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Review article: Biomedical intelligence | Published 14 June 2017 | doi:10.4414/smw.2017.14434 Cite this as: Swiss Med Wkly. 2017;147:w14434
The treatment of iron deficiency without anaemia (in otherwise healthy persons) German E. Clénin
Sportmedizinisches Zentrum Ittigen bei Bern, Ittigen, Switzerland
Summary Iron deficiency is the most widespread and frequent nu- tritional disorder in the world. It affects a high propor- tion of children and women in developing countries and is also significantly prevalent in the industrialised world, with a clear predominance in adolescents and menstru- ating females. Iron is essential for optimal cognitive function and physical performance, not only as a binding site of oxygen but also as a critical constituent of many enzymes. Therefore iron deficiency at all its levels – non- anaemic iron deficiency, iron deficiency with microcyto- sis or hypochromia and iron deficiency anaemia – should be treated. In the presence of normal stores, however, preventative iron administration is inefficient, has side effects and seems to be harmful.
In symptomatic patients with fatigue or in a population at risk for iron deficiency (adolescence, heavy or pro- longed menstruation, high performance sport, vegetar- ian or vegan diet, eating disorder, underweight), a base- line set of blood tests including haemoglobin concentra- tion, haematocrit, mean cellular volume, mean cellular haemoglobin, percentage of hypochromic erythrocytes and serum ferritin levels are important to monitor iron deficiency. To avoid false negative results (high ferritin levels in spite of iron deficiency), an acute phase reac- tion should be excluded by history and measurement of C-reactive protein. An algorithm leads through this diag- nostic process and the decision making for a possible treatment. For healthy males and females aged >15 years, a ferritin cut-off of 30 µg/l is appropriate. For chil- dren from 6–12 years and younger adolescents from 12– 15 years, cut-offs of 15 and 20 µg/l, respectively, are rec- ommended.
As a first step in treatment, counselling and oral iron therapy are usually combined. Integrating haem and
free iron regularly into the diet, looking for enhancers and avoiding inhibitors of iron uptake is beneficial. In or- der to prevent reduced compliance, mainly as a result of gastrointestinal side effects of oral treatment, the use of preparations with reasonable but not excessive ele- mental iron content (28–50 mg) seems appropriate. Only in exceptional cases will an intravenous injection be necessary (e.g., concomitant disease needing urgent treatment, repeated failure of first-step therapy).To measure the success of treatment, the basic blood tests should be repeated after 8 to 10 weeks. Patients with repeatedly low ferritin will benefit from intermittent oral substitution to preserve iron stores and from long term follow-up, with the basic blood tests repeated every 6 or 12 months to monitor iron stores. Long-term daily oral or intravenous iron supplementation in the presence of normal or even high ferritin values is, how- ever, not recommended and is potentially harmful.
Key words: iron deficiency; ferritin, nonanaemic iron deficiency; NAID; treatment with iron; iron therapy; iron and nutrition; overtreatment
Introduction
Iron deficiency is the most common and widespread
deficit globally, with a clear predominance in ado-
lescents and in menstruating women [1]. It greatly
affects developing countries, where it is the major
cause of anaemia [2]. The WHO claims that 40–
50% of these anaemic conditions are iron deficiency
anaemia (IDA), and therefore preventable and treat-
able [3]. In the industrialised world, as iron defi-
ciency is one of the few nutritional deficits, its prev-
alence is significant.
Data from Australia [4], Denmark [5–7], Switzer-
land [8, 9] and the US [10, 11] provide the data on
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prevalence. In childhood, both sexes show similar a
prevalence from 3–9%. In adolescence, with ongo-
ing growth in puberty and the onset of menarche,
iron deficiency is more frequent in females at 11–
33% compared with 3.5–13% in males; this figure
gradually and distinctly declines in post-adolescent
men. During childbearing age the prevalence in
women remains quite high (range 9–22%) com-
pared with men of the same age-group (1–2% only).
After the menopause, ferritin values in women rise
with a lowering of the prevalence of iron deficiency
to 2.3–7%, which comes closer to the values of their
male counterparts with a range of 1.4–4%.
In order to develop the topic of iron deficiency, this
article discusses the general function and metabo-
lism of iron, the influence of iron on performance
and cognition, basic measurements to diagnose iron
deficiency, the stages of iron deficiency and, finally,
treatment.
General function of iron and iron
metabolism in the human body
Iron is a transition metal and has multiple functions
in more than 180 biochemical reactions in the hu-
man body, including electron transport in redox re-
actions (cytochromes, sulphuric proteins), redox
catalytic functions (cytochrome p450, catalase, pe-
roxidase) and reversible storage and transport of O2
(haemoglobin, myoglobin). It also plays an im-
portant role in the production of neurotransmitters,
and is essential in synaptogenesis and myelinisa-
tion. Oxidative phosphorylation is the most critical
biochemical pathway in which iron is involved [12,
13].
The total body content of iron amounts to approxi-
mately 4 g in men and 2.5 g in women. This iron is
divided between three active sites: haemoglobin
65%, myoglobin 10% and enzymes 5%. The rest
(20% of the total) remains as inactive, depot iron in
the form of ferritin and haemosiderin. Finally, 0.2%
of the total iron exists as transport iron in the form
of transferrin. In adolescents, the relative amount of
iron in the different compartments is comparable
but may vary slightly depending on body size and
initiation of menses [12, 14, 15].
The usual loss of iron (1 mg per day in males and 2
mg per day in females) due to gastrointestinal epi-
thelial shedding and menstruation is compensated
by absorption in the small intestine [13, 14]. Of the
10–14 mg of iron ingested, the enterocytes absorb
only about 0.5–2 mg (5–15%) [16, 17]. Neverthe-
less, during increased loss (e.g., menstruation, other
bleeding, haemolysis) and elevated demand (e.g.,
growth, pregnancy, high performance sport [18,
19]), adequate uptake is guaranteed through an up
to four-fold increase in intestinal absorption, as long
as sufficient iron is provided by nutritional intake
[14, 17].
