Review Article

Page 1 of 14

Iron deficiency and iron deficiency anaemia in children:

physiology, epidemiology, aetiology, clinical effects, laboratory
diagnosis and treatment: literature review
Barakat Adeola Animasahun1,2, Adejumoke Y. Itiola1
1
Department of Paediatrics, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria; 2Department of Paediatrics & Child Health, Lagos
State University College of Medicine, Ikeja, Lagos, Nigeria
Contributions: (I) Conception and design: BA Animasahun; (II) Administrative support: Both authors; (III) Provision of study materials or patients:
None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: Both authors; (VII) Final
approval of manuscript: Both authors.
Correspondence to: Prof. Barakat Adeola Animasahun. Department of Paediatrics, Lagos State University Teaching Hospital, 1-5 Oba Akinjobi Way,
GRA, Ikeja, Lagos, Nigeria. Email: deoladebo@yahoo.com.

Objective: This review article aims to describes iron deficiency and iron deficiency anaemia in children
including its physiology, epidemiology, aetiology, clinical effects, laboratory diagnosis and treatment.
Background: Iron deficiency is a nutritional disorder, it is the most common nutritional disorder
worldwide. There are three main stages of reduction of body iron which is a continuous process from
iron depletion followed by iron deficiency and then iron deficiency anaemia. Iron is a cation necessary
for blood formation. Apart from its role in haemoglobin, it is also needed in various enzyme reactions
and cytochromes. It is distributed as an active metabolite and also in storage pools. Iron is an essential
component of virtually all living cells, specifically human cells. Iron is an essential micronutrient. it occurs
as haem (organic) and non-haem iron (non-organic) in the diet. Maternal supplies are the source of the
developing fetus iron stores. 41A normal term infant is born with iron stores for the first four to 6 months
after birth except maternal iron deficiency is severe. Iron is also needed for growth and metabolism in
the post-natal life. It has been estimated that 39% of children younger than 5 years and 48% of children
between 5 to 14 years are iron deficient in non-industrialized world, as against 20% in less than 5 years
and 5.9% in 5–14 years from industrialized world by the World Health Organization. Children in the
developing world are especially vulnerable because of the increased requirements of growth, diets with low
iron bioavailability, and high helminthic burden.
Methods: A search of publications before October 2020 was done. It was limited to publications in English.
Searches were performed using PubMed, Medline, Web of Science, Psych Info and CINAHL, Google,
Access to Research for Development and Innovation (ARDI), Health Inter Network Access to Research
Initiative (HINARI), JSTOR ARCHIVES, EBSCO HOST, Ohio LINK, DOABOOK.
Conclusions: This review article describes the iron deficiency and iron deficiency anaemia in children:
physiology, epidemiology, aetiology, clinical effects, laboratory diagnosis and treatment.

Keywords: Iron; iron deficiency; iron deficiency anaemia; children; treatment

Received: 16 January 2021; Accepted: 26 May 2021; Published: 30 September 2021.

doi: 10.21037/jxym-21-6
View this article at: http://dx.doi.org/10.21037/jxym-21-6

© Journal of Xiangya Medicine. All rights reserved. J Xiangya Med 2021;6:22 | http://dx.doi.org/10.21037/jxym-21-6
Page 2 of 14 Journal of Xiangya Medicine, 2021

