Noncommunicable Diseases, WHO Regional Office for Europe, Copenhagen, Denmark
s lica Medical School, Lisbon, Portugal
Coordinator of the Curricular Units Diabetes, Obesity and Lifestyle, Digestion and Defence, University of Lisbon - Cato
t
Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands
u
Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, UK
v
Laboratory of Human Nutrition, Department of Health Sciences and Technology, ETH Zurich, Switzerland
w
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
x
Department of Biochemistry, Glasgow Royal Infirmary, Glasgow, UK
y
Gelderse Vallei Hospital, Ede and Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
*
WHO Disclaimer: WHO authors alone are responsible for the views expressed in this article, and they do not necessarily represent the views, decisions, or policies of the
WHO or institutions with which they are affiliated.
* Corresponding author. Lausanne University, Faculty of Biology & Medicine, 1011 Lausanne, Switzerland.
E-mail addresses: mette.berger@unil.ch (M.M. Berger), karin.amrein@medunigraz.at (K. Amrein), barazzon@units.it (R. Barazzoni), laure.bindels@uclouvain.be (L. Bindels),
irenebreton@gmail.com (I. Breto n), P.C.Calder@soton.ac.uk (P.C. Calder), stefano.cappa@iusspavia.it (S. Cappa), cuerda.cristina@gmail.com (C. Cuerda), Patrizia.DAmelio@chuv.
ch (P. D'Amelio), ame.deman@amsterdamumc.nl (A. de Man), nathalie.delzenne@uclouvain.be (N.M. Delzenne), alastair.forbes@ut.ee (A. Forbes), Laurence.Genton@hcuge.ch
(L. Genton), adrian.gombart@oregonstate.edu (A.F. Gombart), Francisca.joly@aphp.fr (F. Joly), alessandro.laviano@uniroma1.it (A. Laviano), christophe.matthys@uzleuven.be
(C. Matthys), phyop@who.int (P.P. Phyo), pravasco@ucp.pt (P. Ravasco), m.j.selie@amsterdamumc.nl (M.J. Serlie), shenkin@liverpool.ac.uk (A. Shenkin), nicole.stoffel@hest.
ethz.ch (N.U. Stoffel), dinesh.talwar@ggc.scot.nhs.uk (D. Talwar), zantena@zgv.nl (A.R.H. van Zanten).
https://doi.org/10.1016/j.clnu.2023.12.006
0261-5614/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
M.M. Berger, K. Amrein, R. Barazzoni et al. Clinical Nutrition 43 (2024) 268e283
a r t i c l e i n f o s u m m a r y
Article history: Background & aims: The European Society for Clinical Nutrition and Metabolism published its first
Received 5 November 2023 clinical guidelines for use of micronutrients (MNs) in 2022. A two-day web symposium was organized in
Accepted 7 December 2023 November 2022 discussing how to apply the guidelines in clinical practice. The present paper reports the
main findings of this symposium.
Keywords: Methods: Current evidence was discussed, the first day being devoted to clarifying the biology under-
Trace element
lying the guidelines, especially regarding the definition of deficiency, the impact of inflammation, and the
Vitamin
roles in antioxidant defences and immunity. The second day focused on clinical situations with high
Deficiency
Epidemiology
prevalence of MN depletion and deficiency.
Immunity Results: The importance of the determination of MN status in patients at risk and diagnosis of de-
Inflammation ficiencies is still insufficiently perceived, considering the essential role of MNs in immune and antioxi-
dant defences. Epidemiological data show that deficiencies of several MNs (iron, iodine, vitamin D) are a
global problem that affects human health and well-being including immune responses such as to
vaccination. Clinical conditions frequently associated with MN deficiencies were discussed including
cancer, obesity with impact of bariatric surgery, diseases of the gastrointestinal tract, critical illness, and
aging. In all these conditions, MN deficiency is associated with worsening of outcomes. The recurrent
problem of shortage of MN products, but also lack of individual MN-products is a worldwide problem.
Conclusion: Despite important progress in epidemiology and clinical nutrition, numerous gaps in prac-
tice persist. MN depletion and deficiency are frequently insufficiently searched for in clinical conditions,
leading to inadequate treatment. The symposium concluded that more research and continued education
are required to improve patient outcome.
© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
1. Introduction 3. C-reactive protein (CRP) should be determined at the same time

