Access to this full-text is provided by Springer Nature.
Content available from Biological Trace Element Research
This content is subject to copyright. Terms and conditions apply.
Vol.:(0123456789)
Biological Trace Element Research
https://doi.org/10.1007/s12011-024-04289-z
REVIEW
Iron Metabolism, Calcium, Magnesium andTrace Elements: AReview
TaraRolić1,2 · MazyarYazdani3 · SanjaMandić1 · SoniaDistante3
Received: 29 March 2024 / Accepted: 22 June 2024
© The Author(s) 2024
Abstract
Iron (Fe) is fundamental to life on earth. In the human body, it is both essential and harmful if above threshold. A similar
balance applies to other elements: calcium (Ca), magnesium (Mg), and trace elements including copper (Cu), zinc (Zn),
lead (Pb), cadmium (Cd), mercury (Hg), and nickel (Ni). These elements share some proteins involved in the absorption
and transport of Fe. Cu and Cd can inhibit Fe absorption, while excess of Fe may antagonize Cu metabolism and reduce
ceruloplasmin (Cp). Excessive Fe can hinder Zn absorption and transferrin (Trf) can bind to both Zn and Ni. Ca is able to
inhibit the divalent metal transporter 1 (DMT1) in a dose-dependent manner to reduce Fe absorption and low Mg concentra-
tions can exacerbate Fe deficiency. Pb competitively inhibits Fe distribution and elevated Cd absorption reduces Fe uptake.
Exposure to Hg is associated with higher ferritin concentrations and Ni alters intracellular Fe metabolism. Fe removal by
phlebotomy in hemochromatosis patients has shown to increase the levels of Cd and Pb and alter the concentrations of trace
elements in some types of anemia. Yet, the effects of chronic exposure of most trace elements remain poorly understood.
Introduction
Iron (Fe) is abundant in the human body and is a vital ele-
ment for sustaining life. Its function spans across various
biological processes, from oxygen transport in cells to aid-
ing DNA synthesis [1]. Maintaining a precise balance in Fe
metabolism is essential for human well-being, necessitat-
ing regulation at multiple levels. Central to this regulatory
framework is intestinal Fe absorption which is tightly con-
trolled by a number of proteins such as divalent metal trans-
porter 1 (DMT1), ferroportin (FPN1), transferrin (Trf), and
transferrin receptors (TrfR). Ferroxidases such as duodenal
cytochrome B (DCYTB), ceruloplasmin (Cp), and hephaes-
tin are coordinated by hepcidin (Hep) to ensure efficient Fe
acquisition and utilization. As one dives deeper into Fe
metabolism, the intricate relationships between Fe, calcium
(Ca), magnesium (Mg), and trace elements become apparent
[2]. There are many avenues still to explore for investigating
the interactions of Fe with other elements during absorption
and distribution. The impacts on different organs still need
exploration. In this review, we refer to elements Fe, calcium
(Ca), and magnesium (Mg), and trace elements according to
the definition of Thomas [3].
Adequate intake of Ca, Mg, and trace elements, including
copper (Cu) and zinc (Zn), is essential for human health [4].
These elements not only support basic physiological func-
tions but offer insights into disease states when measured in
diagnostic settings. Some of these non-essential elements
can pose significant health risks due to their interference
with Fe regulatory mechanisms when they are present in the
body. For instance, lead (Pb), cadmium (Cd), mercury (Hg),
and nickel (Ni) whichare categorized as non-essential trace
elements. These elements can enter the body through occu-
pational exposure or environmental contaminants including
factors influenced by lifestyle choices such as diet and smok-
ing [5]. Understanding the impact of these trace elements on
Fe metabolism and overall health is crucial for developing
effective strategies to mitigate their adverse effects. How-
ever, extensive research on how trace elements interact and
influence health is still lacking [6, 7].
The historical narrative surrounding Fe and its impact on
human health is diverse with evidence for its significance
dating back to ancient civilizations [8, 9]. Clinical manifes-
tations of altered Fe homeostasis, e.g., changes in skin color,
have been documented throughout history [8]. Notably, the
influence of Fe on health and disease has been recognized
since Egyptian, Greek, and Roman times. In the seventeenth
* Sonia Distante
sdistant@ous-hf.no
1 Faculty ofMedicine, University ofOsijek, Osijek, Croatia
2 Osijek University Hospital Centre (Klinički bolnički centar
Osijek), Osijek, Croatia
3 Oslo University Hospital, Oslo, Norway
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
T.Rolić et al.
century, a condition described as “green disease” (chlorosis)
was treated with Fe supplements [9]. During the nineteenth
century, a common ailment affecting young women was
described as being characterized by lethargy, decreased work
capacity, paleness, and amenorrhea. Interestingly, young
women working in copper factories did not develop chloro-
sis. With contemporary knowledge regarding the interplay
between Fe and Cu, exposure to Cu-salts in the workplace
seems to have positively influenced Fe homeostasis. Nev-
ertheless, distinguishing Cu deficiency from Fe deficiency
anemia can be challenging [8].
Understanding of the essential role of Fe in hemoglobin
synthesis and oxygen transport began to emerge in the early
twentieth century. In the same century, a condition named
“bronze diabetes” was described, in diabetic patients with
pronounced skin pigmentation [10]. Hemochromatosis (from
the Greek words “blood & color”) was described in 1865 by
a French physician. The association of its phenotype with Fe
overload was established in 1890 by a German pathologist,
deepening the understanding of the relationship between Fe
and health [11].
This review aims to evaluate the biological interaction
with Fe of Ca, Mg, and selected trace elements (Cu, Zn, Pb,
Cd, Hg, and Ni) and their roles in certain diseases. Unrave-
ling the complexities of these interactions may enhance the
understanding of how they affect human health.
Iron
Biochemical Properties
Fe is an essential transitional element in biological systems
and exists in two oxidative states: (1) ferric (Fe3+) ion act-
ing as an electron acceptor; (2) ferrous (Fe2+) ion, acting
as an electron donor. This flexibility renders Fe pivotal in
catalyzing redox reactions acting as a cofactor in numer-
ous enzymes. Examples include Fe-sulfur clusters and
heme groups found in hemoglobin, myoglobin, cytochrome,
myeloperoxidase, and nitric oxide synthetases [12]. Conse-
quently, Fe plays an indispensable role in fundamental cellu-
lar functions and overall biological processes. These encom-
pass oxygen transport, aerobic respiration, intermediary and
xenobiotic metabolism, nucleic acids replication and repair,
innate and acquired immunity, and cell signaling pathways.
Fe is predominantly chaperoned by proteins, enabling cells
to harness its benefits while mitigating its potential harmful
effects [13].
The average total amount of Fe in the human body is
40–50mg/kg in adults, with the majority incorporated into
hemoglobin (approximately 2.5g). The remaining Fe is
stored in ferritin, primarily located in the liver, bone mar-
row, and spleen. Humans efficiently conserve and recycle
Fe primarily through erythrophagocytosis in reticuloen-
dothelial macrophages with a recycling rate exceeding 80%
[14, 15]. Both Fe deficiency and excess are associated with
significant pathophysiological conditions. Fe balance is
tightly controlled at a systemic level through the regulation
of bioavailable Fe absorption. Unlike other elements, there
is no physiological regulatory mechanism for excreting Fe.