The absorbed iron is stored in ferritin in the cyto-
plasm of the enterocytes. For export to the plasma,
iron is carried out by ferroportin on the basolateral
surface of the enterocytes [12]. There, iron is bound
to transferrin and transported to the liver, where it is
stored as ferritin or transferred to iron-consuming
tissues such as bone marrow.
Ferroportin is important in the tight regulation of
iron homeostasis. The main regulatory molecules
are hepcidin and erythroferrone [16, 20, 21]. Hep-
cidin, synthesised in hepatocytes, regulates iron ex-
port out of the storing cells. In phases of high iron
loading and in response to inflammatory processes,
the synthesis of hepcidin is increased, leading to the
internalisation of ferroportin on enterocytes, which
in turn blocks iron transportation into the circula-
tion. The same mechanism leads to a blockade of
iron within the macrophage system, thus preventing
the transfer of iron from macrophages to erythro-
blasts, the precursors of erythrocytes [12, 20] (fig.
1). Hepcidin synthesis is suppressed by erythropoi-
etic activity and anaemia: hypoxia induces erythro-
poietin production in the kidneys, erythropoietin
stimulates the production of erythroferrone in eryth-
roblasts and erythroferrone blocks the production of
hepcidin [21]. This allows increased intestinal ab-
sorption and utilisation of iron from the macro-
phages and enterocytes under conditions of elevated
iron loss or increased demand [16]. Newer results
show that not only iron loading and inflammation,
but also intensive exercise induce hepcidin bursts
causing a blockage of iron [16].
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Figure 1: Iron cycle and mechanisms of adaptation to iron deficiency, adapted from Camaschella 2015 [22] and Camaschella et
al. 2016 [20]. Tissue hypoxia leads to production of hypoxia inducible factor 2 (HIF-2). As a consequence the kidneys produce erythropoietin (EPO), which leads to an enhancement of erythropoiesis, and hypochromic microcytic red cells are produced owing to a low availability of iron. EPO is also influenced in part by body iron via an as yet only partially understood mechanism
[16, 20]. In enterocytes HIF-2 increases the expression of divalent metal transporter (DMT 1) on their apical surface and the uptake of dietary iron will be increased. The increased erythropoiesis suppresses the production of hepcidin through the inter- mediate erythroferrone (ERFE), which is produced in erythroblasts. Hepcidin levels are further depressed in response to a re- duction in the usual signals that maintain its production: low iron content of the liver, increase in inhibitor transmembrane pro- tease, serine 6 (TMPRSS6). Ferroportin (FPN) is no longer degraded because of the low hepcidin levels and it exports the availa- ble iron across the basal membrane of the enterocytes and from macrophage stores to enter circulation. As long as stores are exhausted and no therapy started, iron availability remains low and consequently the uptake of iron by all cells and organs (e.g., heart, skeletal muscle) is reduced.
Influence of iron on physical perfor-
mance and cognition
Iron is, in addition to its function in oxygen
transport, a key component of the enzymatic system
of the respiratory chain. These presumably distinct
roles were investigated in early animal studies [23,
24]. In these studies, the investigators aimed at dif-
ferentiating between a decline in performance due
to anaemia and a decline due to enzymatic impair-
ment. With an animal model in a crossover experi-
ment of iron depletion and crossover transfusion to
correct anaemia, it was shown that not only anaemia
but also iron depletion without anaemia led to a sig-
nificantly decreased number of mitochondria and
reduced activity of the respiratory enzymes. The au-
thors therefore postulated that iron depletion with-
out anaemia affected oxidative capacity, whereas
anaemia affected mostly oxygen transport [23, 24].
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At present the cut-off level of ferritin is still debated,
with values ranging from 15 µg/l from the World
Health Organization (WHO) [2] to 16–32 µg/l [25,
26] in studies that used the “gold standard procedure
of bone marrow staining”. It has to be noted that
studies investigating this matter were not all conclu-
sive and some had controversial results [26, 27].
If not only erythropoiesis, but also clinical symp-
toms of an iron deficiency such as fatigue (but not
yet performance) are considered, the cut-off may be
slightly higher. Recently Krayenbuehl et al., in their
double-blind randomised study of intravenous iron
administration to nonanaemic premenopausal
women with low ferritin and fatigue, showed an im-
provement in mood state in the group with ferritin
<15 µg/l [28]. Two studies looked at fatigue and
mood state in premenopausal nonanaemic women
receiving oral supplementation from a family doctor
[29, 30]. Their proposed cut-off of 50 µg/l must be
interpreted with caution because of methodological
concerns (e.g., stool colouration by iron was not
blinded, definition of iron deficiency was based on
a limited number of variables). Finally, there are a
few studies that included a performance measure-
ment offering more objective data (table 1).
Table 1: Randomised blinded interventional trials investigating nonanaemic iron deficiency and performance.
First au- thor
Performance measurement
No. Study popula- tion
Inclusion cri- teria
Intervention Results Conclusion
Burden 2014 [31]
VO2max
Time to ex- haustion
Running econ- omy
Haemoglobin mass
15
runners, 9F
VO2max 64.5 ml/kg·min
6 min VO2max
76.7 ml/kg·min
F: Hb >120 g/l, Fer <30
g/l
M: Hb >120 g/l, Fer <40
g/l
IV 500 mg Fe carbox- ymaltose vs placebo
Testing at BL, after 7 d and after 4 w
Blood sampling as above and 1 day af- ter injection
– Fer, traSat, se-
rum iron in Tx,
Fer in Pl
– Hepcidin from day 1 up to 4 w in Tx
– Hb mass,
VO2max, running
economy, time to
exhaustion in Tx and Pl
Despite IV iron in abun- dance no improvement in Hb mass and perfor- mance in NAID male (Fer
<40 g/l) and female Fer
<30 g/l runners.