as any micronutrient analysis (alternatives to CRP may be
In November 2022, The European Society for Clinical Nutrition Interleukin-6 or a-acid glycoprotein, but not hs-CRP)
and Metabolism (ESPEN) organised a web symposium aiming at
clarifying the application of its recent micronutrient (MN) guide- As the PICO (Patient, Intervention, Comparison, Outcome) ques-
lines [1] in clinical practice. During the first day, the symposium tion strategy could not be applied to all MNs, the most common
focused on the fundamental physiology of MNs, while the second pathologies seen in patients at high risk of MN deficiencies were
day was oriented towards their clinical application in a selection of listed while providing a systematic approach to the individual MNs.
conditions including cancer, obesity with impact of bariatric sur- For each of them, the relevant section of the guidelines summarized
gery, diseases of the gastrointestinal tract, critical illness, and aging: the main functions, the needs, the biomarkers with recommended
The present papers summarise the different lectures and the dis- analytical methods, the impact of inflammation, the consequences of
cussion from the symposium. deficiency, toxicity, and recommendations about measurement and
doses used for standard nutrition and treatment of deficiency.
1.1. Aims of the ESPEN micronutrient guideline 1.2. Status assessment
Micronutrients i.e., trace elements and vitamins, are essential To orient therapy, MN status assessment may be required as a
components of nutrition, but precise knowledge regarding their baseline assessment upon initiation of MNT or after a long period of
use in clinical settings is not widespread. To assist clinicians in the inadequate intake [1]. Such assessment requires a combination of
identification of specific MN needs and administration as part of history, examination, and laboratory tests. Initially, it also requires
medical nutrition therapy (MNT), the ESPEN MN guidelines were an assessment of recent intake and probable losses, and careful
published in 2022 [1]. They aimed at providing practical informa- examination for traditional signs of MN deficiency.
tion about the assessment of MN status and the prescription of the Biological alterations affecting metabolism may result from MN
different MNs, while attracting attention to specific MN needs in deficiencies and may become apparent before the classical signs of
patients receiving enteral nutrition (EN) or parenteral nutrition deficiency are seen. Examples are increasing blood homocysteine
(PN). The guidelines also aimed at contextualizing the population may reflect folate deficiency, methylmalonic acid that of vitamin B12,
needs formulated as recommended dietary allowances (RDAs) or the excretion of organic acids biotin deficiency, or for molybdenum
the more recent dietary reference intakes (DRIs) and needs in deficiency urinary sulphite, blood xanthine or hypoxanthine.
disease. Glucose intolerance may be a manifestation of chromium deficiency.
An important part of the MN guidelines focused on language Blood testing has numerous pre-analytic caveats such as correct
standardization (Table 1). sampling (e.g. lack of residual infusion or oral intake, lack of
The first three general recommendations of the guidelines apply contamination from needle or tube), or correct timing (e.g. there is
to all MNs: a peak of plasma zinc and iron in the early morning) [2]. Using
validated analytical methods of analysis is essential. For trace ele-
1. Adequate amounts of all essential trace elements and vitamins ments inductively coupled plasma mass spectrometry (ICP-MS) is
shall be supplied to all patients receiving medical nutrition from now the most used and accurate method, with the use of an
the beginning of the period of nutritional support. internationally agreed reference material. For vitamins there is a
2. Micronutrient supplements shall be provided orally or enterally greater variety in methods, many using high performance liquid
if this can be done safely and effectively. chromatography (HPLC) or mass spectrometry e however
269
Table 1
The language defining micronutrient status and prescription.
Status ESPEN definition and comment
Optimal status Intake meets losses; tissue and metabolic functions are optimized (although the latter can be difficult to assess)
Adequate Intake meets losses; plasma concentrations are normal in the absence of inflammation
Depletion Intake does not meet losses or plasma concentrations are low; no physical or metabolic signs of inadequacy are observable
Deficiency Intake does not meet losses or plasma concentrations are low; physical or metabolic signs of inadequacy are present
Toxicity History of inadequate high intakes; blood levels are in the toxic range; presence of clinical signs or symptoms of toxicity
Prescription
Complement Delivery of MNs to cover basal needs, e.g. to complete enteral feeds, such as during insufficient EN [2,3]
Repletion Doses aiming to restore the normal status and where the deficit is known. Sometimes called supplementation when the doses
required to restore status are very high
Supplementation Term used when the aim is to deliver higher than standard doses (i.e. superior to DRI or PN recommendation).
The term does not include pharmaco-nutrition.
interlaboratory comparisons are more difficult because of the lack sensitivity and specificity of blood levels can be problematic in
of an international standard. All laboratories should establish their disease. For some MNs, plasma levels fall only when tissue stores
own appropriate and validated reference ranges. are significantly depleted as for vitamin A. In addition, most MN
Nevertheless, plasma (or serum) concentrations of MNs only functions occur within cells. Plasma concentrations are therefore
reflect extracellular fluid which does not necessarily correlate with indirect and relatively insensitive indicators of status which is
intracellular concentration or functionality. There are alternatives poorly reflected by extra-cellular fluid levels.
to plasma measurements, such as red blood cells (RBCs) for vita- Furthermore, many factors can influence blood levels, inflam-
mins B1, B2, B6, and folate (vitamin B9) and for manganese, sele- mation being preponderant. Part of the response to disease, injury
nium and zinc: these methods are more reliable than plasma. For or infection is the acute phase response (APR), which causes many
vitamin C, leukocytes may be used, while urine collection is used carrier proteins to decline in plasma, these being called negative
for iodine and fluoride. Enzyme activities can be useful biomarkers APR proteins. The effect is to lower the plasma levels of many MNs.
of status, as they reflect functions such as plasma or RBC gluta- Thus, the APR may affect plasma levels independently of tissue
thione peroxidase for selenium, RBC transketolase for vitamin B1, status, as the plasma levels of several MNs fall due to the redistri-
or transaminase for vitamin B6. bution of their binding proteins and uptake by the tissues, making
For a few MNs, the binding and storage proteins may guide plasma levels unreliable indicators of their status.
status assessment: this is the case for iron with transferrin, the In acute inflammation, resulting from even minor physiological
soluble receptor of transferrin, ferritin and hepcidin. Copper status events [3], plasma MN levels can fall transiently by as much as 50 %
assessment is supported by plasma caeruloplasmin, while selenium and tend to normalize without dietary interventions as inflam-
adequacy is defined by the level of selenoprotein P. Holo- mation begins to resolve (Fig. 1). The inflammation-related alter-
transcobalamin reflects Vitamin B12 status. ations start within hours [4].
Each centre should define its own approach using the available This decrease is mainly due to inflammation-driven redistribu-
resources to obtain the most accurate assessment of the combi- tion, and increased cellular uptake (liver, immune cells) and
nation of history, examination, and laboratory testing. excretion; eventual loss can also contribute. It is not possible to
quantify the relative contribution of these different mechanisms on
1.3. Impact of inflammation the basis of plasma MN concentrations.
In chronic inflammation, triggers and causes are multifactorial:
Blood level determination assumes that blood reflects tissue dietary factors, consumption factors and losses will combine,
stores and status, which is not necessarily true. Blood concentra- complicating the assessment. Alternative biomarkers, not or less
tions may be sufficient to indicate frank deficiency or toxicity, but affected by inflammation, will assist in the determination of some
Fig. 1. Status of fat-soluble vitamins and CRP (A) and water-soluble vitamins, albumin and CRP (B) in the days after knee arthroplasty. CRP concentrations peaks at day 2,
accompanied by a transient fall in the plasma level of fat-soluble vitamins (up to 60 %). Similarly, for some of the water-soluble vitamins (e.g. B2 and B6), there is a transient fall of
about 50 % in plasma concentrations at day 2 when the CRP concentration peaks and then a tendency to normalise as inflammation resolves.
270
MNs [2]. Such are available for copper, iron, selenium, and B vita- of endotoxin, use of UV irradiation, or the use of exercise, a high fat
mins (see above). In some cases, plasma MN levels can be corrected meal or a high sugar meal (or drink) with serial blood collection in
to their carrier process (protein, lipoproteins) such as with the the period afterwards. The combination of high dose vitamin E and
vitamin E/cholesterol ratio, vitamin K/triglyceride ratio and zinc/ vitamin C was found to blunt the rise in the concentrations of in-
albumin ratio. Therefore, accurate and reliable MN status de- flammatory cytokines and adhesion molecules that was seen in the
terminations require a systematic structured approach. blood of diabetics following consumption of high fat and high
carbohydrate meals [14]. Although dose is important, there is
2. Immunity and oxidative stress insufficient information about the doseeresponse relationship
between antioxidant vitamins in humans and the inflammatory
2.1. Oxidative stress and inflammation response, and also about effects across the range of possible target
groups.
Inflammation is part of the host defence response; it is initiated
by exposure to triggers (infection, damaged tissue etc.) that activate 2.2. Immunity & infectious diseases
the inflammatory response that is manifested by cellular move-
ment, cellular activation, and the production of a multitude of MNs play key roles in every step of the immune response [15].
chemical mediators. Cellular activation, cell phenotype and chem- Viral, bacterial and parasitic diseases are all worsened by MN de-
ical mediators can all be assessed as a means to diagnose and ficiencies due to multiple adverse effects on immune function. MN
monitor inflammation [5]. In this regard, total white cell count, deficiencies are widespread and compromise not only the immune
acute phase proteins such as CRP and cytokines such as interleukin- system (amongst others), but they hinder child growth and
6 (IL-6) are commonly measured. Inflammation should be self- development. MN deficiency is a worldwide issue, as shown by a
limiting (self-resolving); resolution is an active process [6]. Loss survey including 22 countries demonstrating that globally 372
of resolution results in persistent inflammation that can become million preschool-aged children and 1$2 billion (1$0e1$4) non-
damaging to the host, causing significant pathology (Fig. 2). Chronic pregnant women of reproductive age (15e49 years) had one or
high-grade inflammation is causally linked to overt inflammatory more MN deficiencies [16]. MNs with low status include vitamin D,
and autoimmune conditions such as rheumatoid arthritis, inflam- vitamin B12, folate, vitamin A, iron, and zinc, and these are often
matory bowel disease and asthma as well as to sepsis [7]. Chronic combined. Such deficiency is associated with exacerbation of
low-grade inflammation is a risk factor for common non- existing illness, especially infectious diseases, but also impaired
communicable conditions such as cardiovascular disease, type-2 mental and physical development.
diabetes, and cognitive decline and is linked to loss of muscle and Among the MNs, selenium, iron, zinc and vitamins A, C and D are
bone mass and to many cancers [5,7]. Chronic low-grade inflam- in the first line of defence, as the body's physical barriers, i.e. the
mation increases with age [8] and with obesity [9]. There is a skin and respiratory epithelium, are totally dependent on these
bidirectional interaction between oxidative stress and inflamma- MNs for integrity [15]. Therefore it is not surprising that MN sup-
tion in that oxidative stress can induce inflammation, for example plements, particularly vitamins C and D, reduce the risk of respi-
by activating the nuclear factor kappa-light-chain-enhancer of ratory infections as shown in various meta-analyses, and may even
activated B cells (NFkB) pathway, while inflammation induces shorten an active respiratory tract infection when used as therapy
oxidative stress as part of host defence. [17].
Therefore, at least in theory, antioxidants can reduce inflam- To ensure an optimal immune response against viral infections
mation. This is evident in preclinical cell culture and animal models. requires sufficient intake of MNs [18]. Already in 2001, Beck showed
There is also some evidence from human trials and systematic re- in a mouse model [19] that increased oxidative stress of a host due
views of randomized controlled trials (RCTs) find that vitamins C to selenium deficiency can lead to changes in the genome of some
and E decrease circulating CRP and inflammatory cytokine con- viruses suggesting that host nutritional status may be an important
centrations [10e13]. Such effects are dependent upon dose, dura- mechanism for the development of emerging viral variants with
tion and type of patient studied. Such studies usually measure new pathogenic properties.
inflammatory markers in blood collected before and after a period Evidence in favour of MN supplements reducing the risk of acute
of supplementation; participants are usually in a resting state when infection does exist, with different levels of evidence (Table 2)
the blood is collected. However controlled challenges can be used supporting the rationale of adequate MN status. The odds of
to assess the effect of an intervention on the dynamics of the in- tuberculosis (TB) increase with deficiencies in vitamin A and zinc,
flammatory response; such challenges include the administration which are frequent in several low- and middle-oncome countries
Fig. 2. Differences between a self-limiting inflammation and a chronic high- or low-grade non-resolving inflammation.
271
Table 2
Effects of supplements on reducing the risk of acute infections.
Micronutrient Disease impact Level of evidence
Vitamin A Increased risk of measles and diarrhea in children Low-to-moderate quality