Intestinal absorption of bioavailable Fe determines Fe con-
centration in the body, with all unabsorbed Fe remaining in
the intestine and potentially contributing to oncogenic pro-
cesses. The amount of Fe in feces is ten times higher than in
most tissues [16]. In this regulation process, several proteins
play key roles. For instance, Trf binds Fe3+ to reduce its
toxicity and facilitate blood transport while ferritin serves
as a storage center and can release Fe when it is needed in
the organism.
Intestinal Absorption
Absorption of dietary Fe is a variable and dynamic process
and serves as an initial point for the regulation of Fe balance.
Normally, 1–2mg of Fe is absorbed daily from the diet in
the duodenum, and an equal amount of Fe is lost through
shedding of gastrointestinal cells and epithelial desquama-
tion. In general, humans absorb only 5 to 35% of ingested Fe,
depending on various interactions between food compounds
and the source of Fe. Bioavailable Fe refers to the portion of
Fe absorbed from the diet that is accessible for use by cells
in the body [2, 13, 17–19].
Heme Fe (predominantly from animal sources) is con-
sidered the most available source of Fe with an absorption
rate of 10–70%. Mechanistically, heme Fe is transmitted
across the apical membrane through heme carrier protein
1 (HCP1) into enterocytes, where heme oxygenase releases
Fe while catabolizing heme to biliverdin [19]. Non-heme
Fe (mostly derived from plants) has an absorption ratio of
10–20% [20]. Its absorption is limited to the duodenum,
whilst heme-Fe can be absorbed in other parts of the intes-
tine [21]. Non-heme Fe is primarily in the ferric form, pos-
ing an entry obstacle that is overcome by reduction to Fe2+
by Fe reductase (DCYTB), influenced by factors such as pH
(Fig.1). The Fe2+ then enters the enterocyte through DMT1
or Zrt-Irt-like protein 14 (ZIP14) at the apical membrane.
Upon entry to cells, Fe can be used for protein and nucle-
otide synthesis, mitochondrial pathways regulating tran-
scription via iron responsive element (IRE) binding proteins,
stored in ferritin or released into the blood. The export of
Fe is mediated by FPN1, often aided by hephaestin or Cp.
Hephaestin is a ferroxidase that oxidizes Fe2+ to Fe3+ after
Fe passes the basolateral membrane to bind Trf [21]. Once
bound to Trf, Fe can enter the blood and be delivered to all
cells, primarily through endocytosis of the transferrin recep-
tor (TrfR 1/2). Ferroportin is the only known Fe exporter and
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Iron Metabolism, Calcium, Magnesium andTrace Elements: AReview
is critical in regulating Fe homeostasis at the cellular level
by post-translational regulation [21, 22].
If Fe storage is replete in the body, the liver will pro-
duce Hep which is a key player in controlling Fe absorption
from absorptive enterocytes, Fe-recycling macrophages, and
hepatocytes. Hep binds to FPN1 and induces its internaliza-
tion and degradation in lysosomes, resulting in all absorbed
Fe remaining in the cell and being unavailable for circula-
tion. This is a defensive and immune response of the body
to conserve Fe for physiological needs and make it unavail-
able for microorganisms. Several factors can stimulate or
inhibit this process and errors in this regulation can lead
to Fe deficiency or Fe overload and be associated by Fe-
related diseases [22, 23]. Hep also downregulates both TfR1
and DMT1 through a yet unknown mechanism [24]. Thus,
higher Hep expression inhibits dietary Fe absorption and Fe
release from recycling macrophages and other body stores
[14]. In contrast, a decrease in Hep concentrations promotes
Fe availability. The interaction between Hep and FPN1 is
one aspect of system regulation, other aspects include cyto-
solic iron-responsible and regulatory proteins (IRP-IRE),
hypoxia-responsive pathways (HIF), and erythropoietin
signaling. These types of Fe regulation are beyond the scope
of this review and can be found elsewhere [11, 13, 25].
Fig. 1 The absorption process of iron (Fe) at the enterocyte level.
Heme-Fe is absorbed via the hem carrier protein 1 (HCP-1), while
non-heme Fe is absorbed through the divalent metal transporter 1
(DMT1) after conversion of Fe3+ to Fe2+ by duodenal cytochrome
B (DCYTB). Fe can either be stored in ferritin or exported into the
bloodstream by ferroportin (FPN1), the sole known Fe-exporter,
which is regulated by Hepcidin (Hep) through downregulation.
Hephaestin and ceruloplasmin (Cp) facilitate the oxidation of Fe2+
to Fe3+ for binding to transferrin (Trf). Cells dependent on Fe have
transferrin receptors on their surface, allowing them to uptake Fe
from Trf. Cp also binds copper (Cu) and transports it to cells. Cu
enters the enterocyte via the Copper transporter 1 (CRT1). Magne-
sium (Mg) and calcium (Ca) enter the enterocyte through specific
transporters (TRPM6 and TRPV6), and both elements are exported
into the blood through ATP-ase activity. Zinc (Zn) is imported via
ZIP transporter(s), while efflux is via Zn transporter (ZnT) (created
with BioRender.com)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
T.Rolić et al.
Metabolism andHomeostasis
While all cells have the capability to import, export, or store
Fe, certain cells are specialized for specific Fe-related func-
tions. These include erythroblasts for Fe uptake, enterocytes
and macrophages for Fe export, and hepatocytes for Fe stor-
age [14]. Fe metabolism and homeostasis exemplify a com-
plex circular economy governed by dietary absorption and
regulated by hormones, the expression of relevant proteins
and Fe discharge from macrophages. Anemia is a significant
global public health concern affecting approximately one-
third of the world’s population [26]. Children, adolescents,
women of reproductive age, and the elderly are particu-
larly vulnerable. Diagnosis of anemia relies on measuring
hemoglobin concentration, using cut-off values < 130g/L
for males and < 120g/L for non-pregnant females, though
these thresholds are subject to debate due to ethnic differ-
ences [26]. Fe deficiency ranks among the top three causes
of anemia worldwide, contributing to up to 50% of all cases.
Deficiencies in vitamins, Cu and Mg can also lead to anemia
due to their specific roles in hemoglobin and red blood cell
production. Valuable insights can be obtained by exploring
the interplay of elements including Zn, Cu, Mg, and Ca in
anemia. Studies have found deficiencies in these elements
in anemic children compared to non-anemic individuals
[27]. Serum ferritin concentration is the most commonly
used parameter to diagnose Fe deficiency. However, ferri-
tin concentration can be affected by obesity, inflammation,
chronic alcohol intake, liver or kidney disease, and cancer.
Furthermore, discrepancies in ferritin measurement methods
may hinder result interpretation.