Introduction anaemia in children, latent iron deficiency in children

among others. The materials used included textbooks,
Iron deficiency is a nutritional disorder, it is the most
journals, magazines, newspapers, policy documents,
common nutritional disorder worldwide (1). Sufficient
academic papers, conference papers, Internet materials
supply of iron is important for the functioning of major
which consist of abstracts, reviews, dictionaries, and
processes and reactions involving electron transfer (2).
encyclopedias. This review article aims to describes
Hypoxia and attendant secondary erythrocytosis causes
iron deficiency and iron deficiency anaemia in children
polycythemia and consumption of iron stored (3). Iron
including its physiology, epidemiology, aetiology, clinical
depletion can also be caused by the bleeding tendency
effects, laboratory diagnosis and treatment. Hence, we
as a result of thrombocytopenia and abnormalities of the
present this article in accordance with the Narrative
haemostatic mechanism (4,5).
Review reporting checklist (available at http://dx.doi.
There are three stages involved when iron stores in the
org/10.21037/jxym-21-6).
body is reduced, this ranges from iron depletion, to iron
deficiency and then, iron deficiency anemia (6). When
there is iron depletion, the amount of Iron required in the Discussion
body is more than the amount ingested leading to a gradual
Physiology of iron
reduction in iron stores (6). The reduction in iron stores
shows up as low concentration of serum ferritin (6). In Iron Iron is a cation necessary for blood formation. Also, it is one
deficiency, stored iron is low, associated low absorption of the constituents of Hb, it is also needed in reactions in
of iron to replace normal body losses, there is low mean various enzyme reactions and cytochromes. It is distributed
corpuscular hemoglobin (MCH), mean corpuscular volume as an active metabolite and also in storage pools (1). Iron
(MCV), and serum ferritin (6). The last and most severe is reused effectively from ageing RBCs in humans. It is
stage is Iron deficiency anaemia; it is characterized by red absorbed by the small intestine, (only 10% of dietary iron
blood cells (RBCs) with a lower level of iron, low MCV, low is absorbed). A daily intake of iron is necessary to cover the
mean MCH, low haemoglobin (Hb) level and a reduction iron lost from desquamation of cells of the skin and intestine
serum ferritin. The distinction between “iron deficiency” and also, to maintain growth in children (1). The demand
and “anaemia” is important. for iron is highest during periods of high growth found in
Various laboratory tests for the detection of iron infancy and adolescence. The form of iron when consumed
deficiency such as MCV, serum ferritin and transferrin determines how well it is absorbed (2). It is better absorbed
saturation (Tfsat) are limited in their value because their in the haem form when compared with the non-haem state.
sensitivities and specificities may be affected by acute The non-haem form requires reduction to the ferrous state
inflammatory conditions (7), chronic inflammations (8), and its release from food binders by gastric juices. Also, food
genetic polymorphisms (9), and by sickle cell disease items such as vegetable fiber phytates in cereals and pulses,
states (8). The World Health Organization (WHO) calcium and tannins in tea reduces the absorption of non-haem
recommended combination of various laboratory tests to iron (2). Some other food items such as vitamin C encourages
define iron status in a population (1). the absorption of iron. The absorbed iron is transported by
transferrin, a binding protein produced by the liver. The
synthesis of transferrin by the liver is affected by the iron
Methods
status. The synthesis increases when there is iron deficiency
The search included publications before October 2020. and reduces in chronic disease states. Iron is stored as either
It was limited to publications in English and a subset ferritin or hemosiderin. It is used during erythropoiesis.
of medical databases. Searches were performed using Ferritin is freely available and soluble, it is stored in the
PubMed, Medline, Web of Science, Psych Info and hepatocytes, macrophages (spleen), bone marrow, serum, and
CINAHL, Google, Access to Research for Development RBCs. The amount of ferritin in circulation is parallel to the
and Innovation (ARDI), Health Inter Network Access amount of the total body store (1,2).
to Research Initiative (HINARI), JSTOR ARCHIVES, Reduction of body iron develops in stages and there
EBSCO HOST, Ohio LINK, DOABOOK. The keywords are three main stages: in the first stage referred to as iron
used were: iron deficiency in children, Iron deficiency depletion, this is followed by iron deficiency without

© Journal of Xiangya Medicine. All rights reserved. J Xiangya Med 2021;6:22 | http://dx.doi.org/10.21037/jxym-21-6
Journal of Xiangya Medicine, 2021 Page 3 of 14

anaemia (10). the enterocyte (24). The concentration of iron in breast

milk starts relatively low (0.6 mg/L), and reduces to about
0.2–0.3 mg/L 5–6 months of age (24,25). Although, the
Iron metabolism
bioavailability of breast milk iron is high (15–42%) (26).
Iron is an important component of virtually all living cells, Cows’ milk is low in iron hence consumption of cow milk
specifically human cells (11). Under physiological conditions has an adverse effect on iron status (19). Also, cow milk
the ability of iron to convert between two oxidation states has high casein and high calcium which also inhibit iron
that are thermodynamically stable, the ferric (Fe 3+) form absorption (14,27). Also, cows’ milk allergy can cause
and the ferrous (Fe 2+) form, makes it well suitable for intestinal blood loss which predisposes to the development
the catalysis of various biochemical reactions (10). Quite of iron deficiency (27).
a number of enzymes depend on iron to perform their
functions (12). These include, transfer of electron, storage,
Mechanism of iron absorption
and activation of oxygen, detoxification of activated oxygen
species, nitrogen fixation and deoxyribonucleotide synthesis Iron absorption takes place primarily at the small intestine,
from ribonucleoside diphosphates (12). It is involved in at the apical surface of the duodenum and the upper of the
brain development, it is also an important nutrient involved jejunum (28). Different pathways are responsible for the
in immune response, and energy metabolism (9-13). During absorption of heme and non-heme iron (29). Haem iron
the processes of iron absorption and distribution, it is bound is absorbed intact by an intestinal transporter called heme
to proteins (transferrin) tightly, leaving an extremely low carrier protein 1 (HCP1) (29). It is hydrolyzed from the
concentration of free intracellular iron (11). The regulation protein to which it is attached and is absorbed relatively
of intracellular iron is very important, because even low easily, whereas non-heme iron exists in an oxidized form
concentrations of “free iron” can result is severe damage to that is not bioavailable (29). Dietary components or by
a number of cellular constituents including membranes and ferric reductase enzyme need to reduce non-heme iron for
DNA (11). it to be transported by the divalent metal ion transporter 1
(DMT1) across the intestinal epithelium (29). The efflux
of iron from the duodenum into the plasma is mediated by
Dietary iron intake and intestinal absorption
the iron oxidase, hephaestin and ferroportin 1, a transport
Iron is an essential micronutrient. it occurs as haem (organic) protein (29,30).
and non-haem iron (non-organic) in the diet (14,15). Haem
iron is obtained from poultry and meat. It is also obtained
Transport and distribution of iron in the body
from fish. Haem iron has a higher bioavailability than
non-heme iron. Non-haem iron is mostly obtained from In the body, iron is transported between sites of absorption,
vegetables and grains and nuts (14,15). Ascorbic acid, citric utilization by the plasma glycoprotein transferrin and
acid, haem iron and breast milk promote the absorption storage (Tf) (31). The specific cell membrane Tf receptors
of non-haem iron (15,16). The absorption of non-haem (TfR), is crucial for cellular iron acquisition, it recognizes
iron is inhibited by polyphenols (from plants, phytates the plasma transferrin (32). The receptors bind to iron-
(from seeds and grains), cows’ milk and calcium (17,18). transferrin complex at the surface of the cell and carry the
Phytates and polyphenols reduces the absorption of non- complex into the cell, for iron to be released. Fe3+ released
heme iron by forming complexes which are insoluble, hence from the Tf-TfR complex is reduced within endosomes (32).
makes the non-haem iron unavailable for absorption (19). This is an important step because it helps facilitate iron
Ascorbic acid keeps iron available for absorption through uptake by red cell precursors as excess iron enters functional
several mechanisms (20,21). Firstly, it promotes an acidic compartments or is stored as ferritin (32).
environment which facilitate iron absorption, secondly, it
chelates Fe3+ and maintains it in a stable complex, and lastly,
Regulation of systemic iron
it reduces Fe3+ to Fe2+ forming a soluble complex available
for absorption (22,23). Iron in breast milk is readily For systemic iron homeostasis to be maintained, there has
absorbed because it is bound to lactoferrin which aids the to be an effective communication between cells duodenal
absorption of iron through the lactoferrin receptor into enterocytes that absorb iron from the diet, and the