Distinct rise in hepcidin for at least 4 weeks.
Garvican 2014 [32]
Treadmill run- ning with VO2max, time to exhaustion
Hb mass
27
highly trained distance run- ners
13 M, 14 F
With (low group, LG) or without (con- trol group, CG) low iron status
LG: Fer <35 µg/l; trSat <20% or Fer
<15 g/l
CG: Fer <65
g/l
Oral: 105 g ele- mental iron; 2×/d in LG, 1×/d in CG
vs
IV: 2–4 injections Fe- carboxymaltose based on iron status (mean IV dose CG 375 mg, mean IV
dose LG 550 mg)
Testing at BL and af- ter 6 w
– Fer with oral and IV treatment, signifi-
cantly with IV
– Hb in all groups
– In LG IV: Hb mass,
VO2maxand time to
exhaustion
In CG subgroup with “suboptimal” iron status, no change in Hb mass, VO2max and time to exhaus- tion.
IV iron improves Hb mass and performance only in iron deficient male and female runners (Fer <35 ug/l and trSat
<20% or Fer <15 g/l).
No change with oral treatment, no change with ferritin <65 µg/l.
Della- Valle 2014 [33]
4 km time trial
VO2peak
40
female rowers
at the begin- ning of the season
Hb > 120g/l,
Fer <20 g/l
Oral FeSO4 100 mg/d vs placebo for 6 w
Testing at BL and af- ter 6 w of training
– fat free mass and
VO2peak in Tx and Pl
– Fer in Tx
– energy expendi-
ture in Tx
– lactate response in first half of time
trial in Tx, and 5 min after time trial
6 weeks of oral iron im- proves rowing economy in NAID female rowers
(Fer <20 g/l) at the be- ginning of the season.
The placebo group shows a similar improve- ment in VO2max, how- ever.
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Table 1 (continued)
Waldvo- gel 2012 [34]
Chester step test (r = 0.92 to VO2max)
Fatigue (VAS 10)
154
female blood do- nors
Hb >120 g/l, Fer
30 g/l
Oral FeSO4 80 mg/d vs pla- cebo for 4 w
Testing at BL (1 w after do- nation of 450 ml blood) and after 4 w.
In Tx Hb, Fer compared with Pl
No significant effect for fatigue, aerobic capacity (step test), mood disorder, quality of life
4 weeks of oral iron shows no performance improvement, no improvement of fatigue or mood in female blood donors.
Limitation: substitution not long enough.
McClung 2009 [35]
2 mile running time
Profile of mood state (POMS)
219
female sol- diers during basic com- bat training
Three groups:
IDA (Pl 17, Tx 18)
ID (Pl 14, Tx 14)
normal (Pl 51, Tx 52)
No inclusion cri- teria.
IDA defined as
Hb <120 g/l and
2 of: Fer <12
g/l, traSat <16%, RDW >15%
ID defined as 2 of iron crit.
Oral FeSO4 100 mg/d vs Pl
Testing at BL and after 8 w of basic com- bat training
– RDW, sTfr, Fer in Tx and Pl.
– decrement in iron
status in Tx
– with IDA, 2-mile
running time in Tx; but not in Pl, or in normal.
– POMS in Tx, Pl and normal; only in IDA vigour scores of
POMS
8 weeks of oral iron improve performance in NAID female military recruits.
Hinton 2007 [36]
VO2max
60 min sub- max. cycle er- gometer test (at 60% VO2max)
20
recreation- ally trained (3M, 17F)
Hb >120g/l (F) or >130g/l (M), Fer
<16 g/l, sTfr >8 mg/l or sTfr/log Fer index >4.5
Oral 30 mg/d elemental iron as FeSO4 vs placebo
Testing at BL and after 6 w
– Fer in Tx, Hb and
haematocrit
– in Pl ventilatory
threshold, in Tx ventilatory thresh-
old
– energetic effi- ciency during sub-
maximal test in Tx
6 weeks of oral iron maintain performance and improve sub- maximal energetic efficiency in recreationally trained men and
women (Fer <16 g/l, sTfr >8mg/l, or sTfr/log Fer index >4,5).
compared with a decrease in the placebo group.
Brownlie 2004 [37]
15 km time trial on cycle ergometer
VO2max
41
untrained women
Training of 30 min/d, 5× for the final 4 w
Hb >120 g/dl, Fer
<16 g/l
Oral FeSO4 100 mg/d vs placebo
Testing at BL and after 6 w
Time in time trial, percentage of
VO2max, work
rate in Tx when sTfr >8 mg/l
No difference with normal sTfr
6 weeks of oral iron improve performance in the subgroup of nonanaemic iron deficient untrained women (Fer <16
g/l) with elevated sTfr >8 mg/l.