Despite the clinical significance of elements in Fe-related
pathologies, new biomarkers such as soluble transferrin
receptors (sTrfR), Hep, and non-transferrin bound iron
(NTBI) are not routinely measured due to limited sensitiv-
ity, specificity, and standardization. Standardized sampling
practices are important as serum Fe concentrations meas-
ured by spectrophotometric methods can vary up to 70%
daily within individuals. [28]. Reduced Fe recycling from
macrophages, as observed in inflammation, can lead to ane-
mia. Fe deficiency initially presents clinically as anemia [1].
True Fe deficiency is defined by diminished total Fe stores
but reduced circulating Fe concentration can cause anemia
due to functional Fe deficiency. This impairs erythropoie-
sis despite adequate or elevated Fe stores [13]. Functional
Fe deficiency is a hallmark of anemia of chronic disease or
anemia of inflammation associated with many chronic con-
ditions. Inflammatory cytokines such as interleukin-6 acti-
vate the JAK/STAT3 signal pathway leading to induction of
Hep transcription [13, 19]. Consequently Hep reduces FPN1
expression, inhibiting dietary Fe absorption and Fe recycling
in macrophages contributing to limited Fe bioavailability for
microorganisms or oxidative stress in chronic inflammation
[23, 29].
Iron deficiency is common in chronic kidney disease due
to the decreased Fe absorption caused by elevated Hep con-
centrations. Increased serum Hep in kidney diseases is partly
due to reduced clearance of Hep as indicated by the inverse
correlation of Hep with estimated glomerular filtration rate.
As chronic kidney disease progresses, the kidneys fail to
produce sufficient erythropoietin. This means that Fe cannot
be released from stores rapidly enough to meet the demands
for erythropoiesis, leading to functional Fe deficiency [13,
30, 31]. Conversely, Fe overload often occurs when errors
take place in the Hep-FPN1 axis leading to FPN1 resistance
to Hep and causing hemochromatosis. Hereditary hemochro-
matosis is an autosomal recessive disorder characterized by
excessive Fe absorption and tissue deposition, potentially
leading to severe complications such as cirrhosis and liver
cancer. Assessing body Fe stores is crucial and consistently
elevated ferritin concentrations combined with Trf satura-
tion over 45% are indicative of primarily hemochromatosis.
Mutations in the Hep regulatory and transmembrane pro-
tease serine 6 (TMPRSS6) genes, result in Fe-refractory-Fe
deficiency anemia due to the inability to suppress Hep pro-
duction in the liver [13, 14, 31]. Individuals with this disease
do not respond to oral Fe supplementation and only partially
respond to parenteral Fe supplementation. This is because of
Hep-mediated FPN1 degradation, which mobilizes Fe from
parenteral preparations [13]. Hep regulates FPN1 expression
in macrophages, it is upregulated by heme and downregu-
lated by inflammatory cytokines [14, 22].
The Interplay Between Iron andOther Elements
The dynamic interaction between Fe and other elements
primarily occurs in the small intestine, with the duodenum
and jejunum serving as crucial sites for absorption. The
efficiency of element absorption is a complex process and
it is influenced by various factors. These include the chemi-
cal form of the element, dietary composition, intestinal pH,
the physiological condition of the individual, and the pres-
ence of other minerals, elements, inhibitors, and enhancers.
The mechanisms involved in the absorption of elements are
passive transport (e.g., Zn), active transport (e.g., Ca), or a
combination of both. Research suggests that there may be
competition from other elements for the intestinal Fe absorp-
tion pathway (Fig.1). Notably Cu and Cd have been identi-
fied as significant inhibitors of Fe2+ uptake, whereas Hg and
Pb do not cause such an effect [32].
Humans and animals have developed intricate mecha-
nisms for both absorbing and excreting essential trace ele-
ments as well as Ca and Mg. Disruption in homeostasis
resulting in inadequate balance (deficiency or excess) can
profoundly affect human health. The interaction between
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Iron Metabolism, Calcium, Magnesium andTrace Elements: AReview
Fe, Ca, and Mg with other trace elements is orchestrated by
some key proteins, especially DMT1 and DCYTB. The for-
mer has been implicated in the intestinal transport of Fe, Cu,
Zn, and Cd, whereas the latter is able to change the oxida-
tion state of both Fe and Cu ions [19, 27, 33]. For example,
a main player in Fe export FPN1 may be influenced by Cu.
Cu is actively involved in the function of hephaestin, a Fe2+
oxidase [8, 19]. Understanding the nuanced roles of these
proteins and the broader interaction between Fe, Ca, Mg,
and trace elements is essential not only for advancing our
understanding of human physiology but also for addressing
public health concerns.
In non-anemic adolescents, Choi etal. found that Fe con-
centrations correlated inversely (negatively) with Pb and Cu.
In contrast, Pb correlated positively with Zn and correla-
tion with Fe concentration was not observed for Zn and Cd
[34]. The absorption of both Mg and Ca was found to be
closely related to Fe in β-thalassemic patients compared to
a control group. Mg was found to be high in thalassemic
patients, whilst Ca was lower compared to the control group
[35]. These three elements can compete for absorption in
the intestinal, especially when they are consumed in large
quantities. Whilst consumption of Ca has a reciprocal rela-
tionship with Mg absorption, the mechanism by which they
interact individually or synergistically with Fe metabolism
is still not fully understood [36]. Bolann and coauthors in
their study showed that venipuncture in hemochromatosis
patients led to changes in trace element metabolism, includ-
ing increased the absorption of potentially toxic elements
[37].
Essential Elements: Copper, Zinc, Calcium,
Magnesium
Cu and Fe share some physicochemical properties and their
interactions have been previously acknowledged [8]. Cu may
positively impact the absorption, transport, and utilization
of Fe, whilst Fe may antagonize Cu metabolism. When Fe
stores are depleted, Cu is redistributed to crucial tissues
involved in regulating Fe balance, such as the intestine,
liver, and blood. Cu may enhance Fe transport in enterocytes
and increase the synthesis of Cp in hepatocytes, which is a
significant circulating ferroxidase capable of releasing Fe
from stores. Aceruloplasminemia is a rare genetic disease
characterized by a gene mutation that reduces or abolishes
Cp production, leading to Fe accumulation in tissues [33].
Interestingly, Cu depletion impairs the biosynthesis of Cp
resulting in a similar Fe overload phenotype seen in acerulo-
plasminemia. Cu influences DNA binding activity, hypoxia-
inducing factor (HIF) binding and modulates intestinal Fe
homeostasis [8]. The regulation of Cu metabolism responds
to physiological demand in the organism. Metallothionein, a
protein binding both Cu and Zn with a higher affinity for Cu,
plays a role in this regulation process. Depleted Cu concen-
trations are common in conditions such as hemochromatosis
or when taking high doses of Fe supplements [8]. Notably
in cases of Fe deficiency, Cu promotes Fe absorption in the
intestine however compared to intestinal Fe absorption, less
is known about the regulation of Cu absorption.