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Page 4 of 14 Journal of Xiangya Medicine, 2021

erythroid precursors which utilize iron and iron stored (33). overload (1).
Iron release from the Hb of erythrocytes that are destroyed, Iron deficiency without anemia has two stages: iron
the degradation of iron-containing enzymes, and myoglobin deficient erythropoiesis and iron depletion (1). In iron
are the major pathways of iron turnover (34). The average depletion, the amount of stored iron is reduced but the
lifespan of erythrocyte is about 120 days, they are degraded amount of iron needed to may not be affected, hence
by macrophages in the spleen and Kupffer cells (34). an individual with iron depletion has no iron stores to
Sixty to seventy percent of functional iron in the body is make available if the body needs more iron (1). In iron-
contained in circulating Hb (34). Iron bound to transferrin deficient erythropoiesis, there is depletion of stored iron
form is the way up to 85% of how iron derived from the and further reduction in transport iron, the absorbed iron
breakdown of Hb is re-released to the body (34). The cycle is not sufficient to replace the amount of iron lost or the
is completed when new RBCs enter the circulation in the amount required for body function and growth (1). In Iron
following 7–10 days (34). Iron absorption is increased when deficiency anaemia, which is the most severe form of iron
erythropoietic activity is enhanced (35). Erythropoietin is deficiency, the reduction of iron (storage and transport)
produced by the kidneys. The process of erythropoiesis causes underproduction of iron-containing compounds
is controlled by erythropoietin concentration (35). When needed to function, such as Hb, and myoglobin (1).
there is iron deficiency, iron transfer is increased by
stimulating hepatic synthesis of transferrin, ferroportin
Iron needs during infancy and childhood
expression on macrophages, and increased expression of
transferrin receptor (TfR1) in the bone marrow and other The fetus iron stores are built from maternal supplies (41), a
tissues (34). term infant is born having enough iron stores for at least the
Hepcidin is produced in the liver, it is a hormone first four to 6 months for growth after birth except the mother
and a 25-amino peptide., it is the key regulator of iron has a severe iron deficiency (42), the preterm infant is born
homeostasis in the systemic circulation (36). Hepcidin with lower iron stores because he has less time to accumulate
controls the circulating iron concentration by inhibiting iron in utero (41). Also, a preterm infant may deplete their iron
its uptake from duodenal enterocytes, hepatocytes and stores within 2 to 3 months after birth. because they have a
macrophages, it does so by binding to the iron transporter faster rate of growth than the term infant (41).
ferroportin on these cells (37). This leads to a decrease in The neonate uses iron at a high rate in the first months of
the absorption of dietary iron absorption and a reduction in life for accelerated growth and expansion of blood volume (42).
circulating iron in the blood, while intracellular iron stores There is a need for adequate iron to meet the demands from
increase (36). Iron overload, infection and inflammation rapid growth and erythropoiesis after birth (42). An infant’s
stimulates the synthesis of hepcidin, while hypoxia, iron stores would have reduced by 50% by 4 months of age;
iron deficiency, anaemia and conditions which increase when birth weight is expected to have doubled (43). Children
erythropoietic activity decreases its production (38). become exclusively dependent on dietary iron intake around
6 months of age (43). in infancy up to about 66% of iron losses
are from cells that are shed from the mucosa of the intestine,
Stages of iron deficiency
skin and urinary tract (44). about 0.8 mg/d of dietary iron
In iron deficiency state, iron is not available in sufficient needs to be absorbed by a normal infant (0.6 mg for growth,
amount to maintain the normal physiological function of 0.2 mg to replace ongoing losses in the first year of life (45).
body tissues like the brain, muscles blood and the brain (39). There is a need for supplementation of iron intake so as to
It results from long-term negative iron balance. Hemosiderin meet iron needed to replace normal iron loss and for growth.
and ferritin which are forms of Iron stores are diminished The recommended daily allowance (RDA) ranges from 7.0 to
progressively and are not able to meet the needs of the body 11.0 mg per day and 5.8 to 9.0 mg per day for infant between
any longer (40). As a result, an array of systemic evidence of the age of 5 months to less than 1 year and 1 to 3 years
iron deficiency becomes evident. Symptoms caused by iron respectively (45). Towards the second year of life, routine diet
deficiency are subtle and non-specific, and often become supplies sufficient iron-rich foods to meet demands (45). The
apparent only in its severe stages (39). Iron status ranges RDA reduces to 10mg per day for children aged between 4
from iron deficiency with anaemia (IDA), to iron deficiency to 10 years of age. The RDA at the age of 11 years increases
without anaemia, to normal iron status, and finally iron to 18 mg per day to provide for the increased growth that