BL = baseline; F = female; Fer = ferritin; Hb = haemoglobin, ID = iron deficiency; IDA = iron deficiency anaemia; IV = intravenous; M = male; NAID = nonanaemic iron deficiency; Pl = placebo group; RDW = red cell distribution width; sTfr = soluble transferrin receptor; traSat = transfer- rin saturation; Tx = treatment group
increased significantly; no change; decreased significantly
Since the randomised controlled trial of Bruner et
al. [38] in 1996, which looked at US female adoles-
cents with nonanaemic iron deficiency (NAID) and
which showed an improvement in verbal learning
and memory with oral iron, there is increasing evi-
dence that not only IDA but also NAID affect cog-
nition. Falkingham et al. found, in their 2010 sys-
tematic review and meta-analysis, evidence that
iron supplementation improved attention and con-
centration in adolescents and women with IDA and
NAID, regardless of baseline iron status [39]. Since
then one randomised controlled trial [40], two other
systematic reviews [41, 42] and a pilot study [43]
supporting these findings have been published. All
the authors pointed out that further well-designed,
blinded and independently funded studies of at least
1 year duration, looking at different age groups and
varying levels of baseline iron status, and using val-
idated tests of cognition are needed to confirm and
extend these results. Table 2 gives an overview of
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randomised controlled clinical trials relevant to iron
deficiency and cognitive function.
Based on the cited results, overviews on the influ-
ence of iron deficiency on performance and cogni-
tion, and according to several review articles, a fer-
ritin cut-off of 30 µg/l in adults seems to be the most
plausible [48–55]. According to the available data,
iron treatment of otherwise healthy persons with
ferritin levels above this value does not bring any
benefit, for neither performance [31, 32] nor cogni-
tion [40, 44].
Table 2: Randomised blinded interventional trials investigating nonanaemic iron deficiency and cognition.
First author
Cognition meas- urement
No. Study popu- lation
Inclusion criteria Interven- tion
Results Conclusion
Baum- gartner 2012
[40]
Hopkin’s verbal learning test (HVLT) and sub- scales of Kauf- man assessment battery for chil- dren (KABC)
321
South Afri- can school children, age 6–11 y
79 Fe + DHE/EPA
81 Fe + Pl
81 Pl + DHE/EPA
80 Pl + Pl
Hb >80 g/l and ID defined as either
Fer <20 g/l or ZnPP
>70mol/mol haem or sTfr >8.3 mg/l.
In all four groups about 20% were anaemic (Hb <115 g/l)
2×2 facto- rial trial:
(1) 50 mg FeSO4 + 420 mg DHA / 80 mg EPA
(2) Fe + Pl
(3) Pl + DHA/EPA
(4) Pl + Pl
All 4×/w for 8.5 mo
– with Fe-Tx cogni-
tion (number of words HVLT) vs Pl.
– in children with
NAID, HVLT and
KABC
– in all groups KABC for learning abilities, whereas sequential
processing
– Fer in (1) 21.4–58.4
g/l and (2) 20.0–62.7
g/l
– Hb in all 4 groups
Several months of oral iron improve cognition in iron- deficient South African
school children(Fer<20g/l,
or ZnPP>70mol/mol haem or
sTfr>8.3mg/l)
Limitations: 20% of the chil- dren were anaemic. The complex study design makes it difficult to attribute the observed effects.
Mur- ray- Kolb 2007
[44]
Cognitive abili- ties-attention, cognitive abili- ties-memory, cognitive abili- ties learning, Shipley Inst Scale (IQ)
149
USA women, age 18–35 y
Control-Pl 21
Control-Fe 21
ID-Pl 37
ID-Fe 36
IDA-Pl 15
IDA-Fe 19
Control:
Hb >120 g/l, Fe sta- tus normal (mean
Fer 45 ± 20 g/l)
ID: Hb >120 g/l, 2 abFeSt (mean Fer
8.9 ± 4 g/l)
IDA: Hb 105–119 g/l and 2 abFeSt
Oral ele- mental iron 60 mg/d
For 16 w
– Tx: Fer with 5- to 7-
fold in cognitive per-
formance, in Hb re-
lated speed in com- pleting cognitive tasks.
– Fer in Cn-Fe, ID-Fe, IDA-Fe (mean change
20/16/15g/l) and ID-
Pl (mean change 7g/) but not in Cn-Pl and IDA-Pl
-Hb in IDA-Fe (mean change 12g/l) and in IDA-Pl (mean change
7g/l) but in Cn-Pl, Cn-Fe, ID-Pl, ID-Fe
16 weeks of oral iron im- prove cognitive perfor- mance in NAID US women
(mean Fer 8.9 ± 4 g/l)
Lam- bert 2002
[45]
Visual search and attention (AC), Hopkin’s verbal learning (HVLT), Stroop task, reading span
116
New Zealand female high school stu- dents age 12.5–17.9 y
Fe 57
Pl 59
Hb >120 g/l
Fer <12 g/l
Oral ele- mental Fe 105 mg/d vs placebo
For 8 w
– In Tx, immediate
word recall in HVLT, recall of recent
words and reading
span in Pl all
- Fer in Tx (mean
change 17 g/l), in Pl
8 weeks of oral iron im- proves cognitive perfor- mance
in NAID NZ female high- school students (Fer <12
g/l).
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Table 2 (continued)
Lynn- Harland 1998
[46]
Raven’s Color Pro- gressive Matrices (IQ)
415
England teenag- ers at 7 compre- hensive schools, age 12–16 y
Fe 208
Pl 205
ID:
Fer 12 g/l but any Hb
Control: the others
Oral elemental Fe 80mg/d
16 w
BL (1 w after donation of 450 ml blood) and after 4 w.
In ID, in IQ with a gain of 5.8 IQ points compared with Pl.
16 weeks of oral iron im- proves IQ in iron defi- cient English teenagers
(Fer 12 g/l)
Limitation: no clear in- clusion criteria for hae- moglobin.
Bruner 1996
[38]
Visual search and at- tention, Hopkin’s verbal learning test, digit symbol modali- ties, attention
81
USA adolescent girls, mean age 16.2 y and 15.7 y
Fe 40
Pl 41
African Ameri- can Hb >115 g/l, white American Hb >120 g/l
Fer <12 g/l for all
Oral elemental iron 260 mg/d
For 8 w
– In Fe-Tx, in test of verbal learning and memory com- pared with Pl (p <0.02)
– Fer in Tx (27.3
vs 12.1 g/l, p <0.001)
8 weeks of oral iron im- proves verbal learning and memory in NAID US adolescent girls (Fer <12
g/l).