Vitamin C Decreased cold incidence (>50 %) High quality
Decreased pneumonia in adults and children Low-to-moderate quality
Lower risk of UTI in pregnancy (100 mg) Low-to-moderate quality
Vitamin D Decreased risk of RTIs (daily supplementation optimal) 5 meta-analyses, most high quality
Zinc Decreased risk of ear infections in children, RTI, pneumonia, diarrhea High quality
Multi-vitamin and mineral supplement Fewer Infections in young adults, Low-to-moderate quality
Fewer days of infection in older adults
Most apparent in undernourished >6 months
Abbreviations: UTI ¼ urinary tract infection, RTI ¼ respiratory tract infection.
[20]. TB can be present alone or as coinfection in HIV patients. A RCT Recent studies suggest that iron deficiency not only causes
conducted in Botswana showed that the administration of sele- anemia but may also weaken the immune system. Activated im-
nium alone or in combination with multivitamins to these patients mune cells need high amounts of iron to produce antibodies in
significantly lowered the risk of developing incident TB [17]. In response to vaccines. Iron deficient immune cells proliferate poorly
critical illness also, MN deficiencies favour infections that are pre- and have decreased antibody production [28].
vented/treated by repletion of copper, selenium and zinc as in In a recent birth cohort study, 573 Kenyan infants were followed
burns, with reduction of nosocomial pneumonia [21]. for two years. Infants received polio, DTP (diphtheria, pertussis,
For therapeutic interventions, the evidence is weaker, except for polio), haemophilus and pneumococcal vaccines at 6, 10 and 14
vitamin C regarding severity and duration of common cold symp- weeks of age. Iron status was measured at time of vaccination and
toms [17,18]. Increased intake of vitamin C during the onset of vaccine response was measured at 6 and 18 months. Iron deficiency
illness may also provide added benefit [22]. There are also some and low haemoglobin was the strongest predictor of poor response
benefits with vitamin D treatment in TB, influenza and upper res- to polio, diphtheria and pertussis vaccines [27]. Infants with anemia
piratory tract infections (RTIs) [18]. Zinc acetate doses >75 mg/day had five times the risk of measles vaccine failure and twice the risk
have been shown to efficiently shorten duration of common cold in of diphtheria vaccine failure.
adults and children if administered within 24 h of symptom onset In a secondary analysis of a previous RCT it was investigated
[23]. Zinc is efficient both in prevention and treatment of whether iron given at the time of measles vaccination improves the
diarrhea [24]. vaccine response. 127 iron deficient Kenyan infants received 12 mg
Among the vitamins, vitamin D is particularly important for iron or no iron from 7 to 11 months of age. All infants received the
innate immune function. When macrophages (and epithelial bar- measles vaccine at age 9 months. Infants receiving iron at the time
rier cells) encounter pathogens, they synthesize the active form of measles vaccination had a better primary vaccine response, with
calcitriol 1,25(OH)2D and upregulate vitamin-targeted genes like higher anti-measles antibodies, higher seroconversion rates and
the cathelicidin antimicrobial peptide (CAMP/hCAP-18 and LL37) also greater anti-measles IgG avidity [27].
which are important for the innate immune response to infection.
Low vitamin D status may be a modifiable risk factor for COVID-19. 3. Some specific MN issues
A recent systematic review and meta-analysis that included 72
observational studies showed vitamin D deficiency/insufficiency 3.1. Updating MN needs
increased the odds of developing COVID-19 (odds ratio [OR] 1.46;
P < 0.0001 %), severe disease (OR 1.90; P < 0.0001) and death (OR EURRECA (EURopean micronutrient RECommendations
2.07; P ¼ 0.003) [25]. Subsequently, another meta-analysis which Aligned) is a European network created several years ago to address
included 10 RCTs, and 16 observational studies, showed vitamin D the lack of a standard framework to determine MN recommenda-
supplementation may be associated with lower intubation rate and tions, causing confusion among consumers, producers and policy
shorter length of hospital stay, although it was not associated with makers. Having a standard framework for MN recommendation
any mortality reduction [19]. Vitamin C and zinc did not produce development represents the intakes judged sufficient to meet re-
such beneficial effects [26]. quirements of most healthy individuals within a population
The overall body of evidence emphasizes that improving MN group [29].
status through diet and complementing diet with supplements The steps encompass defining the nutrition-related health
represents a strategy to support the immune system and to reduce problem, defining the process, establishing robust methods,
risk and severity of infectious diseases. Rather than the use of MNs collating sources of evidence, and summarizing and integrating the
like drugs, we should ensure adequate MN intake to optimize im- evidence into recommendations. How to define the endpoints in
mune function and in the case of vitamin C and zinc, consider the determinations of the requirements was the first question that
increasing intake during the appearance of symptoms. considered public health importance, new evidence, and priority
populations, resulting in 28 MNs being identified for 6 different
2.3. Vaccination in children population groups. The second question addressed the issue of
translating requirements to recommendations, considering clinical
Vaccinating against paediatric infectious diseases saves 4e5 outcomes and based on dose response curves.
million lives every year, but these vaccines do not always work well The high prevalence of chronic disease and the relatively higher
in the context of malnutrition and MN deficiencies. Therefore MN needs to prevent them was integrated in the process aiming at
vaccines often underperform in low- and middle-income countries chronic disease risk reduction. These do not replace the DRI cate-
and leave 15e20 % of fully vaccinated children unprotected, gories which have been designed for the global population inde-
contributing to 1.5 million deaths every year from vaccine- pendent of disease, but change how evidence on chronic disease
preventable diseases [27]. risk is assessed and used to modulate the DRI process. A causal
272
relationship was needed for consideration. An example of the iodine status is required. The WHO European Regional Office in
intake response is observed with fibres which decrease risk of collaboration with IGN with the support of Kiwanis International is
disease and rarely have side effects: the balance between optimal developing an updated report on iodine deficiency in Europe (“A
value and deficiency is essential to consider when establishing DRI solution at our doorstep (Part A & B)”) in order to address the key
[30]. Different examples were discussed (omega-3 PUFA, iron) issues such as iodine status data in school-age children, women of
showing the importance of addressing the right population, generic reproductive age and pregnant women; an evidence-based evalu-
polymorphisms and inflammation. Questions are still open such as ation of the consequences of mild and moderate iodine deficiency
defining core outcome measures. in Europe to better define the magnitude of the problem; alterna-
tive sustainable strategies for monitoring iodine status; data on the
3.2. Iodine deficiency in Europe iodized salt distribution and the use of iodized salt in processed
food and alternatives strategies to tackle iodine deficiency inte-
WHO recommends sodium intakes of less than 2 g/day (less grating the regulatory heterogeneity.
than 5 g of salt) while recommending iodine intakes of 150 mg/ Salt reduction policies and salt iodization policies are
day for adults and adolescents (120 mg/day in children) compatible. Both require food industry engagement and similar
increasing to 250 mg/day for pregnant and lactating women. surveillance modalities. Continual monitoring to ensure consis-
Monitoring iodine intake is realised using spot urine samples, as tent delivery of iodine and to allow for adjustments in the