Absorption of Cu starts in the duodenum where Cupric
ion (Cu2+) from the diet needs to be reduced prior to absorp-
tion (to cuprous ion (Cu+)) by DYCTB and hephaestin,
among other cupric reductases. Cu+ is then transported into
enterocytes through specific transporters such as Cu trans-
porter 1 (CTR1) [38]. In Fe depletion, DMT1 can transport
Cu, especially when little or no competing Fe ions are avail-
able for DMT1 in the intestine when Cu becomes a plausible
ligand for this transporter. In the liver, Cu can be utilized,
stored (as metallothionein), or incorporated into Cp. Similar
to Fe, Cu is transported to the liver by binding to proteins
(e.g., albumin) or amino acids (e.g., histidine). Ceruloplas-
min and hephaestin share significant homology to each other
and both incorporate Cu into their active sites and possess
the capability to oxidize Fe [19].
Deficiency of Cu leads to defective Fe absorption with
concomitant impaired erythropoiesis. The impact of Cu
on hemoglobin synthesis is unclear but it is assumed that
Cu may facilitate Fe import or utilization in mitochondria
[8]. Moreover, Cu stimulates the synthesis of the biologi-
cally active form of Hep (Hep-25), which exhibits a high
affinity for Cu binding [39]. Cu treatment of hepatoma cells
through transactivation of the Hep antimicrobial peptide
gene (HAMP) showed changes in the activity and expression
of DMT1 (including its internalization) after Hep signal-
ing, similar to the regulation of Hep-FPN1 interaction [39].
Recently, the Cu-binding properties of Hep-25 were har-
nessed in a novel detection assay for human Hep in serum
[40]. Additionally, Cu may boost the antimicrobial and bac-
tericidal properties of Hep-25 and influence FPN1 [41]. A
deficit of Cu increases Zn absorption, whilst high supple-
mental Zn intake hinders intestinal Cu absorption, which
concomitantly could induce severe Cu deficiency [8, 34].
Zn is a cofactor of 300 enzymes and plays a crucial role in
nucleic acid metabolism, cell replication, tissue repair, and
growth [42]. It also influences production, storage, and secre-
tion of hormones and is ubiquitously present in all tissues, with
the highest concentrations found in muscle, bone, and liver
[43]. Zn has a critical role in heme synthesis (α-aminolevulinic
dehydratase) and erythropoiesis [44, 45]. Its absorption occurs
across the intestinal lining through specific a Zn transporter
family (ZIP) including ZIP4, ZIP5, and ZIP14 which has been
shown to transport both Fe and Zn in hepatocytes [8, 13, 43].
Zn is not a substrate for DMT1, and intestinal interactions are
mediated by non-DMT1 mechanism [43]. The body maintains
a stable concentration of Zn across a broad spectrum of dietary
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
T.Rolić et al.
intake, suggesting the presence of an effective homeostatic
mechanism in the organism to maintain balance [46].
Zn is stored as metallothionein and proteins includ-
ing albumin (60%), α2-macroglobulin, and Trf (10%) are
responsible for transporting Zn in the blood [43]. Transferrin
transports both Fe and Zn, meaning that excessive Fe can
compete with Zn absorption in the intestine and that Zn con-
centration increases when Fe concentration decreases [47].
Zn deficiency is associated with both reduced Fe absorp-
tion and elevated accumulation of Fe in tissue [43]. In a
case–control study, Abdelheim and co-authors found that
Zn concentrations were lower in subjects with Fe deficiency
compared to a healthy control group. The same study pro-
posed joint supplementation of Zn and Fe, particularly in
patients with severe gut epithelial dysfunction.
Biomarkers for Zn deficiency have not been established
to date [43]. Invivo studies suggested the possible role of
FPN1 in exporting Zn and of Trf in binding Zn. Interest-
ingly, excess accumulation of Fe may reduce Zn absorption
and high concentrations of Zn may reduce Fe absorption [8,
34, 47]. Experimental animal models and invitro studies
on Zn deficiency documented Fe deficiency anemia as well
as distribution/accumulation of Fe in tissues via induction
of DMT1 and FPN1 triggering Fe uptake. Moreover, cross-
sectional studies in humans revealed a positive association
between Zn and hemoglobin, red blood cell indices, and fer-
ritin. Biomarkers of Fe were higher in Zn replete subjects
compared to Zn-deficient subjects. It has been suggested
that an underlying Zn deficiency could induce Fe deficiency
by blocking intestinal absorption and Fe mobilization from
tissues [43]. Although Zn deficiency alone does not result in
anemia, it can coexist with Fe deficiency. Excess Zn intake
interferes with Cu uptake and may result in a Cu deficiency
that eventually leads to anemia [45].
Zn is a key modulator of Fe absorption and tissue dis-
tribution. Compromised Zn status leads to a reduction in
pancreatic Zn content, which in turn reduces intestinal Fe
absorption through decreased expression of DMT1 and
FPN1. In terms of mechanisms, the overall impact of Zn
deficiency is linked to the onset of Fe deficiency, caused by
a combination of diminished absorption in the intestines and
reduced mobilization of Fe from storage [43]. Additionally,
Zn may influence Fe homeostasis by regulating Hep expres-
sion in the liver through activation of the hemojuvelin-bone
morphogenetic-SMAD (HJV-BMP-SMAD) pathway. A
Zn-dependent enzyme called matriptase-2 (TMPRSS6)
regulates the levels of HJV by proteolytic degradation. It is
hypothesized that inhibition of matriptase-2 activity under
low Zn concentrations may induce Hep production [43].
Intestinal Zn absorption reduces intestinal absorption of Ca
and Cu, and Ca, Fe, and Cu have a negative impact on Zn
absorption [34, 42]. Some trace elements (e.g., Pb and Zn)
may share the intestinal Fe absorption pathway [2].
Ca is absorbed in the small intestine through a transcel-
lular active transport process mediated by Ca channels and
an electrochemical gradient, as well as through a passive
paracellular process facilitated by tight junctions between
enterocytes [8, 48, 49] (Fig.1). Ca channels play an essen-
tial role in maintaining the steady state intracellular level
of Ca. Despite being a divalent ion, Ca is absorbed by an
independent cellular mechanism (TRPV6) and it is not an
appropriate ligand for DMT1 [49]. Numerous studies have
investigated the effect of Ca on Fe absorption, revealing a Ca
dose-dependent relationship. This is because Ca is the only
element capable of inhibiting both heme and non-heme Fe
absorption, while other inhibitors of Fe affect only non-heme
Fe absorption [2, 49–51]. The negative effect of Ca on Fe
absorption has been examined in single and multiple meal
studies but experimental and epidemiological data from
these studies have not always been consistent, primarily due
to study heterogeneity.
