REVIEW ARTICLE

Iron Deficiency Anemia: Insights into the Prevalence,

Causes, Iron Metabolism, Manifestations, Diagnosis,
and Treatment
J. M. Jbireal1, Azab Elsayed Azab1, Serag Mohamed Hasan2

Department of Physiology, Faculty of Medicine, Sabratha University, Libya, North Africa, 2Department of
1

Medical Laboratory, Teaching Hospital, Sabratha, Libya, North Africa

ABSTRACT

Iron deficiency anemia (IDA) is considered the major public health problems and the most common nutritional
deficiency around the world. IDA is characterized by a decrease of hemoglobin, serum iron, ferritin, and RBCs, and an
increase in total iron-binding capacity (TIBC). Red blood cells become microcytic and hypochromic due to a decrease
in iron content. The present study aimed to highlight the prevalence of iron deficiency anemia, causes, iron metabolism,
manifestations, diagnosis, and treatment. Anemia is a major public health concern in preschool children, schoolchildren,
and pregnant women in the developing world. It is a critical health concern because it affects growth and energy levels
adversely, and damages immune mechanisms, and is also associated with increased morbidity. Young children from
low-income families have a higher risk for developing anemia due to ID that occurs as a result of high demand for
iron during the period of rapid growth. Causes of IDA in developing countries may be due to low intake of enough
iron sources, high intake of cereals, and legumes, which contain iron absorption inhibitors, and/or low intake of iron
enhancers (e.g., ascorbic acid). There is some evidence that ID without anemia affects cognition in adolescent girls
and causes fatigue in adult women. IDA may affect visual and auditory functioning and is weakly associated with poor
cognitive development in children. It produces many systemic abnormalities: the blue sclera, koilonychias, impaired
exercise capacity, urinary discoloration by betanin in beetroot, increased lead absorption, and increased susceptibility
to infection. Dietary iron is available in two forms: Heme iron, which is found in meat, and non-heme iron, which is
found in plant and dairy foods. The bioavailability of non-heme iron requires acid digestion and varies by order of
magnitude depending on the concentration of enhancers (e.g., ascorbate, meat) and inhibitors (e.g., calcium, fiber, tea,
coffee, and wine) found in the diet. Foods containing plant phytates (grains) and tannins (non-herbal tea) are known
to decrease the absorption of non-heme iron. ID results when iron demand by the body is not met by iron absorption
from the diet. The clinical presentation of IDA can range from being completely asymptomatic to varying degrees of
weakness, fatigue, irritability, headache, poor exercise tolerance, and work performance. The typical picture seen in
IDA is low serum ferritin, low transferrin saturation, and increased TIBC. Serum iron, transferrin, transferrin saturation,
and erythrocyte zinc protoporphyrin each have their limitations and are useful in supporting a diagnosis of IDA in
situations. Transfusion should be considered for patients of any age with IDA complaining of symptoms such as fatigue
or dyspnea on exertion. Oral iron therapy is usually the first-line therapy for patients with IDA. It can be concluded
that IDA is a serious health problem among preschool children, schoolchildren, and pregnant women, especially in the
developing world, and there is a need for national intervention strategies and programs to improve the socioeconomic
status and health education which will help significantly in controlling anemia and IDA among preschool children,
schoolchildren and pregnant women.

Key words: Causes, diagnosis, iron deficiency anemia, manifestations, prevalence, treatment

Address for correspondence:

Azab Elsayed Azab, Department of Physiology, Faculty of Medicine, Sabratha University, Libya, North Africa.
https://doi.org/10.33309/2639-8354.030204 www.asclepiusopen.com
© 2020 The Author(s). This open access article is distributed under a Creative Commons Attribution (CC-BY) 4.0 license.