© Journal of Xiangya Medicine. All rights reserved. J Xiangya Med 2021;6:22 | http://dx.doi.org/10.21037/jxym-21-6
Journal of Xiangya Medicine, 2021 Page 5 of 14

characterizes adolescence (46). In males, iron needs are highest of iron deficiency. Children in the developing world are
during peak pubertal development because of increase in more prone to developing iron deficiency due of their need
blood volume, myoglobin and muscle mass (47). In females, for growth (62), diets with low iron bioavailability (63), and
iron needs remain high due to blood loss from menstruation, high helminthic burden (60).
which is approximately 20 to 58 mg in a month (48). Thus, the When there is a disparity between the maximal amount
recommended iron intake for pubertal girls is 15 to 22 mg per of iron absorbed from the diet, and the physiological
day while it is 10 to 13 mg per day for boys (49). requirements which occur when there is increased
physiologic demand leads to iron deficiency (62). In an
infant not given iron-fortified weaning foods or formulae,
Epidemiology of iron deficiency in children
rapid body growth will be the cause of iron deficiency (62).
Worldwide, iron deficiency is the most commonly reported Growth is associated with high iron requirements (48). This
nutritional deficiency (1). According to the WHO, up is clearly demonstrated in preterm babies during the first
to 39% of children who are less than 5 years and 48% of few months and in infancy and adolescence during peak
children who are between 5 to 14 years of age are iron periods of growth (63,64). These periods of rapid growth,
deficient in non-industrialized world, as against 20% in less cause exhaustion of iron stores if additional dietary iron is
than 5 and 5.9% in 5–14 years from industrialized world (1). not provided.
Prevalence rates vary among countries; it affects 2.4 million In a study conducted by Ferlin et al. (63) among 25
children in the USA (50), 5.4% of children in Spain (51), Brazilian newborns who were preterm birth weight of
14.0% in Estonia (52), 30.8% in Brazilian children (53). 1,000 to 1,800 g, and 30 to 35 weeks gestational age, it was
Various studies in Africa have reported prevalence rates of observed that offering iron to these children at 15 days of
between 9.8%% and 20.8% (54-56). The prevalence of iron life as an alternative was justified because at 2 months of
deficiency in Nigerian children vary according to age group age, infants who had not been supplemented were showing
(57-59). A nationwide survey involving 12 states in Nigeria in depleted iron stores already.
2001 using the serum ferritin model as an indicator, reported In populations consuming monotonous plant-based diets
that 27.5% of children under 5 years of age were iron- with little meat, dietary iron bioavailability is low (28). Up to
deficient (57). Fajolu et al. (12) investigated the prevalence 30–70% of iron is haem iron in meat, out of which 15–35%
of iron deficiency in children between 6 to 24 months of is absorbed (18). On the contrary, in plant-based diets most of
age. A total of 282 children who were delivered at term the dietary iron is non-haem iron, and less than is absorbed
were recruited into the study over a 6-month period. The is often (15). The risk of deficiency is highest when iron
authors reported iron deficiency prevalence of 14.9%. requirements are greater than energy needs (65). Low dietary
Akodu et al. (58) investigated 87 children up to 5 years. In iron intake has been associated with iron deficiency (28).
that study subjects were subcategorized into children up to Onimawo et al. (66) assessed the iron intake of school
2 years and greater than 2 years. Amongst the 42 children children in Abia state. When the iron content of collected
less than or equal to 24 months, the prevalence (19%) was food samples was assessed, the iron content of foods
higher than the earlier report by Fajolu et al. (12). The consumed in the community was found to be poor.
prevalence among children up to 5 years reported by Akodu Cereals, legumes, roots and tubers were observed to be the
et al. (58) was 10.1%. Other investigators who studied predominant foods consumed during the interview on food
children up to 5 years reported a prevalence of between intake, also, these types of diet are known to contain high
9.8% and 27.5% (60,61). For children up to 8 years, content of iron inhibitors such as polyphenols and provide
Jeremiah et al. (59) in South Southern Nigeria reported low amounts of bioavailable iron (67). These children also
overall prevalence of 13.7%. In that study, the authors did consumed in low quantities, meat, poultry and fish, which
not categorize the prevalence based on age subcategories. are excellent sources of haem iron and are enhancing factors
It was therefore not possible to compare their findings in for non-haem iron absorption. The researchers concluded
under-5 children with other studies. that the high prevalence of iron deficiency (77.8%) in the
population was attributed to low dietary iron intake below
the recommended value.
Aetiology of iron deficiency
Hook worm infestation and menstruation are among
The underlying cause must always be stated in the diagnosis the common causes of iron deficiency following blood loss.