well as monitoring iodine content of foods. Data from 2007 amount of iodine added to salt is necessary in response to
showed that iodine intake was insufficient in 11 European decreased population sodium intake. The WHO is also working
countries, adequate in 20, and excessive in one country. The on updating the global MN database including iodine and
Iodine Global Network published data in 2021 (some rather old) reviewing current guidance around indicators for the assess-
showing insufficient intakes in several European countries ment of iodine status.
(Fig. 3): iodine deficiency remains a significant health and
socio-economic problem. The costs in terms of productivity are 3.3. Iron in clinical nutrition
likely to be significant but are yet unknown.
Salt fortification is the preferred strategy to deliver iodine, salt Iron has multiple functions beyond oxygen transport. Particu-
being a good vehicle for iodine, and the technology being efficient larly it is involved in immune function as previously discussed. Iron
and inexpensive. According to Iodine global network (IGN) data deficiency is a global public health issue, affecting most women, but
updated in 2016, use of iodized salt is voluntary in 17 countries and also children, adolescents, and older adults. Iron deficiency is a
mandatory in 26 countries, while 7 countries do not have legisla- factor complicating the clinical management of over 50 % of heart
tion on iodine requirements. Accelerating new data collection on failure patients [32].
Fig. 3. Selected national iodine intakes in the European region, with median urine concentrations (mg/L) in the general population based on those in school age children. WHO cut-
offs for children >6 yr: I < 50 mg/l moderate to severe deficiency, 50e99 mg/l insufficient, 100e199 mg/l adequate, 200e299 mg/l above needs, >300 mg/l excessive. Adapted from
WHO 2021 data [31].
273
A retrospective study from the Mayo clinic including 185 pa- The PN-products face a different problem: they are conceived as
tients on home PN, showed that 32.4 % were iron deficient [33]: one-size-fits-all. Therefore, monitoring at intervals is highly rec-
development of deficiency was a question of time, and was most ommended, particularly in home PN patients who depend on these
rapid in patients with intestinal fistulae and bowel obstruction. As preparations for prolonged periods and may not receive adequate
multi-trace element products containing iron were not available, amounts of MNs.
the clinicians had to add iron dextran as maintenance therapy.
The ESPEN guideline [1] strongly recommends assessing status 3.5. MN product availability and shortage
and ensuring that iron is delivered at nutritional doses during both
EN and PN. This has been the case in Europe for over 30 years. This With the publication of guidelines [1], MN administration
insistence is because in many non-European countries, the multi- should be considered part of standard care in patients dependent
trace element products available for PN do not contain iron, lead- on PN. However, not all countries benefit from a complete
ing to the inevitable development of anemia in patients dependent availability of multi-MN products providing the full range of
on PN [33], that compromises outcome. The guideline also rec- essential MNs [39]. Single intravenous trace element (copper,
ommends treating iron deficiency when diagnosed with the recent chromium, selenium, zinc) and vitamin products are non-existent
formulations of iron supplements as their use after the peak of in most countries, preventing individualised corrections of
inflammation has proven safe in randomised trials with signifi- deficiencies.
cantly higher haemoglobin levels [34] and even decreased mor- Historically, the multi-trace element and multi-vitamin prod-
tality [35]. When treating a patient, iron status is threatened by ucts were developed for adult patients on long-term PN. With the
disease, low intakes and poor absorption and is particularly difficult development during the 2 last decades of the use of multi-chamber
to assess in the presence of inflammation. Ferritin, a widely used bags which contain no MNs, the administration falls short of indi-
marker, is misleading because it increases sharply with inflam- vidual adaptation. The multi-MN products should ideally be
mation, being an acute phase response protein. administered separately, as they cannot be premixed for stability
Optimal iron deficiency diagnosis shall include a combination of reasons. Further, to facilitate administration, clinical teams tend to
tests: plasma iron, transferrin, transferrin saturation, ferritin, CRP, inject the MN products into these bags, often under questionable
soluble transferrin receptor (sTfR), hepcidin, and evaluation of red sterility conditions, with associated risks.
blood cell (RBC) morphology [1]. Hepcidin, while still not widely Further, shortage of MN products for intravenous use, especially
available, has been shown to be a reliable biomarker: sTfR is also vitamin preparations, has become a recurrent problem on all con-
only modestly affected by inflammation. tinents, exacerbated by the COVID-19 pandemic. An unpublished
ESPEN survey conducted in 2021 showed that 32 % of 52 intestinal
3.4. MN needs in clinical nutrition failure centres had experienced shortages for durations that varied
between 7 and over 90 days. This raised questions about the criteria
The ESPEN MN recommendations for enteral nutrition (EN) determining prioritization of patients, definition of monitoring
were formulated for a delivery of 1500 kcal/day [1], which, based frequency, modality of individual MNs, administration, and reim-
on an isocaloric formulation of 1 kcal/ml, provides 1500 ml/day bursement of non-IV preparations. ASPEN, having been confronted
(EN is often prescribed in ml). This concept aimed at covering with both vitamin [40] and trace element [41] shortages, and
minimal requirements while delivering clinically realistic BAPEN, with similar experiences [42], had generated recommen-
amounts of feeds. International surveys indicate that, while this dations for their members. The ESPEN dedicated home artificial
amount of energy is the most commonly prescribed target, feed nutrition (HAN) and micronutrient (MN) special interest groups
delivery is generally low, with around 1000 kcal/day often being (SIGs) decided to update and adapt the recommendations for
delivered [36]. Since all the MNs are incorporated in the EN Europe, to provide general principles to assist professionals to deal
formula, the amount of each MN supplied depends on the vol- with the problem [43] (Table 4).
ume of feed that is provided. Table 3 provides the amounts using During shortage, the available MNs should be reserved for some
a commonly used 1 kcal/ml EN product as an example: the table categories of patients highly or totally dependent on MNs e.g. ne-
compares the amounts of 8 selected MNs according to the de- onates, pediatric patients receiving PN and intolerant to oral/
livery of 3 levels of energy compared to the DRI and to the Eu- enteral MNs, patients with inherited metabolic disorders, patients
ropean Council directive [37]. with IF unable to absorb any MNs, patients on long-term PN, pa-
In patients receiving less than 1500 kcal/day, an additional tients on home PN unable to absorb any oral or enteral MNs, IF with
enteral or intravenous provision of MNs may be considered, espe- high GI losses, patients at high risk of refeeding syndrome, and
cially if there is a recent history of poor intake [38]. patients on PN requiring critical care.
Table 3
Amounts of MNs received by patients depending on the quantity of energy delivery using product “XYZ”, which is provided as 500 ml bags. For thiamine, the DRI is covered
with the lowest 900 kcal prescription and even the highest dose does not exceed European Council (EC) safety limits [37]. But for the low intake, DRI needs are not covered with
this solution for vitamins C, D, and E and iron. In no case are the EC upper limits exceeded.
MN XYZ content Prescribed: DRI EC directive [37]
500 ml @ 900 kcal 1500 kcal 1800 kcal