In their review and meta-analysis, Abioye and co-authors
concluded that Ca supplementation in the short term has
a negative effect on Fe status but the magnitude of this
effect is unlikely to be biologically significant [50]. Two
key mechanisms of action have been proposed for Ca and
Fe interactions: (1) the luminal Ca internalization of DMT1
and (2) the interference of Ca with the transfer of Fe across
the enterocyte basolateral membrane [49, 50]. Interestingly,
higher Ca intake had no impact on hemoglobin concentra-
tions [50]. The inhibitory effect depends on the coexistence
of Fe and Ca in the intestine during fasting, so if possible
Ca and Fe supplements should be taken separately [49]. It
remains unclear whether there is a threshold level of Ca
beyond which it can exert inhibitory effects on Fe absorp-
tion. The specific value of the Ca threshold and the potential
factors influencing it are still unknown. Nevertheless, a ran-
domized controlled trial by Keum etal., concluded that high
doses of Ca supplements could reduce the risk of adenomas
progressing to colorectal cancer, and the effect would extend
with continued Ca intake [52].
Mg is widely acknowledged as a cofactor for numerous
enzymes. Its critical role in hemoglobin synthesis means that
deficiency in Mg can disrupt erythrocyte energy metabo-
lism and the inflammatory process, leading to the devel-
opment of anemia. This concept was further supported by
evidence showing that Mg supplementation improved ane-
mia in thalassemic mice and diminished erythrocyte mem-
brane transport abnormalities in patients with sickle cell
disease [53]. Mg is known to be an important coenzyme
of glutathione peroxidase involved in hemoglobin synthesis
based on experiments on animals [54]. In the intestine, Mg
is absorbed through specific transporters like TRPM6 (tran-
sient receptor potential cation channel subfamily M mem-
ber 6) or through passive non-specific diffusion between
cells (Fig.1). Intake of Mg is inversely associated with
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Iron Metabolism, Calcium, Magnesium andTrace Elements: AReview
inflammation, and decreased Mg concentrations in serum
correlate with inflammation, increased production of free
radicals, and decreased Fe serum concentrations. In a cross
sectional study among healthy Chinese adults, intake of Mg
was inversely associated with risk of anemia. The mecha-
nism by which Mg modifies Fe status is unknown however
a lower risk of anemia was observed in individuals with
highest Fe and Mg intakes suggesting Fe and Mg may jointly
affect the risk of anemia [55].
Animal models also demonstrated that Fe deficiency
increased the intestinal absorption of Mg and Ca [56, 57].
In athletes, hemoglobin concentrations and red blood cell
count increased following consumption of Mg supplements
[53]. Deficiency of Fe can lead to an increase in intestinal
Mg absorption and certain Mg salts can raise pH or bind
Fe and therefore negatively affect intestinal Fe absorption
[53, 58]. In an interventional study conducted among female
students, Milinkovic and co-authors suggested that short-
term supplementation with Mg could have a beneficial effect
on Fe biomarkers such as transferrin saturation [53]. An
invitro study showed that Fe absorption can be inhibited by
Mg, however, the combination of Fe supplements with Mg
was not considered a clinical problem. In a case report, Mg
overuse led to Fe deficiency anemia which was refractory
to long-term Fe supplements [59]. Mg deficiency has been
shown to be closely related to a higher rate of anemia occur-
rence, especially among women and older subjects [54].
Non‑essential Trace Elements: Lead,
Cadmium, Mercury, Nickel
Non-essential, xenobiotic, or toxic elements are commonly
present in detectable concentrations within the human
body. They typically infiltrate organisms by mimicking
essential elements and exploiting their inherent transport
systems. These elements gain entry through environmen-
tal, occupational, or intentional exposure, often resulting
in toxicity and the development of pathological conditions
[60, 61].
Pb present in measurable concentrations in the human
body typically results from dietary ingestion. Plants have
the ability to absorb Pb from contaminated soil and water
(with regional variation); Pb can then transfer from plants
to animals and humans. Pb is a harmful trace element and
can affect Fe metabolism, especially in Fe deficiency dis-
ease. In children, Pb can lead to anemia and impair cogni-
tive development [2, 62]. Upon absorption in the intestine
via DMT1, Pb inhibits Fe uptake and can also interfere
with Fe-dependent metabolic processes such as heme bio-
synthesis [27]. Fe deficit increases the absorption of Pb,
whereas a high dietary Fe reduces Pb absorption in the
intestine [27]. A study by Yazdani etal. found that Pb
concentrations in hemochromatosis patients were raised
after venipuncture therapy [63]. Similarly, another study
involving hemochromatosis patients revealed increased Cd
concentrations after venipuncture, compared to healthy
subjects [64].
Cd is among the most widespread toxic elements. With
properties similar to Ca, Cd can disrupt metabolism, lead-
ing to elevated Ca concentrations in urine. Cd has similar
properties to Ca and therefore can disrupt its metabolism
and cause elevated Ca concentration in urine. Cd toxic-
ity is increased in the presence of Ca deficiency and Cd
absorption also reduces concentrations of Fe, Cu, and Zn
[42]. One well-known characteristic of Cd is its accumula-
tion in the kidneys, where its long half-life causes it to act
as a potential. Smokers in particular, are exposed to Cd due
to its presence in tobacco plants that, directly absorb Cd
from the soil [65]. Animal studies suggest that Cd decreases
Fe concentrations by suppressing the expression of DMT1,
FPN1, DCYTB, and Hep at mRNA level [42]. While Cd
may inhibit Fe absorption in the intestine, the interactions
between Cd and Fe remain unclear. In the case of Fe defi-
ciency where DMT1 and FPN1 are upregulated, Cd absorp-
tion is increased [62]. Furthermore, Cd can induce various
forms of anemia: (1) Fe deficiency anemia by competing
with duodenal Fe absorption; (2) hemolytic anemia by
deforming peripheral blood cells; (3) renal induced anemia
by reducing erythropoietin production. Although Cd is able
to bind to DMT1, this protein is not the sole transporter of
Cd in the intestine. In a study using Caco-2 cells (a type
of colorectal carcinoma cell line), Cd was found to inhibit
the expression of the DMT1 gene, leading to decreased Fe
concentrations in serum and resulting in anemia by suppress-
ing Fe transport in the intestine. Cd may also inhibit genes
related to the transport of both non-heme and heme Fe [66].
Similar to Cd, Hg serves no physiological function in
the body. However, both elements have a high affinity for
protein sulfhydryl groups and can be readily transported in
the bloodstream [42].
Environmental Hg contamination primarily affects fish,
shellfish, and other seafood, making dietary intake a com-
mon route of exposure and potentially leading to carci-
nogenic effects in humans. Methylmercury, is efficiently
absorbed by the intestine (up to 95%) and predominantly
bound to hemoglobin (> 90%), it can readily traverse the
blood–brain barrier and accumulate in the brain. Addition-
ally, Hg can contribute to the generation of reactive oxygen
species within cells. In a study by Zabinski and colleagues,
workers exposed to Hg exhibited higher ferritin concentra-
tions compared to control groups [67]. Consistent with these
findings, a positive correlation between Hg and ferritin was
observed by Barany etal. [62]. However, Iturri and col-
leagues concluded that Hg did not significantly inhibit Fe
uptake in mouse models [32].