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 Jbireal, et al.: Iron deficiency anaemia: Prevalence, causes, manifestations, diagnosis, and treatment

INTRODUCTION Objectives
The present study aimed to highlight the prevalence of iron

A
nemia is a major public health concern in preschool deficiency anemia, causes, iron metabolism, manifestations,
children, schoolchildren, and pregnant women diagnosis, and treatment.
in the developing world. “Anemia” refers to a
condition in which the hemoglobin content of the blood is ANEMIA
lower than normal as a result of deficiency of one or more
essential nutrients,[1] heavy blood loss, parasitic infections, Anemia is defined by a decrease in the total amount of
and congenital hemolytic diseases.[2] Globally, anemia is a hemoglobin or the number of red blood cells. IDA is a form
public health problem-affecting people in both developed of anemia due to the lack of sufficient iron to form normal red
and developing countries with bad consequences for human blood cells. IDA is typically caused by inadequate intake of
health as well as social and economic development.[3,4] Anemia iron, chronic blood loss, or a combination of both.[15,16]
is a critical health concern because it affects growth and
energy levels adversely.[2] It damages immune mechanisms IDA is the most common nutritional deficiency worldwide. It
and is associated with increased morbidity.[3] It occurs in all can cause reduced work capacity in adults and impact motor
age groups but is more prevalent in pregnant women and and mental development in children and adolescents.[17] There
children.[2] Especially, young children from low-income is some evidence that ID without anemia affects cognition in
families have a higher risk for developing anemia due to iron adolescent girls[18] and causes fatigue in adult women.[19] In
deficiency (ID) that occurs as a result of high demand for iron addition, IDA may affect visual and auditory functioning[18]
during the period of rapid growth.[5] and is weakly associated with poor cognitive development
in children.[19] The prevalence of Iron deficiency anaemia in
ID and ID anemia (IDA) is considered the major public differentWHO regions shown in the Table 1.
health problems and the most common nutritional deficiency
around the world.[6] The prevalence of anemia in the world PREVALENCE OF IDA
is 24.8%.[7] Furthermore, it is estimated that ID contributes
toward 50% of the approximated 600 million global anemia In a study done by Tabib et al.[20] in Libya 2016, they found
cases in preschool and school-aged children.[8] This high that Hb less than 7 g/dL reported in 22.5% of patients
prevalence of IDA in developing countries is associated with (11 male, 37 female) and Hb between 7–10 g/dL reported
poor sanitation conditions, low socioeconomic conditions, in 77.5% of patients (57 male, 108 female). The highest
restricted access to food, and lack of knowledge for good prevalence of IDA was found between 22 and 39 years of
dietary practices.[9] Anemia has multiple consequences which age, Hb mean was 7.9 ± 0.08. In the study by Achouri et al.[21]
can be extremely severe.[10,11] It affects the physical and to detect the prevalence of IDA among schoolchildren in
mental development of an individual leading to decreased Kenitra, northwest of Morocco, the prevalence of anemia was
working capacity, which in turn affects the development of 16.2%. The mean hemoglobin concentration was 12.53 g/dL
the country.[12] The causes of IDA in developing countries are in boys and 12.52 g/dL in girls. The results suggested that
many. It can be due to low intake of enough iron sources ID is an important determinant of anemia in this population.
(meat/fish/poultry), high intake of cereals and legumes There was a significant relationship between education of the
(which contain iron absorption inhibitors), and/or low intake mother and anemia in children (P = 0.004) but not with the
of iron enhancers, that is, ascorbic acid. In addition, the family income. In Sabratha in 1999, the prevalence of anemia
poor socioeconomic status of the vast majority of people is (Hb<12 g/dL) was 11% among 370 male children aged 6–14
reflected in the poor health services provided and unsanitary years and 13% among 341 female children of the same age.[22]
living conditions that cause diarrhea and worms infestation, In addition, the prevalence of IDA among schoolchildren in
thus leading indirectly to EDA. different countries was observed. Ethiopia 37.4%,[23] Yemen
34.2%,[24] Palestine 4.5%,[25] Morocco 16.2%,[21] India
IDA is characterized by a decrease of Hb (hemoglobin), 23.1%,[26] Iran 29.1%,[27] and Pakistan 33.2%[28] [Table 2].
serum iron, ferritin, and RBC (red blood cells) (shape and
size). In addition, it is characterized by an increase in total AETIOLOGY
iron-binding capacity (TIBC). Red blood cells become
microcytic and hypochromic due to a decrease in iron content. Iron metabolism is controlled by absorption rather than
Inadequate treatment of IDA leads to increased morbidity, excretion. Iron is only lost through blood loss or loss of cells
poor life quality, and inefficient daily activities.[13,14] Early as they slough. Men and no menstruating women lose about
diagnosis, treatment, and prevention reduce healthcare costs 1 mg of iron per day.[17] Menstruating women lose from 0.6 to
through the reduction of unplanned hospital admissions and 2.5% more per day. An average 60-kg woman might lose an
other health-services. extra 10 mg of iron per menstruation cycle, but the loss could