1 kcal/ml
Vit B1 mg 0.65 1.2 2.0 2.3 1.1e1.2 0.9e7.5

Vit C mg 33.5 60.3 100.5 120.6 75e90 34e330
Vit D mg 5 9.0 15.0 18.0 15e20 7.5e37.5
Vit E mg 6.5 11.7 19.5 23.4 15 7.5e45
Copper mg 0.665 1.2 2.0 2.4 0.9 0.9e7.5
Iron mg 6.5 11.7 19.5 23.4 30 7.5e30
Selenium mg 33.5 60.3 100.5 120.6 55 37.5e150
Zinc mg 6 10.8 18.0 21.6 8e11 7.5e22.5
274
Table 4
General principles to apply in case of MN product shortage.
Reserve IV multivitamins or multi trace elements for some priority indications and temporarily use oral/enteral route for multivitamin or multi trace element
administration if this can be done in a safe and effective manner.
Assess each patient regarding the indication for PN and provide vitamins and trace elements via the sublingual, oral or enteral route when possible and deemed to be safe
(excluding patients with malabsorption syndromes). The vitamin profile should be reviewed, and missing components supplemented, if available.
All the measures which “compensate the shortage” should be considered as “degraded alternatives” and therefore patients require increased monitoring of micronutrient
status.
As soon as shortage resolves, the current recommendations of IV multivitamin and trace element prescription should be applied.
The type of intestinal failure, and the duration of the required PN advice should be always sought before initiating or continuing MN
are important determinants of the “rescue” strategy. And in case of supplementation.
shortage, monitoring becomes even more important than usual [2]: Nevertheless, a poor diet present before and during cancer
it should be more frequent. therapy can result in malnutrition and deficiencies that are dele-
terious: therefore while cautioning against high doses of any MN, it
4. Micronutrients and disease is recommended to use multi-MN products with doses close to the
DRIs [48,49].
4.1. Cancer
4.1.2. Impact of antitumor therapy on MN status
4.1.1. Antioxidants - friends or foes in cancer? Malnutrition is frequent in cancer and is the principal, though
Increased oxidative stress contributes to tumor initiation and not only, cause of MN deficiencies (Fig. 4) [50]. In breast and
progression. Several MNs counteract oxidative stress, and therefore colorectal cancers, low vitamin D seems associated with worse
patients with cancer frequently use them, even during chemo- survival and poor prognosis. Other associations have been sug-
therapy. More than 80 % of patients with breast cancer take gested with deficient vitamin D status, i.e. higher severity of
multivitamin supplements, vitamin C, D and E being the more radiation-induced acute proctitis, osseous effectiveness of
prevalent [44]. However, chemotherapy may be based on induced bisphosphonates, and high risk of melanoma.
oxidative stress to kill cancer cells, and thus MNs with antioxidant L-carnitine deficiency is associated with cancer risk and poor
properties may reduce the clinical efficacy of the treatment. A study outcome: 80 % of patients with advanced disease are carnitine
including 1134 patients with breast cancer, showed that the use of deficient due to inadequate diet and competition with cytostatics
antioxidants/MNs before and during treatment does not influence (anthracyclines for the transporter OCTN2, necessary to transport L-
survival, whereas iron or vitamin B12 supplementation negatively carnitine into cells, disruption of L-carnitine biosynthesis by
influences outcome with poorer disease-free survival (P < 0.01) and anthracyclines, increased renal excretion by cisplatin/ifosfamide).
overall survival (P < 0.01) [45]. The findings of this study suggest Vitamin C deficiency is found particularly in patients with
caution for patients when considering the use of MNs and urge advanced disease; patients with lower vitamin C seem to have
them to report their use to the attending oncologist. Regular use of increased inflammatory activity (higher CRP), poor nutritional
MN supplements may also reveal a philosophical approach to condition, and shorter survival time. Zinc has also been explored: a
therapy. In this regard, breast cancer patients consuming dietary scoping review including 34 articles showed an association be-
supplements tend to consult and start chemotherapy later, which tween low zinc and dysgeusia and dysosmia in lung cancer pa-
may be detrimental [46]. Animal studies appear to suggest a benefit tients, and tailored zinc supplementation has been suggested [51].
when combining immune checkpoint inhibitors with ascorbic acid, Depending on cancer nature, site, and stage, 30%e90 % of pa-
but clinical confirmation is still lacking [47]. In summary, no general tients have an inadequate diet. Malnutrition affects intake and
recommendations can be delivered at this stage, and medical availability of MNs. Evidence shows that patients who consume
€ber et al. [50].

Fig. 4. Causes of malnutrition and micronutrients deficiencies in cancer. Adapted from Gro
275
<60 % daily energy requirements for 7e10 days have inadequate disease, mesenteric ischemia, surgical complications, chronic
supply of MNs and losses and requirements may be increased by pseudo-obstruction, and radiation enteritis. Survival rate of these
the effects of chemo or radiotherapy (vomiting, diarrhea, dysgeu- patients when on PN is good, for example 80 % at 5 years.
sia) and inflammatory processes. Weaning off PN depends on the remaining length and function
At the start of treatment, MNs with limited storage capacity of the bowel. Food intake in these patients is highly variable, as is
(vitamins B1, C, folate, K) are particularly critical. In patients with absorptive capacity and transit time, all factors that affect MN
surgery and/or bleeding, zinc deficiency is frequent. Optimal supply status. Absorption of MNs is either through passive transport or
of MNs (RDA amounts) should be assured, in addition to an specific transporters and most MNs are absorbed in the proximal
adequate supply of energy substrates (proteins, fats, carbohy- gut (duodenum and jejunum).
drates). Cancer- and/or treatment-induced MN deficiency impacts Assessment of MN status is challenging as it is often compro-
the disease course and effectiveness of cytoreductive measures, mised by the presence of systemic inflammation (see earlier). The
increasing risk of complications. Diagnosis of deficiency and treatment needs to be personalized as the deficiencies depend on
optimal supply of MNs should be monitored. the intestinal segments that are affected by disease. Patients on PN
are usually supplemented with intravenous MNs and therefore
4.1.3. Cancer cachexia and MNs timing of MN assessment, i.e. time of blood drawing, is variable
The prevalence of cachexia differs with cancer type, is a deter- affecting the laboratory result: a few hours should probably sepa-
minant of prognosis and may cause cancer treatment interruption rate end of MN infusion from blood sampling. Preliminary data
[52,53]. The gut microbiota directly influences host immunity and show that in 114 patients with chronic IF on PN, the prevalence of
metabolism: in animals, a synbiotic intervention restored intestinal high concentrations of the trace elements zinc and selenium is
homeostasis and improved outcome by reducing cancer prolifera- between 20 and 30 % while below reference range concentrations
tion and cachexia [54]. of zinc were present in less than 10 % of the population. In 300
Treatment of cachexia is multifactorial and includes physical patients with chronic IF and on PN, deficiencies of vitamins A and D
activity, pharmacological interventions, and nutritional therapy: were most prevalent while above reference range concentrations of
the latter is currently poorly defined with studies including heter- vitamin B6 were present in 45 % of patients.
ogenous populations and different MNs [55]. Among vitamins, B12 is especially vulnerable in those with short
Vitamin D has been investigated more in depth as it exerts bowel, but being well-known is easy to handle; most other vita-
biological actions on myogenic precursor proliferation and differ- mins are usually adequately catered for by commercial fixed-ratio
entiation, impinging on muscle regeneration: deficiency has been vials. In lipid-free PN, vitamin K deficiency can become a problem
shown to cause abnormalities in skeletal muscle and muscle as it is absent from some vials: in that case, vitamin K should be
wasting. In cancer, a retrospective study [56] showed 47 % of pa- added as complement. Biotin deficiency can also be a problem
tients were vitamin D deficient. An encouraging retrospective study because it is not present in all products. There are no problems with
in breast cancer patients showed that the patients who were sup- vitamin excess, nor any major problems with vitamin premixed
plemented with vitamin D during chemotherapy had a longer bags for home PN. Among minerals, magnesium requires special
disease-free survival and a tendency to higher BMI [57]. However, attention.
data are still insufficient to generate a firm recommendation, the For trace elements, standard commercial mixtures are less
more so that the optimal biomarker and vitamin D form are still satisfactory with generally too little selenium, and too much
unsettled. manganese. The limited availability of individual trace elements
makes ideal management difficult or impossible.
4.2. Diseases of the GI tract As an example, Abdalian et al. [59] showed that, despite excess
in prescription compared to recommendations (Table 5), blood zinc
4.2.1. MN absorption and needs in intestinal failure level was normal, manganese was high, and selenium was low. The
Intestinal failure (IF) is defined as a reduction of gut function manganese excess is a problem as it can result in a Parkinson-like
below the minimum necessary for absorption of nutrients, and pathology. Copper excess, or more rarely deficiency, can present
results in intravenous supplementation being required. The with hematological problems or neurological symptoms.
diseased population is very heterogeneous [58]. Iron deficiency is common in IF, although its treatment is
In short-term type I intestinal failure, vitamin provision is of theoretically straightforward with modern single-agent iron in-
critical importance, while issues with trace elements are rare. In fusions, given that the amount of iron that can be added to PN
longer-term IF, adequate vitamin replenishment remains crucial, without stability problems is very low. However, continued man-
particularly with vitamin D, but the problems with correct management is challenging as iron deficient patients have increased
agement of trace elements increase, seen both as deficiency and as gastrointestinal iron absorption, and in patients on supplementary
toxicity. There are fewer problems in the patients who have less PN it is therefore difficult to estimate the amount needed paren-
dependence on PN. terally for maintenance without risk of iron overload.
While acute IF occurs with increasing frequency, chronic IF is a Copper toxicity is a concern in long-term care. A Canadian HPN
rare disease [58]. Diseases leading to chronic IF include Crohn's survey indicated that excessive amounts were regularly being
Table 5
Comparison of average daily prescribed MNs in 135 Canadian patients on home PN compared to ASPEN and ESPEN recommendations (adapted from Abdalian et al. [59]).
Trace element Prescribed mean ± SD mg (mmol) ASPEN 2002 guideline [60] mg (mmol) ESPEN 2022 guideline [1] mg Provision versus guidelines
Copper 0.64 ± 0.35 (10.1 ± 5.6) 0.3e0.5 (4.73e7.88) 0.3e0.5 Excess