Groner 1986
[47]
Vocab (IQ), digit symbol, arithmetic, consonant trigram, Rey auditory verbal learning, digit span
38
USA pregnant women, age 14– 24 y
Vitamins with Fe 19
Pl (vitamins alone) 19
Hb >120 g/l
Fer <40–60
g/l
Oral elemental iron 60 mg/d
For 4 w
– In Fe-Tx, in most sensitive measure of short-term memory and three subtests.
– Hb in Tx
4 weeks of oral iron im- proves short term memory in nonanaemic pregnant women with
ferritin <40–60 g/l.
2 abFeSt = 2 or more abnormal iron status parameters; DHE = docosahexaenoic acid; EPA = eicosapentaenoic acid Fer = ferritin; Hb = haemo- globin; ID = iron deficiency; NAID = nonanaemic iron deficiency; Pl = placebo group; RDW = red cell distribution width; traSat = transferrin satu- ration; Tx = treatment group; Zn = zinc protoporphyrin
increased significantly; no change; reduced significantly
Basic measurements to diagnose iron
deficiency
The basic measurements needed to diagnose iron
deficiency are shown in table 3: these are haemo-
globin, haematocrit and erythrocyte count, with cal-
culation or measurement of the red cell indices
mean corpuscular volume (MCV) and mean corpus-
cular haemoglobin (MCH), the percentage of hypo-
chromic erythrocytes (%HYPO), ferritin and C-re-
active protein. The algorithm presented in figure 2
summarises the diagnostic process.
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Figure 2: Algorithm for diagnosis and treatment of iron deficiency (in otherwise healthy adults). BE = basic blood examination; IDA = iron deficiency with anaemia; IDMH = iron deficiency with microcytosis and/or hypochromia; NAID = nonanaemic iron deficiency. Relative, dilutional pseudoanaemia is explained in reference [48].
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Table 3: Relevant tests to define anaemia, NAID, IDMH and IDA.
Parameter Cut-off Comment/caveat
Hb Women: >120 g/l
Men: >140 g/l
Defines diagnosis of anaemia. Cut-off values are affected by gender, age, and ethnicity.
WHO definition is >120 g/l for women and >130 g/l for men.
MCH >28 pg Categorises anaemia
MCV >80 fl Categorises anaemia (owing to a certain instability after blood sampling, less useful than MCH)
%HYPO Percent- age of hypo- chromic erythro- cytes [56–58]
%HYPO <10 Indicates an iron deficiency and its influence on haematopoiesis at an earlier stage, particularly IDMH. Iron deficiency affecting erythropoiesis is followed by an increase in %HYPO within 1–2 weeks. In patients with low ferritin (meaning empty iron stores), a normal %HYPO indicates that erythropoiesis is not yet affected.
Limitation: availability of the method, careful interpretation needed in cases of possible thalassaemia, as in these patients %HYPO rises with normal iron stores [59].
Reticulocyte count, absolute
20–100 × 109/l
Reference values of the manufacturer need to be respected.
Assesses red blood cell production and helps to further classify an anae- mia (hypo- and hyper-regenerative)
Reticulocyte indi- ces [60–63]
MCVr 92–120 fl
(mean cellular volume of reticulocytes)
CHr 28–35 pg [60]
(amount of Hb in reticulo- cytes, measured in Advia 120)
Ret-He 28–35 pg [64]
(amount of Hb in reticulo- cytes, measured in Sysmex NE 2100)
A lowering of the MCVr and, even more specifically, the CHr or Ret-He are very early indicators of the iron demand of erythropoesis. A value <28 pg is equivalent to a functional iron deficiency. CHr or Ret-He react quickly, within 48–72 h, to an increased demand or lowered supply, as compared with e.g. MCV and MCH which react only within weeks.
Limitation: availability of the method
Ferritin 30 g/l The most widely used parameter for IDA.
Limitations: as an acute phase protein, ferritin is increased during in- flammation and infection, after intensive exercise, in pregnancy and with liver damage, see also CRP.
CRP <3 mg/l Acute phase protein, indicating infection and inflammation
Free serum iron - Obsolete, as not representative of the amount of body iron. Only to be used for acute iron intoxication and to calculate transferrin saturation.
Limitations: daytime and interindividual variability. In the morning, val- ues are showing a peak being more than twice as high as values meas- ured 12 hours later. Lowered in acute phase reactions and elevated in haemolysis after blood sampling.
Transferrin satu- ration
>20% <20% indicates iron deficiency
Limitations: acute phase reactions lower the transferrin saturation with- out iron deficiency. Moreover, as free serum iron is used for the calcula- tion transferrin saturation may also vary [65].
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Table 3 (continued)
sTfR Reference values of the manu- facturer need to be respected, as they differ substantially.
Woman: 0.75–1.5 mg/l
Men: 0.75–1.75 mg/l
Indirect marker to define IDMH and NAID. Similar sensitivity to ZnPP for NAID and IDMH. Not influenced by inflammation and ex- ercise [52].
Limitation: mostly elevated during erythropoiesis, so may only be of additional value.
ZnPP [66, 67] <50 mol/mol Hb excludes iron deficient erythropoiesis,
>100 mol/mol Hb indicates iron deficient erythropoiesis
Indirect marker to define IDMH and NAID. Early marker of NAID and increases to higher values in IDMH [53].
Not as much influenced by inflammation as ferritin, is entering routine testing and is of additional value for judging iron status of erythropoiesis.