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
T.Rolić et al.
Ni is considered essential for proper function of some
organisms as it is known to enhance hormonal activity and
is involved in lipid metabolism [68]. However, epidemio-
logical invivo and invitro studies have also demonstrated
its carcinogenic effect [69]. Absorption can occur through
environmental and occupational exposures via the respira-
tory tract, digestive system, and skin. Occupational expo-
sure to Ni through inhalation in factory workers has been
linked to higher rates of lung and nasal cancers [69]. Ni is
transported into the body and cells through Ca channels and
DMT1. It specifically impacts on Ca homeostasis and mim-
ics a hypoxia response, eventually leading cells to undergo
carcinogenic transformation [69]. Ni can prevent the bind-
ing of Fe to Trf and in addition to competing for Fe uptake,
Ni may alter Fe metabolism by increasing Fe IRP-1 bind-
ing activity and reducing Fe availability at the intracellular
level [70]. Untreated and unrecognized Fe deficiency anemia
may result in heightened sensitivity to Ni toxicity [71]. As
described in a case report by Divya etal. a patient’s symp-
toms of urticaria were correlated with the consumption of
green leafy vegetables, chocolates and nuts (i.e., foods rich
in Ni). After proper Fe therapy, urticaria reduced and hemo-
globin concentrations improved in the patient [72].
Conclusion andFuture Perspectives
Iron, similar to “Janus”, the two-faced Roman god can
be toxic as it is essential. Disturbed Fe homeostasis may
result in long-term consequences. This review considers
the complex interplay and regulation of Fe with Ca, Mg,
and selected trace elements, reflecting on the importance
of Fe in selected diseases. The intestinal absorption and
regulatory mechanisms governing systematic Fe homeosta-
sis in relation to other elements, especially divalent ions,
remain insufficiently explained. Numerous proteins includ-
ing DMT1 (which imports Fe2+, Cu, Pb, and Ni), Cp, Hep,
hephaestin (Cu is important in the structure), and Trf (binds
Fe3+, Ni, and Zn) play crucial roles in mediating interac-
tions among elements. Disruption in the absorption or tis-
sue distribution of one element can change the homeostasis
of other(s). Anemia, hemochromatosis, kidney disease, and
carcinogenesis are among the diseases associated with dis-
rupted Fe homeostasis, yet descriptions of the involvement
of other elements in these conditions are scarce. Deficiencies
in Cu, Mg, and Zn can lead to anemia due to their specific
roles in hemoglobin synthesis. Depletion of Cp results in the
accumulation of Fe in tissues. Hemochromatosis patients,
who can experience complications such as liver cirrhosis
and cancer if untreated, can also display elevated Pb and Cd
concentrations when treated with bloodlettings. In kidney
diseases, elevated Hep reduces Fe absorption and contrib-
utes to the development of anemia of chronic disease. Cd
exposure and possible accumulation may complicate kidney
disease. The interplay of elements forms a vicious circle
in the onset of various diseases, making it challenging to
discern cause and effect. The interaction of Fe with other
elements is of particular concern in vulnerable populations,
such as children and adolescents exposed to Pb and women
of reproductive age exposed to Cd. Accordingly, any imbal-
ance in Fe concentration and resulting disease should be
viewed as a complex mechanism involving other elements
and proteins. Today, many laboratories can measure most
of these elements and proteins and thus give a better insight
into the causes of the Fe imbalance. With such a comprehen-
sive approach, it would be possible to achieve more effec-
tive treatment of the patient with improved and longer-term
results.
Future research should focus on a thorough understanding
of the proteins involved in intestinal absorption and tissue
distribution of elements (DMT1, FPN1, Cp, Hep, hephaes-
tin, Trf, and ferritin) and their interaction. Considering the
diverse binding affinities of different elements to proteins,
diverse sample types (full blood, serum, plasma, and urine)
should be differentiated when measuring protein and ele-
ment concentrations. Additionally, the approach to therapy,
whether through dietary intake or supplements, is crucial
in the treatment of long-term anemic patients (suggesting
Ca and Mg supplementation). This review looks at a given
limited number of elements influencing Fe metabolism, pos-
sible Fe interactions with other not here mentioned elements
is an interesting topic for future research.
Abbreviations DCYTB:Duodenal cytochrome B; DMT1:Divalent
metal transporter 1; Ca:Calcium; Cd: Cadmium; Cp: Ceruloplas-
min; CTR :Copper transporter; Cu:Copper; Fe: Iron; FPN1:Fer-
roportin; HAMP:Hepcidin antimicrobial peptide gene; HJV-BMP-
SMAD:Hemojuvelin-bone morphogenetic-SMAD; HCP1:Heme
carrier protein 1; Hep:Hepcidin; Hg:Mercury; HIF:Hypoxia-respon-
sive pathway; IRE:Iron responsive element; IRP:Iron responsive pro-
tein; Mg:Magnesium; Ni:Nickel; NTBI:Non-transferrin bound iron;
Pb:Lead; TMPRSS6:Transmembrane protease serine 6, matriptase-2;
sTrfR:Soluble transferrin receptors; Trf:Transferrin; TrfR:Transfer-
rin receptor; TRPM6:Transient receptor potential cation channel sub-
family M member 6, magnesium channel; TRPV6:Transient recep-
tor potential vanilloid-6, calcium channel; ZIP:Zrt-Irt-like protein;
Zn:Zinc; ZnT:Zinc transporter
Acknowledgements The review stems from a collaborative effort
enabled by the EFLM LabX program, which serves as a professional
exchange platform for laboratory medicine professionals under the
European Federation of Clinical Chemistry and Laboratory Medicine
(EFLM). The authors express heartfelt appreciation to the EFLM for
their invaluable support, as well as to Oslo University Hospital and
Osijek University Hospital for their active involvement in the program.
The authors thank Daniel Charles Turnock, Department of Clinical
Biochemistry, York Hospital NHS, Wigginton, UK for reading the
manuscript and providing valuable feedback.
Author contributions T. R., M. Y., S. M., and S. D. designed and con-
ceptualized. T. R. wrote the main text with cooperation of M. Y., S. M.,
and S. D.and prepared the figure. M. Y., S. M., and S. D. edited and
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Iron Metabolism, Calcium, Magnesium andTrace Elements: AReview
crticaly reviewed the main text. All authors (T. R., M. Y., S. M., and S.
D.) reviewed and approved final version of the manuscript.
Funding Open access funding provided by University of Oslo (incl
Oslo University Hospital).
Declarations
Competing Interests The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
References
1. Silvestri L, Pettinato M, Furiosi V, Bavuso Volpe L, Nai A, Pagani
A (2023) Managing the dual nature of iron to preserve health. Int
J Mol Sci 24:3995
2. Abbaspour N, Hurrell R, Kelishadi R (2014) Review on iron and
importance for human health. J Res Med Sci 19:164–174
3. Thomas L (2023) Clinical laboratory diagnostics. Available online
from: https:// www. clini cal- labor atory- diagn ostics. com/ index.
html. Accessed 20 Oct 2023
4. Sousa C, Vinha AF, Moutinho C, Matos C (2019) Trace miner-
als in human health: iron, zinc, copper, manganese and fluorine.