Chromium 11 ± 5 (0.21 ± 0.10) 10e15 (0.19e0.29) 10e15 Adequate
Selenium 78 ± 45 (0.99 ± 0.57) 20e60 (0.25e0.76) 60e100 Adequate
Manganese 452 ± 184 (8.2 ± 3.3) 60e100 (1.09e1.82) 55 Excess
Zinc 8.6 ± 5.5 (130.9 ± 84.2) 2.5e5.0 (38.8e76.5) 3e5 Excess
Iodine 77 ± 42 (0.61 ± 0.33) Not defined 130 Insufficient
276
administered [59], and an American study indicated excess serum been reported to be associated with complications. During the
copper in a quarter of patients [61]. Although typical European COVID-19 pandemic, numerous studies reported associations be-
prescribing in HPN does not often appear to cause copper toxicity tween low vitamin D levels, obesity, and severe forms of the disease
[62], there have been considerable concerns in patients with [45,70].
cholestasis of any cause, and especially in patients with intestinal For the reasons summarized above, MN status should be
failure-associated liver disease (previously attributed only to PN) assessed in those patients seeking nutrition therapy, particularly in
[63]. The liver copper is pathologically elevated in such patients: it those exposed to low energy-diets or with planned bariatric sur-
is possible that copper has a modest casual role in the condition gery that may favour or worsen MN deficiencies. Doses of MNs may
itself. need to be adapted to BMI as shown by Sadat-Ali et al. for vitamin
Together these problems form a strong rationale for regular MN D: the standard fixed 2000 IU/d dose did not correct deficiency,
status monitoring in patients dependent on HPN. whereas the higher (125 IU/kg/m2) BMI adapted dose did [71]. The
DRIs are likely to underestimate the MN needs of such patients and
4.2.2. Microbiome e MN synthesis further research is needed to develop optimal treatment strategies.
The gut microbiome secretes numerous metabolites including B
group vitamins and vitamin K2 [64]. The capacity of the human 4.3.2. MNs after bariatric surgery
intestine to absorb the B vitamins produced by the microbiome is With the increasing obesity pandemic, the number of bariatric
still uncertain: animal data seem to indicate that it occurs. In procedures has increased worldwide to over 700,000 per year.
humans, gut microbiome studies indicate this might be the case as Sleeve gastrectomy is the most frequently performed; Roux-en-Y
urinary excretion is higher than intake [65], but not all B vitamins gastric bypass and other malabsorptive procedures, such as on-
are absorbed (like B2). Recent studies unravelled the role of mi- anastomosis gastric bypass, bilio-pancreatic diversion or SADI-S
crobial production of vitamins in the management of host meta- are associated with the most striking alterations of MN status.
bolism, namely in the context of obesity [66]. The microbiome The risk factors for MN deficiency include pre-operative defi-
synthesis of vitamins may also contribute to intestinal immunity. ciency, low intake (food intolerance, taste alteration, eating disor-
Severe obesity has been shown to be associated with an abso- der, depression, poor socio-economic status), low adherence to
lute deficiency in bacterial biotin producers and transporters, supplementation and malabsorption, due to the surgical technique
whose abundances correlate with host metabolic and inflamma- itself or to complications (bacterial overgrowth, SIBO (Small In-
tory phenotypes: there are suboptimal circulating biotin levels in testinal Bacterial Overgrowth)) (Table 6). It is important to be aware
severe obesity and altered expression of biotin-associated genes in of these deficits as MN deficiency, particularly zinc and iron, can
human adipose tissue [67]. Strategies combining biotin and prebi- worsen the status by inducing anorexia, taste disturbances and
otic supplementation might be integrated as future treatment malabsorption. Therefore, MN supplementation needs to be
options. adapted to the patient's clinical condition and surgical procedure.
Oral intake of vitamins and other MNs can also affect the Patient adherence needs to be monitored as it is highly variable and
development of specific micro-organisms and thus MNs play a role influenced by numerous factors including economic factors such as
in determining the gut ecology. There is cross-feeding between gut the cost of multi-MN treatment, and health care related factors
bacteria, some being prototrophs (produce vitamins) and other such as annual medical visits [72].
autotrophs (depend on vitamins produced by other bacteria). Some MN deficiencies result in high-risk of severe complica-
Furthermore, the microbiome may influence the absorption of tions. Thiamine deficiency can occur in patients with low dietary
minerals and trace elements, especially increasing that of iron and intake and nausea/vomiting and has been described with all bar-
zinc at the colonic level. The involvement of individual microbiome iatric surgery techniques. Neurological manifestations, ranging
characteristics in MN status appears a complex but interesting and from confusion to peripheral neuropathy, may have dramatic
important facet to study in the future. consequences and require prompt therapy. Neurological sequelae
may occur despite treatment. Deficiencies of other MNs, such as
4.3. Obesity and bariatric surgery niacin, pyridoxine, riboflavin, ascorbic acid, and vitamins B12, A and
E, as well as copper, can also lead to neurological disturbances after
4.3.1. MN status in patients living with obesity bariatric surgery [73,74].
MN deficiencies are frequent in patients living with obesity. This Particular attention should be given to pregnant women, as
has led the WHO to emphasize the “double burden of malnutrition” deficiencies also have consequences for fetal development and risk
with MN deficiencies associated with macronutrient-energy of miscarriage and other complications: this is particularly true for
excess. The level of evidence varies for different MNs, but as a folic acid and risk of neural tube defects [75]. Iron, vitamin D and
notable example, vitamin D deficiency has repeatedly been shown
in obesity as confirmed by comprehensive meta-analyses [68]. Still
different MN profiles are assessed and described in different Table 6
Risk factors for micronutrient deficiency after bariatric surgery.
studies, with heterogeneity possibly partly depending on age, sex,
comorbidities, and body composition as well as fat distribution. The Micronutrient deficiency prior to surgery
most frequent cause of deficiency is considered to be low MN Iron, zinc, vitamin D, folate
Pre-surgical evaluation of nutritional status is needed
intake due to poor diet quality: vitamin D and E intakes may be Decreased intake
most strikingly reduced, but vitamins A, B12, folate and zinc are Food intolerance, taste alteration, eating pattern (e.g. vegans)
also reported to be affected [69]. The additional question of po- Malabsorption
tential higher MN requirements in obesity is still unresolved but Surgical technique, complications (SIBO, fistula, etc.)
Low adherence to supplementation
may be an issue related to the higher body mass.
Post-operative complaints, cost, inappropriate medication for swallowing
The consequences of MN deficiencies have been described difficulty
especially regarding vitamin D, which may favour increased Other clinical conditions
inflammation, loss of insulin sensitivity, loss of muscle mass and of GI diseases, any other acute or chronic disease
bone density, leading to a higher prevalence of diabetes mellitus, Alcoholism, depression, eating disorders
Pregnancy
sarcopenia, and osteoporosis. Iron deficiency and anemia have also
277
zinc deficiencies are frequent and particularly relevant during Vitamin A blood levels are decreased in 65e81 % of the patients
pregnancy [76]. The doses of MNs required after bariatric surgery with sepsis. A trial tested 100,000 IU given intramuscularly for 7
during pregnancy are higher than those of other patients [77]. days: the 28-day mortality rates were non-significantly higher in
the vitamin A group (34 % vs 28 %) [82]. The recommended upper
4.4. Critical care limit remains at 1500 ug/day [1]. Vitamin E is also generally low in
patients with sepsis. In the absence of positive intervention evi-
4.4.1. Vitamins in sepsis dence, only repletion doses are recommended.
Sepsis is a potentially deadly disease. Hypovitaminosis is
frequent and MNs are candidates as co-adjuvant therapy because 4.4.2. Selenium
they have numerous sites of action on the immune system. While Selenium was first known for its toxicity, but in the 1990s it was
blood levels of most MNs are decreased in sepsis, there is little recognized as an essential MN. Selenium is unevenly distributed
information about their optimum level and how this relates to worldwide with selenium-rich and selenium-deficient areas.
tissue levels. Edema and inflammation that causes redistribution Endemic Keshan disease in China drew attention to the importance
complicate the assessment of status. of selenium in cardiac function [83] . The disease was caused by a