Hepcidin Not yet a routine laboratory test
Key regulator of iron absorption from erythrocytes [20]
Elevation impairs haematopoiesis [16, 68]
CRP = C-reactive protein; Hb = haemoglobin; IDA = iron deficiency anaemia; IDMA = iron deficiency with microcytosis or hy- pochromia; MCH = mean cellular haemoglobin; MCV = mean cellular volume; NAID = nonanaemic iron deficiency; sTfR = so- luble transferrin receptor; ZnPP = zinc protoporphyrin
Stages of iron deficiency
Figure 3 depicts the stages in the continuum of iron
deficiency, in accordance with the proposition in the
recent consensus paper of the Swiss Society of
Sports Medicine on iron deficiency [48]. When iron
losses exceed absorption or absorption falls below
demand, initially iron stores will deplete, resulting
in a reduced ferritin level. At a certain point, the
stored iron is too low to provide the tissues with suf-
ficient iron. This will induce the production of zinc
protoporphyrin and an increase of soluble transfer-
rin receptor (sTfR). As at this point haemoglobin,
MCV and MCH are still normal; this condition is
called nonanaemic iron deficiency (NAID). NAID
is defined as a deficiency of iron without affecting
haematopoiesis.
If iron balance remains negative, the youngest red
cells will be insufficiently haemoglobinised and
thus appear hypochromic and microcytic, with first
a rise in the percentage of hypochromic erythrocytes
(%HYPO) and a slight but possibly not yet visible
reduction in the MCH and MCV of the entire cell
population [57, 58]. If iron deficiency continues,
MCH and MCV will drop below the lower limit of
the normal ranges (28 pg and 80 fl, respectively) and
iron deficiency with microcytosis and/or hypochro-
mia (IDMH) develops. IDMH is defined as an iron
deficiency affecting haematopoiesis. In this case,
ferritin is <30 µg/l, %HYPO is above 10%, the red
cell indices are quite often, but not always, affected
and the concentration of haemoglobin is still normal
(men >140 g/l, women >120 g/l: haemoglobin limits
defining an anaemia for middle-aged persons origi-
nating from Western European countries) [69].
Ultimately, haemoglobin concentrations will drop
below the lower limit of the normal range and frank
IDA is established. In IDA, ferritin and haemoglo-
bin are lowered and the red cell indices are reduced
or normal [69]. In the diagnostic process it is im-
portant to understand where the iron deficiency
comes from. In addition to identifying populations
at risk, the medical history needs to focus on possi-
ble blood loss (mainly gastrointestinal, possibly re-
lapsing nose bleeding), nutritional deficits and other
gastrointestinal irregularities, the latter possibly re-
vealing a problem with iron uptake, such as coeliac
disease, an important differential diagnosis in a case
of relapsing iron deficiency. In cases of unexplained
IDA, an extensive diagnostic work-up is indicated.
Another interesting situation is the functional iron
deficiency encountered in patients with anaemia of
chronic disorder or a tumour, or haemodialysis pa-
tients. Here, iron demand is higher than the iron sup-
ply out of iron stores. In consequence, hypochromic
reticulocytes and erythrocytes are formed, the hae-
moglobin in reticulocytes (CHr or Ret-He, for expla-
nation see footnote to table 1) falls to <28 pg [60,
61]. This situation is due to elevated interleukin-6
and hepcidin levels seriously impairing iron turno-
ver and may therefore occur with normal or often
even elevated ferritin values, reflecting normal iron
stores [20, 60].
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Figure 3: Stages of iron deficiency. %HYPO = percentage of hypochromic erythrocytes; IDA = iron deficiency anaemia; IDMH = iron deficiency with microcytosis and/or hypochromia; MCH = mean cellular haemoglobin; MCV = mean cellular volume; NAID = nonanaemic iron deficiency; sTfr = soluble transferrin receptor; ZnPP = zinc protoporphyrin
Treatment of iron deficiency
Nutrition
The first step in the treatment of iron deficiency is
correction of the nutritional iron intake. In nutrition,
iron is present as haem iron (mainly in meat) and
free iron (Fe2+ or Fe3+). Oral uptake studies show
that the uptake of haem iron is much better than the
uptake of free iron [70]. For the latter, uptake of Fe2+
is better than uptake of Fe3+ [71]. Meat, liver, poul-
try or fish contain haem iron as well as free iron. A
vegetarian diet contains only free iron. The bioavail-
ability of iron is very variable, ranging from 5 to
15%, and greatly depends on iron stores [72]. In the
case of iron deficiency, a significant increase in iron
bioavailability up to 35% can be observed [73]. Fur-
thermore, iron uptake in the intestinal tract is influ-
enced by various nutritional factors, including both
enhancers and inhibitors. Substances enhancing
iron uptake are vitamin C, peptides from partially
digested muscle tissue, fermented food, and organic
acids like malate or citrate. Substances inhibiting
iron uptake are phytates, oxalates, polyphenols (in
black tea and coffee), peptides from partially di-
gested vegetable proteins and calcium [49, 50]. The
nutritional intake should be 14 mg per day [74, 75].
General recommendations for an optimal dietary
iron intake in sports include an adequate energy in-
take, especially for athletes with low body mass in-
dex as they suffer more frequently from iron defi-
ciency [18, 19, 76]. Whether catabolism related to
low energy intake influences the hepcidin regulation
and down-regulates iron uptake remains open to de-
bate. In general, regular consumption of meat, poul-
try or fish at least five times per week is recom-
mended as they are the main contributors to nutri-
tional iron intake. Complementary eating of whole-
meal products and daily legumes and green vegeta-
bles is suggested. Furthermore, it is beneficial to re-
place tea and coffee by a glass of orange or citrus
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fruit juice with an iron containing meal as vitamin
C enhances iron uptake [50, 73]. For vegetarians,
the goal is to reach a high load of iron through their
vegetable diet. Even if nutrition is important in iron
homeostasis, in the human organism an IDA cannot
be corrected by nutrition alone, as this would mean
eating kilograms of iron-containing products (e.g.,
liver).