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 Jbireal, et al.: Iron deficiency anaemia: Prevalence, causes, manifestations, diagnosis, and treatment

Table 1: The prevalence of iron deficiency anemia WHO region[12]

Region Total Population affected by Percent
population anemia affected
Africa 535 244 46
Americas 751 141 19
South East Asia 1364 779 57
Europe 860 84 10
Eastern 408 184 45
Mediterranean
Western Pacific 1574 598 38
The Total 5491 2030 37

Table 2: Iron deficiency anemia among young IRON METABOLISM

children in different countries[21,23-28]
No Countries %
Iron is a trace element that is required for numerous cellular
Prevalence metabolic functions. As iron is toxic when present in
abundance, tight regulation is required to avoid ID or iron
1 Morocco (2008) 16.2
overload.[30,31] The adult body contains 3–4 g of iron. The
2 Pakistan (2011) 33.2 usual Western diet contains approximately 7 mg of iron per
3 Ethiopia (2013) 37.4 1000 kcal; however, only 1–2 mg is normally absorbed each
4 Yemen (2014) 34.2 day.[32] The human diet contains two forms of iron: Heme
5 Palestine 4.5 iron and non-heme iron. Heme iron is derived from meat
(2009) and is well absorbed. Pancreatic enzymes digest hem to free
6 India (2011) 23.1 it from the globin molecule in the intestinal lumen. Iron is
then absorbed into the enterocytes as metalloporphyrin and
7 Iran (2007) 29.1
degraded by heme oxygenase-1 to release non-heme iron.
Subsequently, iron is exported by ferroportin located on the
be more than 42 mg per cycle, depending on how heavily she basolateral aspect of the enterocyte. Non-heme dietary iron,
menstruates.[17] A pregnancy takes about 700 mg of iron, and which is found in cereals, beans, and some vegetables, is less
a whole blood donation of 500 cc contains 250 mg of iron.[29] well absorbed. Non-heme iron is present as either ferric (Fe+3)
or ferrous (Fe+2) iron. The acidic environment of the stomach
Iron absorption, which occurs mostly in the jejunum, is only and certain foods are known to increase the bioavailability
5–10% of dietary intake in persons in homeostasis.[29] of dietary iron.[33-35] Vitamin C, for example, functions to
prevent the precipitation of ferric iron in the duodenum.
In states of overload, absorption decreases. Absorption can Other foods containing plant phytates (grains) and tannins
increase three-to-five fold in states of depletion. Dietary (non-herbal tea) are known to decrease the absorption of non-
iron is available in two forms: Heme iron, which is found in heme iron.[34,35]
meat, and non-heme iron, which is found in plant and dairy
foods. Absorption of hem iron is minimally affected by After entry of ferric iron into the duodenum, it must first be
dietary factors, whereas non-heme iron makes up the bulk reduced to the ferrous form by duodenal cytochrome b before
of consumed iron. The bioavailability of non-heme iron absorption. Duodenal cytochrome b is a reductase located
requires acid digestion and varies by order of magnitude in the brush border of the duodenum and proximal jejunum.
depending on the concentration of enhancers (e.g., Once reduced, the divalent metal transporter 1, the only
ascorbate, meat) and inhibitors (e.g., calcium, fiber, tea, currently known intestinal iron importer, transports ferrous
coffee, and wine) found in the diet.[17] ID results when iron iron from the proximal small intestinal lumen into the apical
demand by the body is not met by iron absorption from the membrane of the enterocyte.[32] After entry into the cell,
diet. Thus, patients with IDA presenting in primary care may ferrous iron may either be stored as ferritin or transverses
have an inadequate dietary intake, hampered absorption, the cell to the basolateral aspect of the enterocyte, where the
or physiologic losses in a woman of reproductive age. It ferroportin is located. Ferroportin is present in the mucosa
also could be a sign of blood loss, known or occult. IDA is of the proximal small intestine, macrophages, hepatocytes,
never an end diagnosis; the workup is not complete until the and syncytiotrophoblasts of the placenta. Ferroportin,
reason for IDA is known.[29] along with ceruloplasmin and hephaestin, facilitates their