Thiamine and ascorbic acid (AA) levels are often low to very combination of a coxsackie B3 infection and selenium deficiency,
low in sepsis and potential supplement candidates due to their the latter increasing the virulence of the virus by lack of antioxidant
functions [78]: causes for the low levels are numerous [79] defence. Selenoproteins have multiple functions including essential
(Fig. 5). Recent studies show that around 70 % of critically ill antioxidant function via different glutathione peroxidases (GPXs),
patients had hypovitaminosis C (plasma concentration redox signalling, thyroid hormones, protein folding, immunity,
<23 mmol/l) and about 30 % had vitamin C depletion/deficiency transport, and storage [84]. Most of these functions are heavily
(plasma concentration <11 mmol/l): these percentages were involved in heart function.
even higher in patients with sepsis (88 % and 38 %, respectively) Selenium has a narrow therapeutic window, with increasing
[79]. The prevalence of thiamine depletion/deficiency in criti- mortality with selenium levels below 100 mg/l and exceeding
cally ill patients is about 20 %, and may increase up to 70 % 150 mg/l [85]. Blood selenium is strongly impacted by inflamma-
during ICU stay, being associated with an increase in mortality tion: with CRP >40 mg/l, abnormal selenium levels are observed,
of up to 50 % [79]. which makes the simultaneous determination of biomarkers such
Both vitamins have important antioxidant functions: thia- as plasma GPX or selenoprotein P necessary for more precise
mine is essential for energy production, and AA is an immu- assessment of selenium status [2].
nomodulator and essential for synthesis of catecholamines and Initial promising selenium supplementation trial results in
endothelial stability [79]. After the HAT (hydrocortisone, ascor- critical illness showed reduced mortality that seemed confirmed by
bic acid, thiamine) trial many studies were conducted, without a meta-analysis [86]. The initial positive results were not confirmed
repeating the same success. The recent LOVIT trial showed more by a German multicentre trial [87] and the REDOXS study [88], but
persistent organ dysfunction and deaths in the vitamin C group different high and very-high doses were used. The latest meta-
[80]. Despite this trial (and including it) a meta-analysis analysis distinguished between high doses (1000 mg) which were
including 18 RCTs, showed a significant improvement of the associated with prolonged ICU stay, and lower doses (500 mg)
delta SOFA (p ¼ 0.001 with IV vitamin C [81]. For the moment, which were associated with reduced renal failure, as in the initial
the guidelines maintain the use of repletion doses but not of studies [89]. The difference may be related to a preexisting or acute
very high doses [1]. depletion that justified correcting it as in major burns. Indeed in
major burns, where acute depletion develops due to large exuda-
tive losses, doses of 300e500 mg have consistently been shown to
exert positive effects [90].
The ESPEN guidelines insist on ensuring at least minimum
amounts of selenium are provided in case of plasma
values < 0.4 mmol/l in patients with elevated inflammation [1]: they
also insist on delivering the full combination of essential MNs to all
patients receiving PN.
4.4.3. Vitamin D
Vitamin D deficiency is a frequent worldwide problem affecting
about 70 % of ICU patients and 40 % of the general population. It is
associated with excess morbidity and mortality. This is related to
the numerous functions of this prohormone [91,92]. A Cochrane
review including 95,276 study participants showed that vitamin D
supplementation was associated with a 6 % mortality reduction
[93]: 150 people treated over five years were required (NNT) to
prevent one additional death. Vitamin D supplementation also re-
duces acute respiratory tract infections [94], the effect being
greatest in vitamin D deficient subjects. Emerging data also suggest
a beneficial effect for oral vitamin D in reducing the progression to
diabetes in subjects with prediabetes as shown in a meta-analysis
of 3 high quality trials [95].
The use of single ultra-high bolus doses, although attractive, has
been shown to be ineffective in rickets and other conditions [96].
Fig. 5. Causes of vitamin C and thiamine deficiencies in critical illness. Reproduced The reason is that a single bolus dose induces long-term expression
with permission from [79]. Abbreviation use: DHA, dehydroascorbic acid. of the catabolic enzyme 24-hydroxylase and fibroblast growth
278
factor 23 (FGF23), both of which have vitamin D inactivating Considering the risks associated with RFS, a strategy to admin-
effects [97]. ister feeding progressively over the first few days is recommended
A 2022 meta-analysis on vitamin D3 in the ICU found that [34]. After energy restriction, energy intake should be increased
vitamin D may reduce mortality and that the parenteral route may stepwise to the target, ideally measured by indirect calorimetry as
confer greater benefits [98]. The ongoing VITDALIZE trial delivers per ESPEN-ICU guidelines [103] (Fig. 6).
a bolus of 540,000 UI followed by 4,000 IU/day of vitamin D3 in Additionally, thiamine supplementation should be considered
critically ill patients [99]. Current recommendations are to for patients with RFS, even though a recent RCT did not demon-
determine blood levels in case of suspected deficiency, and to strate significant clinical benefits of vitamin B1 supplementation in
deliver at least 2,000 IU per day, but not to deliver high single ICU patients [104].
doses [1]. RFS is not rare, with approximately one-third of long-stay crit-
ically ill patients experiencing it [32,36]. Given its prevalence,
phosphate monitoring remains the primary means of detecting RFS
4.4.4. Refeeding syndrome (RFS) in the ICU. Managing RFS in critically ill patients requires a multi-
This syndrome occurs during the reintroduction of feeding after faceted approach that involves careful phosphate monitoring and
a period of starvation or fasting. It is characterized by electrolyte gradual feeding progression. The importance of early detection and
and glucose metabolism abnormalities, particularly insulin resis- tailored management strategies cannot be overstated, as they can
tance, putting patients at risk of thiamine deficiency. significantly impact patient outcomes.
Upon reintroduction of feeding, increasing blood glucose levels
trigger insulin secretion, which leads to the movement of phos-
phorus, magnesium, and potassium into cells. This can result in 4.4.5. Micronutrients and physical activity
various complex clinical signs and symptoms that are challenging The information on the link between MNs and physical activity
to distinguish from other critical illness manifestations [100]. is scarce. Human studies evaluated the potential ergogenic effect of
A prospective observational study among 337 patients, MNs on physical performance in athletes but not in normally active
including 124 individuals with hypophosphatemia upon initiation people or patients with disease. MNs directly involved in physical
of feeding, underscored the importance of phosphate monitoring. activity in muscle are vitamins B, C and E with trace elements
Interestingly, baseline characteristics did not significantly differ copper, iron and zinc and the electrolyte magnesium (Fig. 7).
between those who developed hypophosphatemia, except for a In athletes, as in other subjects, MN depletion occurs especially
minor and clinically non-relevant reduction in potassium and during energy restriction, extreme weight loss practices, elimina-
magnesium levels upon admission, which was observed in patients tion of one or more food groups, and globally poor diets. Iron,
who developed RFS [101]. vitamin D and antioxidant vitamins are key MNs in athletes and
Doig et al. showed that in ICU patients with a drop of phosphate have been associated, for instance, with muscle function, oxidative
to below 0.65 mmol/l upon feeding initiation, energy restriction up stress, and physical performance.
to maximum of 500 kcal for 48 h improved survival rates [102]. This This raises the question of whether MN supplementation im-
finding was corroborated by Olthof et al. [101]. Moreover, non- proves physical fitness. In a systematic review, iron supplementa-
nutritional energy sources such as propofol, citrate, and glucose tion in endurance sports has been shown to increase VO2 max
can also induce RFS, further emphasizing the importance of phos- [106]. Vitamin D supplementation in athletes seemed not to be
phate monitoring even when no nutrition is provided [101]. effective, with no improvement of muscle strength or power [107]:
Fig. 6. Refeeding hypophosphatemia protocol for the ICU with gradual progression of energy intake and with daily phosphate monitoring. Example of the adaptation of the ESPEN
guidelines to the Wageningen University hospital. # indicates that in a computerized ICU, the protocol enables handling the phosphate issue, sparing the dieticians for specialised
tasks.
279
Data linking antioxidant MNs with sarcopenia are sparse. In a