© Journal of Xiangya Medicine. All rights reserved. J Xiangya Med 2021;6:22 | http://dx.doi.org/10.21037/jxym-21-6
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Menstruation in adolescent girls has been documented to be of genes, growth and differentiation of cells, binding
associated with decreased iron stores (68,69). This is more and transport of oxygen, use and storage of oxygen in
problematic in a population that consumes low iron diet (63). the muscles, enzyme reactions, synthesis of proteins and
Menstruation results in an average loss of around 20 mg of neurotransmitters (13). Thus, deficiency of iron is a multi-
iron in a month, the iron loss but may be up to 58 mg per systemic disorder, rather than a purely haematological
month in some individuals (48). condition associated with anaemia only. Adverse health
Moschoni et al. (68), studied adolescent girls aged effects of iron deficiency in children includes; growth
9–13 years in Greece. A comparison of the iron status of retardation (62), impaired immune function (13), impaired
children who were menstruating with controls, revealed behavioural, mental and psychomotor development (7,80)
that menses was significantly associated with ID among the as well as decreased work capacity (81).
study subjects. This position was corroborated by authors Iron is required for cell growth and differentiation (82).
in Nigeria who demonstrated that iron status was inversely The iron-containing enzyme ribonucleotide reductase
related to menstrual blood loss (63,69). initiates the synthesis of DNA, which is a limiting factor in
Chronic intestinal blood loss is one of the mechanisms the rate of the replication of the cells. Thus, iron deficiency
through which hookworm infestation induces iron limits cellular proliferation (83). Soliman et al. (62), studied
deficiency (70). Ancylostoma duodenale and Necator americanus linear growth of 40 children with iron deficiency aged
are the two species of hookworms, about 0.2 and 0.15 mL 17.2±12.4 months before and after iron supplementation.
of blood loss per day are caused respectively (70). The authors reported that children with iron deficiency
Hookworms also release anti-clotting factors which were statistically significantly shorter and had reduced
contributes to continuous blood loss. The susceptibility of growth when compared with their controls. Also, it was
children to parasitic infections is due to their lower immune reported that after treatment, the growth indices of children
response (71) compared to adults, poor hygiene, and with iron deficiency significantly improved.
poor sanitary and environmental conditions. Hookworm Iron is also an important component of the nitrous
infestation afflicts 740 million people in developing nations oxide-generating enzymes and the peroxide-generating
of the tropics (72). A study of children Zanzibar in his enzymes that are important for the functioning of enzymes
study of children showed that 62% of the subjects were involved in immune cells (13). Also, iron is involved in
anaemic, 82% of this anaemia was attributable to iron the regulation of the production of cytokine (13). The
deficiency, of which the strongest predictor was hook worm relationship between iron deficiency and immune status was
infestation (73). Osazuwa et al. (60) in Edo State, Nigeria investigated by Ekiz et al. (84). The authors compared the
studied 316 children aged 1 to 15 years living in rural percentages of T-lymphocyte, phagocytic activity, the level
communities. The authors reported a significant association of serum interleukin-6 (IL-6), levels of immunoglobulin
between hookworm infestation and iron deficiency. This of children with iron deficiency to those of controls. It was
finding was corroborated by authors who studied children thus concluded that iron deficiency significantly impairs
in other regions of Nigeria (74,75). cellular and humoral immunity as well as synthesis of
Protein energy malnutrition will impair absorption immunoglobulin. This position was supported by the
of iron thereby worsening the iron deficiency that the findings of Macdougall et al. (85), when the cellular and
malnourished children have almost invariably (76). Other humoral defense mechanisms were evaluated in 20 children
causes impaired iron absorption, which are rare in children, with iron deficiency, and in seven children with latent iron
includes chronic diarrhoea and malabsorption syndromes deficiency. The serum immunoglobulin concentrations,
such as inflammatory bowel disease (77), partial or total complements and salivary IgA were measured. The
gastrectomy (78) and rarely genetically determined subsequent assessment of lymphocyte and neutrophil
absorptive defect for iron (79). function showed impaired delayed hypersensitivity reaction
and decreased bactericidal function respectively. The
finding of these abnormalities in patients with latent iron
Clinical effects of iron deficiency
deficiency, suggests that alteration in immunologic function
The clinical manifestations seen in iron deficiency are was an early feature of iron deficiency (85).
attributed to depletion of iron stores. The functions of The effect of iron deficiency on central nervous
iron in all cells includes; metabolism of energy, regulation system (CNS) is also very important. Iron is required for

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Journal of Xiangya Medicine, 2021 Page 7 of 14