Oral iron
Usually, dietary counselling and oral iron therapy
are combined. Oral preparations differ in the
amount and type of iron (Fe2+ or Fe3+), their com-
plex-forming substrate and their galenic form.
Novel products combine iron with vitamin C. In a
dosage-finding study in elderly patients with IDA,
Rimon et al. compared three dosages of oral iron:
15, 50 and 150 mg per day. They were able to show
that iron supplementation at the level of the recom-
mended daily allowance (RDA: 15 mg of elemental
iron) already led to significant increases in the iron
status. In these anaemic elderly people, administra-
tion of 50 and 150 mg of elemental iron did not
show further benefit, but had significantly more side
effects, particularly in the highest dose group [77].
As there is further evidence that oral iron loading
increases circulating hepcidin [78], the recom-
mended dose of oral iron should not be too high. In
a recent comparison of randomised controlled trials
of oral iron supplementation that looked at iron sta-
tus and performance in active women, 100 mg of
FeSO4 (approximately 20 mg elemental iron) was
shown to be effective [79]. We therefore recom-
mend a supplement of 28 to 50 mg of elemental iron
once daily. Oral iron is in general well tolerated and
effective [80]. Side effects of oral therapy are
mainly gastrointestinal, including nausea, dyspep-
sia, constipation or diarrhoea [49, 50, 81]. They are
usually not severe, but are directly proportional to
the amount of iron ingested. Some individuals with
an existing tendency to constipation benefit from
drinking additional fruit juice to prevent heavy con-
stipation. Otherwise compliance may be seriously
affected.
Intravenous iron
Only when oral therapy repeatedly fails or immedi-
ate restoration is needed should intravenous therapy
be considered. At the moment, two preparations are
available in Switzerland, one containing a Fe3+-sac-
charose complex [82] and the other a Fe3+-carboxy-
maltose complex [83]. The dosage is dependent on
the severity of the iron deficiency. In one admin-
istration, 200 mg Fe-saccharose, or 500 to 1000 mg
Fe-carboxymaltose can usually be given [81]. In the
case of IDA, the iron deficit to be replaced may be
calculated with the Ganzoni equation: total iron def-
icit = weight (kg) × (target Hb – actual Hb) (g/l)
×2.4 + iron stores (mg); as iron stores in patients
weighing >35 kg, 500 mg should be used. This
equation helps to estimate the amount of iron
needed.
The main advantage of intravenous therapy is the
immediate correction of the iron deficiency and res-
toration of the empty iron stores. Generally, compli-
ance with intravenous iron supplements is good.
Side effects may include transient disturbance of
taste, headache, dizziness, myalgia and fever. Seri-
ous adverse reactions, such as hypotonic and ana-
phylactoid reactions, tachycardia and arrhythmia,
dyspnoea and bronchospasm may be observed, alt-
hough they are very rare [81]. Moreover, transient
and usually asymptomatic hypophosphataemia is
frequently observed after the administration of Fe-
carboxymaltose. It is still under discussion whether
hypophosphataemia may possibly be a cofactor for
cardiac events [84]. Nowadays, serious side effects
are rare. For Fe-saccharose and Fe-carboxymaltose,
no fatal outcome has been reported in Switzerland.
Internationally there has been just one fatality: an
already severely ill patient treated with Fe-carboxy-
maltose. This is in contrast to the previously used
iron-dextran products, which have a much higher
rate of serious and fatal side effects. In 2013, an-
other type of intravenous iron, Fe-oxytol, was with-
drawn because of severe hypersensitivity reactions
in four patients, including one with fatal outcome,
observed within 9 months after approval by the li-
censing authorities in Switzerland [85, 86]. Even
with the use of the new preparations, serious ad-
verse reactions cannot be excluded, and the admin-
istration of intravenous iron preparations is only
recommended in settings where resuscitation skills
are available and patient observation for 30 minutes
after the end of iron administration can be guaran-
teed [82, 83]. In general, the frequency of side ef-
fects seems to be lower when the intravenous iron is
administered as an infusion instead of a slow bolus
injection. Importantly, the exact dilution given by
the manufacturer needs to be followed.
Control of adequate iron stores and prevention
of excessive treatment
To monitor the efficacy of therapeutic measures we
recommend repeating the basic blood tests 6 to 8
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weeks after the start of the nutritional measures, oral
therapy or intravenous iron administration.
Depending on the blood results, therapy will be con-
tinued or modified with the aim to reach or keep iron
stores within the normal range. Treatment ap-
proaches may be combined. Athletes with recurrent
low iron stores may benefit from intermittent oral
substitution to preserve iron stores (e.g., two iron
tablets per week or daily supplementation with 14
or 28 mg), as well as nutritional counselling. For
vegetarians, a similar therapeutic approach to pre-
vent iron deficiency may be recommended: 28 to 50
mg elemental iron three times per week instead of
meat intake, or daily supplementation with at least
14 or 28 mg of iron, will usually cover iron demand.
As iron homeostasis is exclusively and meticulously
controlled by iron uptake through the intestinal tract
[87], and as there is no pathway to eliminate iron in
the event of overload, iron supplementation should
always be careful. In extreme cases, chronic over-
load may lead to secondary haemochromatosis. Fur-
thermore, excessive supplementation of oral or in-
travenous iron is thought to increase oxidative stress
and production of free radicals [88, 89], and oxida-
tive stress is suggested to play a role in causing can-
cer [90, 91]. This must be critically appraised as the
intention of treatment for iron deficiency is still
“first do no harm” [92].