large prospective cohort with a 12-year follow-up, higher intakes of
total carotenoids, lycopene, and lutein þ zeaxanthin were associ-
ated with increased muscle strength, and all antioxidants except for
vitamin C were associated with faster gait speed [112]. Nutritional
supplementation with vitamin D combined with whey protein or
BCAAs is effective in improving muscle strength regardless of the
addition of physical exercise [113].
Although the optimal treatment strategy for older frail and
sarcopenic patients is still not clear, the treatment of these patients
must include protein and/or BCAAs supplementation associated
with Vitamin D and physical exercise; the role for MN supple-
mentation is not yet established.
4.5.2. MNs and cognitive impairement

Alzheimer's disease (AD) is the most epidemiologically relevant
cause of cognitive decline in the elderly population. The current
model of AD is dynamic, based on the concept of a pathological
process evolving over decades, with a long asymptomatic stage,
followed by the onset of progressive memory decline (Mild
Cognitive Impairment), subsequently leading to dementia of
increasing severity. There is now ample evidence supporting the
effectiveness of modifying the risk factors associated with cognitive
decline as an important prevention tool in AD. Nutrition is one of
these factors, as indicated by several meta-analyses of dietary
intervention studies supporting a key role for the Mediterranean
diet in lowering risk [114].
Several MNs have been investigated for a potential protective
role. These include B vitamins (folate, B6, B12), trace elements
Fig. 7. Sites of action of the different MNs within the muscle. Abbreviations: RBC, red
blood cell; ROS, reactive oxygen species. Adapted from Thomas et al. [105].
(copper, iron, zinc) and antioxidants (vitamin A, lutein, lycopene,
zeaxanthin, cryptoxanthin, carotene, vitamins C and E) and also
long chain fatty acids (docosahexaenoic acid). Neuroimaging
there is uncertainty about existence of an optimal vitamin D level,
studies of cortical thickness, an excellent marker of brain health
as the normal values are derived from osteoporosis studies. Finally,
have reported a positive association with the consumption of
antioxidant supplementation might even decrease physical fitness
several dietary factors including vegetables, alpha-linolenic acid,
in untrained individuals [108].
beta-carotene and vitamin C [115]. Detailed information about the
The only indications that are actually recognized in physically
role of MNs remains however limited. In a recent study of 140 frail
active people are iron and vitamin D for treatment of depletion,
patients, nutritional status (assessed by the MNA-SF) was shown to
while administration of antioxidants is controversial [105]: food
be related to cognitive health, but no relation could be found with
recording is important as athletes may have unbalanced diets with
any individual MN [116].
poor calcium, iron, selenium, and vitamin C and D intakes.
5. Conclusion
4.5. Geriatric requirements
The science of MNs has progressed during the last 2 decades.
4.5.1. MNs in sarcopenia and frailty However, despite this progress, numerous gaps persist, especially
Healthy aging is of paramount importance in the face of regarding diagnosis of MN deficiencies in clinical situations, leading
increased life expectancy, and balanced nutrition positively affects to insufficient treatment. The above clinical situations emphasize
healthy ageing. Healthy aging is opposed to frail aging; frailty is a the importance of monitoring the MN status. Research and
multi-component syndrome associated with poor health outcomes continued education about MNs are required to improve patient
and loss of independence. Age-related chronic diseases signifi- outcome. The recent ESPEN guideline [1] should be followed.
cantly contribute to frail aging, among these sarcopenia plays a
fundamental role. The prevalence of sarcopenia varies between Conflict of interest
different studies reaching up to 29 % in community based older
adults. Sarcopenia has characteristic features and significantly dif- The authors declare no conflict of interest. There was no external
fers from healthy muscle aging [109]. Mitochondrial function is funding.
significantly altered in sarcopenia and nutritional intervention may
rescue this as well as the clinical phenotype of sarcopenia. Several References
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Micronutrients in Neurology and Disease

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Clinical Nutrition 43 (2024) 268e283

Contents lists available at ScienceDirect

ESPEN Endorsed Recommendation

The science of micronutrients in clinical practice e Report on the

1. Introduction 3. C-reactive protein (CRP) should be determined at the same time

1.1. Aims of the ESPEN micronutrient guideline 1.2. Status assessment

Status ESPEN deﬁnition and comment

Micronutrient Disease impact Level of evidence

Vitamin A Increased risk of measles and diarrhea in children Low-to-moderate quality

Abbreviations: UTI ¼ urinary tract infection, RTI ¼ respiratory tract infection.

MN XYZ content Prescribed: DRI EC directive [37]

500 ml @ 900 kcal 1500 kcal 1800 kcal

Vit B1 mg 0.65 1.2 2.0 2.3 1.1e1.2 0.9e7.5

€ber et al. [50].

Copper 0.64 ± 0.35 (10.1 ± 5.6) 0.3e0.5 (4.73e7.88) 0.3e0.5 Excess

Data linking antioxidant MNs with sarcopenia are sparse. In a

4.5.2. MNs and cognitive impairement

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