brain cell proliferation, differentiation, myelination and iron in senescent RBCs each day which get removed and
dopamine neurotransmission (86). Iron deficiency thus replaced (34). After macrophages in the bone marrow and
leads to reduced learning capacity and impaired cognitive spleen has ingested the aged red cells, iron is removed
function (87). In a short-term treatment trial conducted from Hb and returned to the plasma where it becomes
in children less than 3 years of age, it was observed that bound to transferrin tightly, which is its dedicated
children that received short-term iron preparations showed extracellular carrier (40). After 1–2 hours, the iron-
improvement in Bayley Test of Mental Development (88). containing transferrin attaches to specific receptors located
Studies have also reported that iron deficiency during predominantly on the surface of red-cell precursors in
early life can have lasting cognitive effects even after iron the bone marrow (39). The newly formed erythrocytes
repletion (87,89). Lozoff et al. (7) in a longitudinal study are returned to the circulation over the next 7 to 10 days
investigated the likelihood that iron deficient infants may and this completes the iron cycle (34). It is important
be “functionally isolated”. He compared the behaviour to interpret the measurements of iron status according
of 52 Costa Rican infants with iron deficiency aged 12 to the specific compartments of iron they represent. A
to 24 months with that of control who had better level deficit in storage iron is the first to occur, then deficits
of iron status. The investigator observed the during free in the iron transport, followed by deficit in the erythroid
play and also tested them with the same motor and mental compartments (40).
protocols. Infants with iron deficiency were made fewer Ferritin contains approximately 20% iron, and it is
attempts at test items easily tired, hesitant and warier, they a high-molecular-weight protein (93). It occurs as iron
were less attentive to instructions, and were less playful. reserves reticuloendothelial cells, hepatocytes and normally
This finding supports the authors’ hypothesis that iron- in almost all tissues of the body (94). It is also present in
deficient infants engage less with their environment. The small amounts in the serum, where it reflects iron stores
authors also documented persistent cognitive impairment in normal individuals (90). Ferritin is important in the
as well as poor socio-emotional function, in children with absorption, storage, and release of iron. It is the storage
ID over the 10-year period. form of iron, and it remains in the body tissues until it is
Decreased work capacity has been associated with iron needed for erythropoiesis (65). When iron molecule is
deficiency (90). Muscular work which lasts for more than needed, they are released from the apo ferritin shell and
a few minutes needs the oxidative production of energy in bind to transferrin, the circulating plasma protein that
the mitochondria of the muscles, which requires the iron transports iron to the erythropoietic cells (62).
containing cytochromes, iron-sulphur proteins and electron Serum ferritin is the most useful laboratory measure
transport proteins (91). of iron status (10). It is a readily available test which has
Tay et al. (81) studied the relationship between iron measurement that is well-standardized (90). An important
deficiency and exercise tolerance in 25 iron-deficient characteristic of the measurement is that the concentration
patients with cyanotic congenital heart disease (CHD) is directly proportional to body iron stores in healthy
over a period of 5 months. Iron replacement therapy was individuals; 1 mg/L serum ferritin corresponds to 8–10 or
administered to the subjects and cardiopulmonary exercise 120 mg storage iron/kg body weight (42). Serum ferritin
testing was carried out at onset and after 3 months of of less than 15 ng/mL for children greater than or equal
treatment. The researchers reported that 3 months of to 5 years and 12 ng/mL in children less than 5 years has
iron replacement therapy in iron-deficient subjects gave a been defined as Iron deficiency criterion by the WHO with
significant improvement in the quality of life of subject their a sensitivity and specificity of 89% and 96% respectively
tolerance to exercise. In severe iron deficiency, symptoms (1,94). Using a cut off of less than 30 ng/mL in inflammatory
of anaemia such as fatigue, shortness of breath, irritability, states, which has a specificity and a sensitivity and of 98%
weakness and anorexia may occur (92). and 92% respectively improves the diagnostic yield of
serum ferritin (95). Various studies have documented that
ferritin measurement is superior to other markers of iron
Laboratory diagnosis of iron deficiency
deficiency (94,96).
In order to understand the laboratory measurement of Khan (97) studied the significance of serum ferritin in
iron status, there is a need to be familiar with the major iron deficient children in comparison to other biochemical
internal iron circuit resulting from about 30–40 mg Hb and haematological indices of serum iron. Children aged

© Journal of Xiangya Medicine. All rights reserved. J Xiangya Med 2021;6:22 | http://dx.doi.org/10.21037/jxym-21-6
Page 8 of 14 Journal of Xiangya Medicine, 2021