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 Jbireal, et al.: Iron deficiency anaemia: Prevalence, causes, manifestations, diagnosis, and treatment

oxidation of ferrous iron to ferric iron, which must occur These two pathways are vital for the enhancement of
before exportation. Transferrin has a high affinity for ferric iron absorption associated with ID.[33] Within limits, iron
iron and binds it so quickly that there is essentially no free absorption enhancement is proportional to the degree of
iron circulating in the plasma. Binding of iron to transferring ID (i.e., the synthesis of key proteins, such as transferrin
occurs through the Apo transferrin receptor pathway.[32,35] receptor, divalent metal transporter1, ferritin, and ferroportin,
is regulated in an iron-dependent manner).[31] This system is
Once in the plasma, the iron is transported by transferring checked by hepcidin, a hormone that is synthesized in the
to the bone marrow for the synthesis of hemoglobin and liver, secreted into the blood, and systemically controls the
incorporation into the erythrocytes. Normal erythrocytes rate of iron absorption as well as its mobilization from stores.
circulate for roughly 120 days before being degraded. Hepcidin binds to, and negatively modulates, the function
Senescent red blood cells are engulfed by macrophages in of ferroportin. Janus kinase 2 is activated upon binding of
their reticuloendothelial system, primarily in the spleen and hepcidin to ferroportin and results in the internalization,
liver, where they are degraded and catabolized by the cytosolic ubiquitination, and degradation of ferroportin.
hemeoxygenase-1 to release the bound iron. Recycling of
heme iron from senescent red blood cells is the primary Thus, activation of Janus kinase 2 is associated with limiting
source of iron for erythropoiesis and accounts for delivery of iron exportation and ultimately decreasing erythropoiesis.[37]
40–60 mg iron/day to the bone marrow.[36] Some of the iron Hepcidin expression is most notably suppressed by hypoxia,
from senescent red blood cells is also stored in macrophages erythropoietin (a hormone essential for erythrocyte
as ferritin (the major storage form of iron) or hemosiderin (the differentiation), twisted gastrulation (a protein secreted
water-soluble form of iron), and the majority of it is released by immature red blood cell precursors during the early
through ferroportin into the plasma bound to transferring stages of erythropoiesis), and growth differentiation factor
for recycling. Around 70% of the total body iron is in heme 15 (a protein secreted by erythroblasts during the final stages
compounds (e.g. hemoglobin and myoglobin), 29% is of erythropoiesis). The synthesis of hepcidin is up-regulated
stored as ferritin and hemosiderin, <1% is incorporated into by inflammatory cytokines (particularly interleukin-6),
heme-containing enzymes (e.g., cytochromes, catalase, and irrespective of the total level of iron in the body. This
peroxidase), and <0.2% is found circulating in the plasma relationship most likely accounts for the development of
bound to transferrin.[32,34] During states of intravascular anemia of chronic disease. The anemia of chronic disease is
hemolysis, red blood cells are destroyed and hemoglobin outside the scope of this discussion.[33,34]
is released into the plasma. The hemoglobin-haptoglobin
complex is then removed by the reticuloendothelial system
and the iron salvaged. The binding potential of haptoglobin
MANIFESTATIONS OF ID
is limited by the amount of circulating molecules and quickly
IDA produces many systemic abnormalities: Blue
becomes saturated in moderate to severe hemolytic states.
sclera, koilonychias, impaired exercise capacity, urinary
No physiologic mechanism for iron excretion exists and only
discoloration by betanin in beetroot, increased lead
1–2 mg of iron is lost each day as a result of sloughing of
absorption, and increased susceptibility to infection.
cells (i.e., from the mucosal lining of the gastrointestinal
Abnormal developmental performance and poor growth are
tract, skin, and renal tubules). In women, approximately
particularly important features and are considered in more
0.006 mg iron/kg/day is lost during normal menstruation.[34]
detail.[38]
Thus, normally iron loss and gain are in balance, with the
amount lost daily being equal to the amount absorbed daily.
DIAGNOSIS OF IDA
The body has the increase intestinal iron absorption depends
on the body’s iron needs. When the pendulum swings toward Anemia cannot be reliably diagnosed by clinical presentation.
more iron being lost than is absorbed, iron stores become The clinical presentation of IDA can range from being
depleted, and the patient develops ID. If the process continues, completely asymptomatic (found on routine testing) to
the patient develops IDA. ID is associated with up-regulation varying degrees of weakness, fatigue, irritability, headache,
of iron absorption from the gut by way of an increase in the poor exercise tolerance, and work performance.[12] Pica may
production of key proteins, such as duodenal cytochrome be seen in some cases of ID with pagophagia (irresistible
b, divalent metal transporter 1, and ferroportin. Hypoxia- appetite for ice) being quite specific for ID.[39] Ask about
inducible, factor-mediated signaling, and iron regulatory overt blood loss as well as symptoms of gastrointestinal
proteins also play critical roles in the local regulation of iron (GI) disease (abdominal pain, change in bowel habit, weight
absorption. Hypoxia-inducible factor-signaling up-regulates loss, and dysphagia). Use of medications such as aspirin
the expression of duodenal cytochrome b and divalent or NSAIDs should also be noted. A family history of GI
metal transporter1; iron regulatory proteins up-regulate the malignancy, hematological disorders, and bleeding disorders
expression of divalent metal transporter 1 and ferroportin. (e.g., hereditary hemorrhagic telangiectasia) is important,