It has been shown in mice that oral iron supplemen-
tation enhances colonic tumour development [93].
Data in humans suggest that iron may increase the
risk of colorectal cancer [94]. A recent meta-analy-
sis showed on the one hand a tendency toward a pos-
itive association between high intake of haem iron
and cancer risk; on the other hand, high levels of bi-
omarkers of iron stores implied a low cancer risk
[95]. Further prospective and experimental studies
are needed to evaluate the possible influence of iron
in carcinogenesis.
Iron deficiency in children and adoles-
cents
Total iron requirements in children and adolescents
are markedly increased because of additional needs
for the expansion of the total blood volume and
mean haemoglobin mass, as well as for the increase
in lean body mass during growth [96]. In adolescent
females the onset of menarche is associated with an
increased requirement for iron. The mean total iron
requirement for adolescents reaches 1.8 mg per day
for boys and 2.2 mg per day for girls (in females
with heavy periods it is considerably more), which
corresponds to more than double that in the preado-
lescent period [15, 97]. Haematological normal val-
ues for children and adolescents are different from
adults and this should always be considered. We
recommend defining the lower level of normal fer-
ritin as 15 µg/l for children aged between 6 and 12
years, 20 µg/l between 12 and 15 years and 30 µg/l
for 15- to 18-year-old adolescents [69].
As in adults, in a case of NAID, dietary counselling
is the first step, often combined with oral therapy.
Iron requirements (RDA) are 8 mg per day for 9- to
13-year-old children, and 11 mg per day for male
and 15 mg per day for female adolescents older than
13 years. Careful management, especially of the
menstruating teenage girl and the vegetarian athlete,
is warranted [19, 75]. If the iron deficiency results
in IDMH or IDA, further supplementation should be
considered. Comparable to the therapy in adults, ei-
ther Fe2+ or Fe3+ preparations can be used for oral
substitution. The dosage for both preparations is 3
mg/kg/d up to a maximum of 50 mg elemental iron
for 3 months in two or three doses per day. The Fe2+
preparation is recommended as medication of
choice owing to a better bioavailability. As in
adults, measurement of haemoglobin, red cell indi-
ces, ferritin and CRP after 6–8 weeks of treatment
is necessary in order to observe any response to and
compliance with treatment.
Conclusions and recommendations
Iron deficiency is frequent and relevant as all stages
of iron deficiency, IDA, IDMH and NAID affect
physical performance and cognition.
To diagnose iron deficiency haemoglobin, haema-
tocrit, % HYPO, MCV, MCH and ferritin are first-
line parameters to assess. For a valid interpretation
of the results it is necessary to exclude acute phase
reactions that may interfere, such as training ses-
sions and infectious diseases (patient history and
measurement of CRP). In unclear situations a sec-
ond measurement of the same parameters or the ad-
ditional measurement of zinc protoporphyrin, solu-
ble transferrin receptor and transferrin saturation
may be helpful.
Ferritin values below <15 µg/l are very specific for
empty iron stores. Ferritin values from 15 to 30 µg/l
correspond to low iron stores. A ferritin value of 30
µg/l should be taken as a reasonable cut-off for adult
men and women and older adolescents (15 years and
older). For younger adolescents aged from 12 to 15
years a cut-off of 20 µg/l and for children from 6 to
12 years a cut-off of 15 µg/l are recommended.
Every case of unexplained or relapsing iron defi-
ciency anaemia warrants an extended diagnostic
work up.
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Therapy of iron deficiency consists of nutritional
counselling, including a sufficient energy intake and
haem iron intake (meat, poultry, fish) five times per
week with the addition of legumes and green vege-
tables (e.g., spinach, fennel), usually combined with
oral iron supplementation. Oral iron preparations at
a dosage of 28 to 50 mg of elemental iron daily are
appropriate, as the nonserious but disturbing gastro-
intestinal side effects are related to iron dosage and
preparation. Consider enhancers (vitamin C) and
recommend avoidance of inhibitors (coffee, black
tea, phytates, calcium) of iron uptake to increase ab-
sorption. Patients with repeatedly low ferritin values
benefit from intermittent oral substitution to pre-
serve iron stores, for example two iron tablets per
week as maintenance therapy. Only in selected
cases with severe incompatibility with oral therapy,
a concomitant disease (e.g., depression) or repeated
and plausible nonresponse to oral treatment, intra-
venous iron therapy may be considered.
Long-term daily oral iron intake or intravenous sup-
plementation in the presence of normal or high fer-
ritin values is not recommended and may be harm-
ful.
Parts of this article have already been published in:
Clénin G, Cordes M, Huber A, Schumacher YO, No-
ack P, Scales J, Kriemler S. Iron deficiency in sports
– definition, influence on performance and therapy.
Swiss Med Wkly. 2015;145:w14196.
Acknowledgements
We thank the author team of the consensus paper of the Swiss
Society of Sports Medicine “Iron deficiency in sports - defini-
tion, influence on performance and therapy” recently published
in this journal: Dr Mareike Cordes, Prof. Dr Andreas Huber,
Prof. Dr Yorck Olaf Schumacher, Dr Patrik Noack, Dr John
Scales and Prof. Dr Susi Kriemler. This consensus paper and
the contribution of all named authors was the foundation for this
“current opinion” article.
Disclosure statement
No financial support and no other potential conflict of interest
relevant to this article was reported.
Correspondence:
German Clénin
Sportmedizinisches Zentrum Ittigen bei Bern Haus des Sports
CH-3063 Ittigen
german.clenin[at]smzbi.ch
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