5 months to 12 years were studied. Red cell morphology, extracellular iron is transported by binding to transferrin,
Hb, serum iron and ferritin levels were measured. Serum thus TIBC measures the transferrin level indirectly.
ferritin had a sensitivity of 100% while total iron binding Transferrin level increases as serum iron concentration
capacity (TIBC) and Tfsat had a sensitivity of 95% and decreases (41). The TIBC is low in patients who have
82% respectively. The researchers concluded that serum malnutrition, malignancy and chronic infection (1).
ferritin was a more sensitive indicator as compared to Tfsat reflects iron transport, it indicates the number of
other parameters. Similarly, Guyatt et al. (95) studied the iron-binding sites that are occupied (40). It is calculated by
diagnostic values of laboratory test used in the diagnosis dividing the serum iron concentration divided by TIBC,
of iron deficiency. The authors reported ferritin to have expressed as a percent (40). Low Tfsat suggests low serum
a predictive value of 0.95 in diagnosis iron deficiency iron levels compared with the iron-binding sites that is
compared to 0.77 for MCV, 0.74 for Tfsat and 0.62 for available, suggesting low iron stores (31). It decreases
absolute red cell distribution width (RDW). Serum ferritin before anaemia develops, but not early enough to identify
is elevated in patients with acute or chronic inflammation, iron depletion (31). It is influenced by the same factors
malignancy, or liver disease hence its use as a marker of that affect TIBC and serum iron concentration and is less
iron status in those patients is limited (39). Hence, ferritin sensitive to changes in iron stores than serum ferritin (40).
results should be interpreted with C-reactive protein (CRP), A reduction in transferrin below 16% is a reliable index of
a biomarker of acute infection (98). CRP is an acute phase an under supply of iron to the developing red cell (1).
protein which performs a crucial role in the removal of The red cell indices [mean corpuscular Hb concentration
damaged apoptotic cell, pathogen killing, and complement (MCHC), MCV, Red cell count, mean corpuscular Hb
activation. (94). During infections or inflammatory disease (MCH), Hb concentration and haematocrit] are all low
states, the level of CRP increases rapidly in the first 6 in Iron deficiency anaemia (1). Red cell abnormalities
to 8 hours and peak at levels of about 350–400 mg/L tend to occur relatively late in the progression from
after 48 hours (99). CRP binds to phosphocholine on depletion in iron stores to absent iron store (102). Hb
the surface of damaged cells, and the Pepto saccharides or haematocrit determination has been used widely as a
and polysaccharides and present on micro-organism like screening tool for detection of iron deficiency anaemia (1).
parasites, fungi and bacteria (100). This binding activates The major limitation is that it has low sensitivity and
the classical complement cascade of the immune system, specificity because many other factors such as malnutrition,
modulates the activity of phagocytic cells, hence, supporting haemoglobinopathies, and chronic infection (103). The
the role of CRP in the opsonization of infectious agents amount and Hb content of red cells are evaluated by the
and dead or dying cells (100). The CRP level falls once the standard indices MCV and MCH. The major limitation
inflammation is resolve. This makes CRP a useful marker of these haematological parameters is the time required
for monitoring disease activity (98,101). A serum CRP after the onset of iron deficiency for the level to become
level of <5 mg/L was suggested by WHO to define normal abnormal (40). Beutler et al. (104) documented that MCH
values when using a rapid test, or <3 to 10 mg/L when using and MCV were not sensitive indicators for either exclusion
immunoassays (e.g., ELISA) (101) or confirmation of iron deficiency. The researchers found
Latent iron deficiency depicting the phase of iron that the controls had abnormal indices in 10% of cases
depletion before iron deficiency occurs has been described while the subjects had normal MCH and MCV in 20%
as serum ferritin levels less than 20 ng/mL (102). Further and 50% of cases respectively. It was also observed that the
decline in body iron after iron stores are fully depleted, leads likelihood of abnormal indices increased with increasing
to a reduction in the concentration of plasma iron which severity of anaemia, which suggest that abnormal indices
is measured in tandem with transferrin its specific plasma are a late occurrence in the progression to iron deficiency
transport protein (65). Tfsat is often determined from serum clinically (104).
iron and the TIBC (40). As iron stores are depleted, serum RDW is a sensitive indicator for Iron deficiency anaemia,
iron reduces (101). Measurement of serum iron may not and used as a screening tool (105). High RDW equivalent
represent iron stores accurately because serum iron level is to anisocytosis observed in a peripheral blood smear (102).
affected by the absorption of iron from meals, inflammation, When the level of RDW is significantly increased, it can be
inflammation and diurnal variation (40). The TIBC used to diagnose Iron deficiency anaemia (sensitivity 81.0%,
measures the availability of iron at the binding sites (1). The specificity 53.4%) (105). There is an inverse relationship

© Journal of Xiangya Medicine. All rights reserved. J Xiangya Med 2021;6:22 | http://dx.doi.org/10.21037/jxym-21-6
Journal of Xiangya Medicine, 2021 Page 9 of 14