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 Jbireal, et al.: Iron deficiency anaemia: Prevalence, causes, manifestations, diagnosis, and treatment

as is the patient’s ethnicity when suspecting thalassemia in supporting a diagnosis of IDA in situations where serum
or coeliac disease. On examination, patients may have ferritin is equivocal.[47,49] Interestingly, the combination of
pallor (related to anemia), cheilosis, or atrophic glossitis. serum ferritin and transferrin saturations offers no advantage
Severe, long-standing ID presenting as Plummer–Vinson over serum ferritin alone.[49]
syndrome (post-cricoid dysphagia, IDA, and oesophageal
webs), koilonychias, blue sclera, and chlorosis have become Examination of bone marrow aspirate or biopsy was widely
extremely rare.[40] Urine testing for microscopic hematuria regarded as the gold standard for diagnosis of ID. However,
and a rectal examination should be included in the physical expense, high interobserver variability, and invasive nature
examination.[41,42] of the test have made it less favorable. Bone marrow
examination should only be considered when the diagnosis
LABORATORY DIAGNOSIS of ID is still uncertain after biochemical investigations.[45]
The concentration of serum transferrin receptor (sTfR) is a
The World Health Organization defines anemia as the level quantitative measure of total erythropoietin activity, which is
of hemoglobin below 13 g/dl in males over 15 years of age elevated in ID but is not significantly affected by inflammation,
and below 12 g/dl in non-pregnant women over 15 years of infection, age, sex, or pregnancy.[12] This makes it a
age.[12] Although there is no consensus on the level of anemia potentially useful test in identifying ID in patients with
that requires investigation, there is good evidence to suggest inflammatory disease and to discriminate IDA from anemia
that even individuals with ID without anemia are at increased of chronic disease, although studies have shown conflicting
risk of GI malignancy compared with those without ID, results.[48,55-57] The accuracy of sTfR is limited in the presence
especially if over the age of 50 years.[43,44] Therefore, any of hematological disorders.[12,57] The incorporation of sTfR
level of anemia should be investigated in patients with ID, into the sTfR-ferritin index (log10 serum ferritin) has shown
with greater urgency placed on those with a hemoglobin promise as a strong indicator of iron depletion in chronic
level of less than 9 g/dl. Diagnosis of IDA relies on the disease;[55] however, this has failed to be adopted into
interpretation of iron studies. The typical picture seen in IDA common clinical practice.
is low serum ferritin, low transferrin saturation, and increased
TIBC. Serum ferritin is by far the best biochemical test as an TREATMENT
indicator of iron stores and has replaced the more invasive
bone marrow iron stores as the gold standard for diagnosis Transfusion should be considered for patients of any age with
of IDA.[12,45-47] Hypothyroidism and acerbate deficiency, both IDA complaining of symptoms such as fatigue or dyspnea