IJSRM Human 13:57–80
5. Chen QY, DesMarais T, Costa M (2019) Metals and mechanisms
of carcinogenesis. Annu Rev Pharmacol Toxicol 59:537–554
6. Rawee P, Kremer D, Nolte IM, Leuvenink HGD, Touw DJ, De
Borst MH etal (2023) Iron deficiency and nephrotoxic heavy met-
als: a dangerous interplay? Int J Mol Sci 24:5315
7. Savarese G, von Haehling S, Butler J, Cleland JGF, Ponikowski
P, Anker SD (2023) Iron deficiency and cardiovascular disease.
Eur Heart J 44:14–27
8. Doguer C, Ha JH, Collins JF (2018) Intersection of iron and cop-
per metabolism in the mammalian intestine and liver. Compr
Physiol 8:1433–1461
9. Fox PL (2003) The copper-iron chronicles: the story of an intimate
relationship. Biometals 16:9–40
10. Hanot V (1896) Diabete bronze. Br Med J 25:206–207
11. Pantopoulos K (2004) Iron metabolism and the IRE/IRP regula-
tory system: an update. Ann N Y Acad Sci 1012:1–13
12. Ploumi C, Kyriakakis E, Tavernarakis N (2019) Dynamics of iron
homeostasis in health and disease: molecular mechanisms and
methods for iron determination. In: Thermodynamics and Bio-
physics of Biomedical Nanosystems. Demetzos, Pippa. Springer
Nature Singapore Pte Ltd., Series in BioEngineering
13. Dev S, Babitt JL (2017) Overview of iron metabolism in health
and disease. Hemodial Int 21(Suppl 1):S6-20
14. Camaschella C, Nai A, Silvestri L (2020) Iron metabolism and
iron disorders revisited in the hepcidin era. Haematologica
105:260–272
15. Knutson M, Wessling-Resnick M (2003) Iron metabolism in the
reticuloendothelial system. Crit Rev Biochem Mol Biol 38:61–88
16. Banjari I, Hjartaker A (2018) Dietary sources of iron and vitamin
B12: Is this the missing link in colorectal carcinogenesis? Med
Hypotheses 116:105–110
17. Hallberg L, Hulthen L (2000) Prediction of dietary iron absorp-
tion: an algorithm for calculating absorption and bioavailability
of dietary iron. Am J Clin Nutr 71:1147–1160
18. Silva B, Faustino P (2015) An overview of molecular basis of iron
metabolism regulation and the associated pathologies. Biochim
Biophys Acta 1852:1347–1359
19. Yiannikourides A, Latunde-Dada GO (2019) A short review of
iron metabolism and pathophysiology of iron disorders. Medicines
6:85 (Basel)
20. Fuqua BK, Vulpe CD, Anderson GJ (2012) Intestinal iron absorp-
tion. J Trace Elem Med Biol 26:115–119
21. Anderson GJ, Frazer DM (2017) Current understanding of iron
homeostasis. Am J Clin Nutr 106(Suppl 6):S1559–S1566
22. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A,
McVey Ward D etal (2004) Hepcidin regulates cellular iron efflux
by binding to ferroportin and inducing its internalization. Science
306:2090–2093
23. Nemeth E, Ganz T (2009) The role of hepcidin in iron metabo-
lism. Acta Haematol 122:78–86
24. Du F, Qian C, Qian ZM, Wu XM, Xie H, Yung WH etal (2011)
Hepcidin directly inhibits transferrin receptor 1 expression in
astrocytes via a cyclic AMP-protein kinase A pathway. Glia
59:936–945
25. Anderson CP, Shen M, Eisenstein RS, Leibold EA (2012) Mam-
malian iron metabolism and its control by iron regulatory proteins.
Biochim Biophys Acta 1823:1468–1483
26. World Health Organization (2001) Iron deficiency anaemia;
assessment, prevention and control: WHO; [Available online
from: https:// www. who. int/ publi catio ns/m/ item/ iron- child ren-
6to23-- archi ved- iron- defic iency- anaem ia- asses sment- preve ntion-
and- contr ol.] Accessed 16 Oct 2023
27. Babu SS, Reddy YS, Jayapal V, Kumar B (2022) Lead (Pb), cad-
mium (Cd) and essential element levels and their interactions: a
hospital based case control study in anemic children. Clin Case
Rep Int 6:1273
28. EFLM Biological Variation Database (n.d.) European Federa-
tion of Clinical Chemistry and Laboratory Medicine. [Available
online from: https:// biolo gical varia tion. eu/ search? query= Iron2
024. ] Accessed 16 Oct 2023
29. Loreal O, Cavey T, Bardou-Jacquet E, Guggenbuhl P, Ropert M,
Brissot P (2014) Iron, Hep, and the metal connection. Front Phar-
macol 5:128
30. Ganz T, Nemeth E (2016) Iron balance and the role of hepcidin
in chronic kidney disease. Semin Nephrol 36:87–93
31. Ganz T, Nemeth E (2012) The hepcidin-ferroportin system as a
therapeutic target in anemias and iron overload disorders. Hema-
tology Am Soc Hematol Educ Program 2011:538–542
32. Iturri S, Nunez MT (1988) Effect of copper, cadmium, mercury,
manganese and lead on Fe2+ and Fe3+ absorption in perfused
mouse intestine. Digestion 59:671–675
33. De Domenico I, McVey Ward D, Kaplan J (2008) Regulation of
iron acquisition and storage: consequences for iron-linked disor-
ders. Nat Rev Mol Cell Biol 9:72–81
34. Choi JW, Ki KS (2005) Relationships of lead, copper, zinc, and
cadmium levels versus hematopoiesis and iron parameters in
healthy adolescents. Ann Clin Lab Sci 35:428–434
35. Sahin A, Er EO, Oz E, Yildirmak ZY, Bakirdere S (2021) Sodium,
magnesium, calcium, manganese, iron, copper, and zinc in
serums of beta thalassemia major patients. Biol Trace Elem Res
199:888–894
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
T.Rolić et al.