between the serum Hb and the RDW in iron deficiency TfR synthesis (40). In established cellular iron deficiency,
anaemia (40). The absolute values of red cell indices may serum TfR rises proportionally to the degree of iron
vary and be confusing in diseases such as heterozygous deficiency (109). When combined with serum ferritin,
thalassemia syndromes. The trend of RDW and MCV serum TfR will give a complete information on iron status.
over time can be quite instructive (104); Iron deficiency The serum ferritin reflects iron stores in the absence of
manifests as a falling MCV accompanied by a rising RDW chronic inflammatory diseases and the TfR reflecting
initially, due to the increasing preponderance of microcytes tissue iron store (111). The plasma TfR concentration
in the circulation (106). With iron treatment, marked is not increased with infection or inflammation, unlike
reticulocytosis occurring in the first four weeks following plasma ferritin. Hence, measurement of the plasma TfR
therapy. This manifest as a sudden increase of RDW, concentration may be especially helpful in differentiating
sometimes to over 30% (58). Thus, a pattern of falling between anaemia of iron deficiency and the anaemia
MCV accompanied by a rising RDW should alert the associated with chronic inflammatory disorders (111).
clinician to the suspicion of the presence of possible iron However, cytokines such as tumor necrosis factor and
deficiency anaemia. IL-6 have been suggested to reduce TfR expression in in-
Zinc erythrocyte protoporphyrin (ZEP) is the immediate vitro experiments (112). Various authors have studied the
precursor of Hb (107). ZEP is formed when zinc is plasma TfR concentration as a diagnostic tool for iron
incorporated into protoporphyrin in place of iron during deficiency (95,113). Mast et al. (96) studied the clinical
the final step of heme biosynthesis (107). The concentration utility of plasma TfR in diagnosing iron deficiency.
of ZEP in blood increases when insufficient iron is available The researchers studied 62 anemic patients whose bone
for Hb production (40). In iron deficiency anaemia, divalent marrow examination had showed iron deficiency. The
metal transporter-1 (a protein that transports a number diagnostic sensitivity and specificity of plasma TfR were
of divalent metals, including Fe2+) is up regulated, which 92% and 84% respectively with a positive predictive value
increases zinc transport across the intestinal membrane of 42%. Similarly, Nadeem et al. (114) studied 80 anemic
to replace the missing iron in the formation of the subjects who had absent iron stores on bone marrow
protoporphyrin ring (95). examination. The plasma TfR assay in the subjects showed
ZEP assay is a sensitive test, but its specificity is limited a diagnostic accuracy of 91%. Other studies have compared
because ZEP increases when there is lead poisoning, the plasma TfR to ferritin as a diagnostic method of iron
inflammation, and haemoglobinopathies (95). The deficiency have found plasma TfR to have a specificity and
sensitivity of ZEP to predict iron deficiency in children and sensitivity of 82% and 92% respectively while serum ferritin
adolescents aged 6 months to 17 years is 42%, its estimated had a specificity of 84% and sensitivity of 92% (115). The
specificity is 61% (107). Serdar (108) studied the function researchers concluded that assaying plasma TfRs did not
of zinc erythrocyte protoporphyrin in the diagnosis of iron provide additional information to ferritin assay and thus not
deficiency in children. The researchers evaluated 72 subjects warrant it routine use in diagnosing iron deficiency (115).
and assayed their serum zinc erythrocyte protoporphyrin, The peripheral blood smears examination for the
serum ferritin and MCV values were measured. ZEP was morphology of red cells is not specific in diagnosing iron
found to be the most sensitive test in diagnosing iron deficiency anaemia, because the blood cells are often
deficiency but less specific that serum ferritin while MCV normochromic and normocytic and the blood smear may
was the least diagnostic test. The researchers recommended be within normal limits in mild degree of anemia. Also,
that ZEP can be used as a screening tool in the evaluation when hypochromia and microcytosis are seen, it may be due
of iron deficiency. Similar findings have been documented to other causes including the anaemia of chronic disease,
by other authors (109,110). sideroblastic anemia and thalassemia (40). The peripheral
TfRs are the membrane-binding sites for circulating blood smear may show microcytic, hypochromic RBCs
transferrin-bound iron prior to uptake into the cell (32). with occasional target, elliptical, teardrop, fragmented red
It has been suggested that serum TfR provides a new and cells and anisocytosis in iron deficiency anaemia (116).
reliable method for assessing cellular iron status (40). TfR Fairbanks (117) studied the reliability of peripheral blood
is a transmembrane protein, present in all cells, it binds film in diagnosing iron deficiency anaemia. Serum iron
transferrin and iron and transports it to the cell interior (34). was assayed in subjects and controls and compared to their
Any reduction in iron supply results in an increase in erythrocyte morphology. The researchers found out that the

© Journal of Xiangya Medicine. All rights reserved. J Xiangya Med 2021;6:22 | http://dx.doi.org/10.21037/jxym-21-6
Page 10 of 14 Journal of Xiangya Medicine, 2021

experienced observers suggested features of iron deficiency inappropriate venesection and cautious treatment of iron
in 5.8% of the 24 controls, and were unable to detect deficient cyanotic patients with close monitoring of Hb
features of iron deficiency in 49% of the 38 patients with level (121).
iron deficiency. The researchers concluded that erythrocyte
morphology is an insensitive indicator for either exclusion
Acknowledgments
or confirmation of iron deficiency anemia.
Examination of a slide of a bone marrow aspirate Funding: None.
is generally regarded as the definitive marker of iron
deficiency but involves an invasive, cumbersome procedure
Footnote
that is impractical for routine use (118). Bone marrow
examination in iron deficiency anaemia would show Reporting Checklist: The authors have completed the
normoblastic hyperplasia of erythroid elements, and Narrative Review reporting checklist. Available at http://
decreased or absent stainable iron (119). If stainable iron in dx.doi.org/10.21037/jxym-21-6.
a bone marrow aspirate that contains spicules is absent with
a simultaneous control specimen containing stainable iron Conflicts of Interest: Both authors have completed the
indicates significant iron depletion, but is not conclusive ICMJE uniform disclosure form (available at http://dx.doi.
evidence of this as iron may be available in the form of org/10.21037/jxym-21-6). The authors have no conflicts of
histochemical unstainable ferritin (118). The bone marrow interest to declare.
examination is not helpful in the diagnosis of iron deficiency
in infants and small children because little or no iron is Ethical Statement: The authors are accountable for all
stored as marrow hemosiderin at those ages (120). aspects of the work in ensuring that questions related
to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
Treatment of iron deficiency

The treatment of iron deficiency is done with oral iron Open Access Statement: This is an Open Access article
salts, most of the time, over-the-counter ferrous sulfate, distributed in accordance with the Creative Commons
which is cheap and well absorbed relatively. Dosages Attribution-NonCommercial-NoDerivs 4.0 International
are calculated using the elemental iron: children receive License (CC BY-NC-ND 4.0), which permits the non-
3 to 6 mg/kg per day, while 60 mg/dose is given to commercial replication and distribution of the article with
adolescents (40). The response to iron therapy typically is the strict proviso that no changes or edits are made and the
rapid if the iron deficiency is nutritional (39). If oral iron original work is properly cited (including links to both the
is not tolerated, parenteral form is given; intramuscular formal publication through the relevant DOI and the license).
iron injections usually are not appropriate (40). The See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
use of erythrocyte transfusion is advised if there is any
of the following: severe cardiovascular compromise or
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