of which interfere with ferritin synthesis, are the only two on exertion. It also should be considered for asymptomatic
conditions other than ID capable of lowering serum ferritin.[46] cardiac patients with hemoglobin less than 10 g/dL (100 g/L).
However, oral iron therapy is usually the first-line therapy
Serum ferritin of less than 15 ng/ml is essentially diagnostic of for patients with IDA.[58] Iron absorption varies widely based
ID with a sensitivity of 59% and a specificity of 99%.[46] The on the type of diet and other factors. Bone marrow response
diagnostic yield of serum ferritin may be improved by using to iron is limited to 20 mg per day of elemental iron. An
a cut off of less than 30 ng/ml, which has a sensitivity and a increase in the hemoglobin level of 1 g/dL (10 g/L) should
specificity of 92 and 98%, respectively.[48] Best demonstrated occur every 2–3 weeks on iron therapy; however, it may take
the superiority of serum ferritin over other markers of ID, up to 4 months for the iron stores to return to normal after
including serum transferrin, MCV, and erythrocyte zinc the hemoglobin has corrected.[59] Iron sulfate in a dose of 300
protoporphyrin in a review of 55 studies.[46] Since serum mg provides 60 mg of elemental iron, whereas 325 mg of
ferritin is an acute-phase reactant, its usefulness is limited in iron gluconate provides 36 mg of elemental iron. Sustained-
the presence of infection, malignancies, and acute or chronic release formulations of iron are not recommended as initial
inflammation.[12,45,48,49] therapy because they reduce the amount of iron that is
presented for absorption to the duodenal villi. GI absorption
Elevation of ferritin out of proportion to iron stores is also seen of elemental iron is enhanced in the presence of an acidic
in liver disease, alcoholism, and chronic renal failure.[47,49] A gastric environment. This can be accomplished through
higher cutoff for serum ferritin such as less than 60 ng/ml[50] simultaneous intake of ascorbic acid (i.e., Vitamin C).[60]
or less than 70 ng/ml[46] may be required to diagnose ID in Although iron absorption occurs more readily when taken on
this population of patients. Attempts to improve the diagnostic an empty stomach, this increases the likelihood of stomach
value of serum ferritin by using norm grams between ferritin upset because of iron therapy. Increased patient adherence
and erythrocyte sedimentation rate or C-reactive protein have should be weighed against the inferior absorption. Foods rich
shown promise in some studies[51,52] but not in others.[53,54] in tenants (e.g., tea)[61] or phytates (e.g., bran, cereal)[62] or
medications that raise the gastric pH (e.g., antacids, proton
Serum iron, transferrin, transferrin saturation, and erythrocyte pump inhibitors, and histamine H2 blockers)[63] reduce
zinc protoporphyrin each have their limitations and are useful iron absorption and should be avoided if possible. Some

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 Jbireal, et al.: Iron deficiency anaemia: Prevalence, causes, manifestations, diagnosis, and treatment

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