36. Rosanoff A, Dai Q, Shapses SA (2016) Essential nutrient inter-
actions: does low or suboptimal magnesium status interact with
vitamin D and/or calcium status? Adv Nutr 7:25–43
37. Bolann BJ, Distante S, Morkrid L, Ulvik RJ (2015) Bloodletting
therapy in hemochromatosis: Does it affect trace element homeo-
stasis? J Trace Elem Med Biol 31:225–229
38. Nose Y, Kim BE, Thiele DJ (2006) Ctr1 drives intestinal copper
absorption and is essential for growth, iron metabolism, and neo-
natal cardiac function. Cell Metab 4(3):235–244
39. Balesaria S, Ramesh B, McArdle H, Bayele HK, Srai SK (2010)
Divalent metal-dependent regulation of hepcidin expression by
MTF-1. FEBS Lett 584:719–725
40. Konz T, Alonso-Garcia J, Montes-Bayon M, Sanz-Medel A (2013)
Comparison of copper labeling followed by liquid chromatogra-
phy-inductively coupled plasma mass spectrometry and immuno-
chemical assays for serum hepcidin-25 determination. Anal Chim
Acta 799:1–7
41. Tselepis C, Ford SJ, McKie AT, Vogel W, Zoller H, Simpson
RJ etal (2010) Characterization of the transition-metal-binding
properties of hepcidin. Biochem J 427:289–296
42. Ciosek Z, Kot K, Rotter I (2023) Iron, zinc, copper, cadmium,
mercury, and bone tissue. Int J Environ Res Public Health 20:2197
43. Kondaiah P, Yaduvanshi PS, Sharp PA, Pullakhandam R (2019)
Iron and zinc homeostasis and interactions: does enteric zinc
excretion cross-talk with intestinal iron absorption? Nutrients
11:1885
44. Abdelhaleim AF, Abdo Soliman JS, Amer AY, Abdo Soliman JS
(2019) Association of zinc deficiency with iron deficiency ane-
mia and its symptoms: results from a case-control study. Cureus
11:e3811
45. Jeng SS, Chen YH (2022) Association of zinc with anemia. Nutri-
ents 14:4918
46. Vallee BL, Falchuk KH (1993) The biochemical basis of zinc
physiology. Physiol Rev 73(1):79–118
47. Bhattacharya PT, Misra SR, Hussain M (2016) Nutritional aspects
of essential trace elements in oral health and disease: an extensive
review. Scientifica 2016:5464373 (Cairo)
48. Bronner F (2003) Mechanisms of intestinal calcium absorption. J
Cell Biochem 88(387):93
49. Lynch SR (2000) The effect of calcium on iron absorption. Nutr
Res Rev 13:141–158
50. Abioye AI, Okuneye TA, Odesanya AO, Adisa O, Abioye AI,
Soipe AI etal (2021) Calcium intake and iron status in human
studies: a systematic review and dose-response meta-analysis of
randomized trials and crossover studies. J Nutr 151:1084–1101
51. Hallberg L, Rossander-Hulthen L, Brune M, Gleerup A (1993)
Inhibition of haem-iron absorption in man by calcium. Br J Nutr
69:533–540
52. Keum N, Lee DH, Greenwood DC, Zhang X, Giovannucci
EL (2015) Calcium intake and colorectal adenoma risk: dose-
response meta-analysis of prospective observational studies. Int J
Cancer 136:1680–1687
53. Milinkovic N, Zekovic M, Dodevska M, Dordevic B, Radosavlje-
vic B, Ignjatovic S etal (2022) Magnesium supplementation and
iron status among female students: the intervention study. J Med
Biochem 41:316–326
54. Huang J, Xu J, Ye P, Xin X (2023) Association between magne-
sium intake and the risk of anemia among adults in the United
States. Front Nutr 10:1046749
55. Shi Z, Hu X, He K, Yuan B, Garg M (2008) Joint association of
magnesium and iron intake with anemia among Chinese adults.
Nutrition 24:977–984
56. Gomez-Ayala AE, Lisbona F, Lopez-Aliaga I, Pallares I, Barri-
onuevo M, Hartiti S etal (1998) The absorption of iron, calcium,
phosphorus, magnesium, copper and zinc in the jejunum-ileum
of control and iron-deficient rats. Lab Anim 32:72–79
57. Sanchez-Morito N, Planells E, Aranda P, Llopis J (2000) Influ-
ence of magnesium deficiency on the bioavailability and tissue
distribution of iron in the rat. J Nutr Biochem 11:103–108
58. Disch G, Classen HG, Haubold W, Spatling L (1994) Interac-
tions between magnesium and iron. Invitro studies. Arzneimit-
telforschung 44:647–650
59. Sugimoto H, Yamada U (2019) Iron deficiency anemia induced
by magnesium overuse: a case report. Biopsychosoc Med 13:18
60. Farina M, Avila DS, da Rocha JB, Aschner M (2013) Metals, oxi-
dative stress and neurodegeneration: a focus on iron, manganese
and mercury. Neurochem Int 62:575–594
61. Martinez-Finley EJ, Chakraborty S, Fretham SJ, Aschner M
(2012) Cellular transport and homeostasis of essential and non-
essential metals. Metallomics 4:593–605
62. Barany E, Bergdahl IA, Bratteby LE, Lundh T, Samuelson G,
Skerfving S etal (2005) Iron status influences trace element levels
in human blood and serum. Environ Res 98:215–223
63. Yazdani M, Distante S, Morkrid L, Ulvik RJ, Bolann BJ (2023)
Bloodlettings in hemochromatosis result in increased blood lead
(Pb) concentrations. Biol Trace Elem Res 201:3193–3201
64. Akesson A, Stal P, Vahter M (2000) Phlebotomy increases cad-
mium uptake in hemochromatosis. Environ Health Perspect
108:289–291
65. Moshtaghie AA, Taghikhani M, Sandughchin M (1994) Cadmium
interaction with iron metabolism, invitro and invivo studies. Med
J Islamic World Acad Sci 7:145–150
66. Fujiwara Y, Lee JY, Banno H, Imai S, Tokumoto M, Hasegawa
T etal (2020) Cadmium induces iron deficiency anemia through
the suppression of iron transport in the duodenum. Toxicol Lett
332:130–139
67. Zabiński Z, Rutowski J, Moszczyński P, Dabrowski Z (2006) Red
cell system and selected red cell enzymes in men occupationally
exposed to mercury vapours. Przegl Lek 63(Suppl 7):74–83
68. Zdrojewicz Z, Popowicz E, Winiarski J (2016) Nickel - role
in human organism and toxic effects. Pol Merkur Lekarski
41:115–118
69. Davidson T, Chen H, Garrick MD, D’Angelo G, Costa M (2005)
Soluble nickel interferes with cellular iron homeostasis. Mol Cell
Biochem 279:157–162
70. Chen H, Davidson T, Singleton S, Garrick MD, Costa M (2005)
Nickel decreases cellular iron level and converts cytosolic aco-
nitase to iron-regulatory protein 1 in A549 cells. Toxicol Appl
Pharmacol 206(3):275–287
71. Tallkvist J, Bowlus CL, Lonnerdal B (2003) Effect of iron treat-
ment on nickel absorption and gene expression of the divalent
metal transporter (DMT1) by human intestinal Caco-2 cells. Phar-
macol Toxicol 92:121–124
72. Divya VC, Karthikeyan BS (2017) Enhanced nickel sensitivity in
iron deficiency anemia. Indian J Public Health 61:215
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com
Available via license: CC BY 4.0
Content may be subject to copyright.
Content uploaded by Tara Rolić
Author content
All content in this area was uploaded by Tara Rolić on Jul 08, 2024
Content may be subject to copyright.
