Ministry of Higher Education

And Scientific Research

AL Noor University College
Department of Medical Laboratories
Techniques

Iron in Human Body

Graduation Project Submitted in Partial Fulfillment for the Bachelor’s Degree in
Medical Laboratories Techniques / AL Noor University College

Prepared By
Muhammed Salih Ibrahim
Mustafa Nawzad Hashim

Supervised by
Prof. Dr. AbdulGhany Muhammed Al-Dhaher

1445 2023
 ‫َ ْ ََ ُ ْ‬ ‫ََ ْ‬ ‫ْ‬ ‫ََ ْ َ‬
‫َ‬ ‫ع‬ ‫م‬ ‫َ‬ ‫َ‬ ‫َ‬ ‫َ‬
‫﴿ لقد أ ْرَسلنا ُرُسلنا بالبِّينات َوأنزلنا ه ُم ألكِن َ‬ ‫َ‬
‫ات‬ ‫ِ ِ ِ‬
‫ْ‬ ‫َ ْ ْ‬ ‫ْ‬ ‫َ‬ ‫ُ‬ ‫ْ‬
‫َ‬ ‫َ‬ ‫َ‬ ‫َ‬ ‫َ‬ ‫ِّ‬ ‫َ‬
‫َ لمي َ لبق َ‬ ‫َ‬
‫دبد ِفن ِه باس‬ ‫ح‬ ‫اس بالق ْسطۖ َوأنزلنا أل‬ ‫وم ألن ُ‬ ‫وأِ زأن ِ‬
‫ِ‬ ‫ِ ِ ِ‬
‫َ‬ ‫ُ‬ ‫َ‬ ‫َ َ‬ ‫َ َ ُ َِّ‬
‫ُ‬ ‫ُ‬ ‫ُ‬ ‫َ‬ ‫ُ‬ ‫ص‬ ‫ُ‬ ‫ن‬ ‫َ‬ ‫م‬ ‫ُ‬ ‫َ‬ ‫ْ‬ ‫َ‬ ‫َ‬ ‫َ‬
‫س‬
‫اس وِ م ألل ن زه ور له‬ ‫ي‬ ‫ل‬ ‫ع‬ ‫ب‬ ‫ل‬ ‫ل‬ ‫ف‬ ‫م‬
‫دبد و ناِ ع ِ لن ِ‬ ‫سِ‬
‫َ‬ ‫ْ‬ ‫َ‬ ‫ْ‬
‫َ‬ ‫ِّ‬ ‫َ‬ ‫َ‬
‫ب ۖ ِأ ِّن ألل ق ِوي ع ِزنز﴾ [الحديد‪.]25:‬‬ ‫ِبالغب ِ‬
‫بدأنا بأكثر من يــد و قاسينا من اهلم و عانينا من الصعوبات و ها حنن اليوم و احلمد‬

‫هلل نطوي سهر الليايل و تعب األيــام‪ .‬أهدي ما بني يدي‪:‬‬

‫إىل من تعب و شقى ألنعم بالراحة واهلناء ‪ ،‬الذي مل يبخل بشيء من أجل دفعي لـطريق‬

‫النجاح ‪ ،‬الذي علمين أن أرتقي ســلم احليــاة حبركة و صرب ‪:‬‬

‫( والــدي العزيز )‬

‫و إىل من أرضعتين احلب و احلنان ‪ ،‬إىل رمز احلب و بلسم الشفاء ‪ ،‬اىل القلب الناصع‬

‫بالبياض‪:‬‬

‫( والــدتي احلبيبة )‪.‬‬

‫وإىل من علمونا حروف من ذهب و كلمات من دُرر و عبارات من أمسى و أجلى‬

‫عبارات يف العلم ‪ ،‬إىل من صاغوا لنا علمهم حروفاً و من فكرهم منارة تنري لنا سري‬

‫العلم و النجاح‪ ،‬إىل ( أساتذتنا ) يف قسم تقنيات املختربات الطبية‪.‬‬

‫الباحثان‬
‫الحمد لله رب العاملني و الصالة و السالم على سيد المرسلين‬

‫محمد (صلى اهلل لليه و لله و سل ) ‪.‬‬

‫أتقدم بجزيل الشكر و عظيم االمتنان الى االستاذ الدكتور‬

‫(لبد الغني حممد الظاهر) لتقديمه النصائح و المعلومات التي‬

‫اضافت الى هذا البحث طابعا ً و لونا ً خاصا ً ‪ ,‬كما اتقدم بالشكر الى كافة‬
‫الهيئة التدريسية في قسم تقنيات المختبرات الطبية ‪ ,‬الذين بذلوا قُصارى‬
‫جهدهم ليبنوا شباب المستقبل‪ ,‬الذين يسيرون ارض العراق العظيم من‬
‫جديد ْ‬
‫إن شاء هللا‬
‫فجزاهم هللا خير الجزاء‪.‬‬

‫الباحثان‬
 Table of Contents

No. Subject Page

1 Introduction 1
2 Types of Iron 2
2-1 Heme and Non-Heme Iron 2
3 Body iron stores 3
4 Iron Distribution in the Human Body 4
5 Iron Functions in the Body 5
6 Hemoglobin and Myoglobin 5
6–1 Hemoglobin 5
6–2 Myoglobin 5
7 Sources of Iron 6-9
8 Human Requirements of Iron 9-10
9 Iron Absorption 10-14
10 Iron-deficiency 14-21
11 Causes of iron deficiency 21-22
12 Iron overload 22-24
13 Iron Toxicity 24
14 Iron and Diseases 25-28
15 Conclusions 29-30
16 References 31-36
1. Introduction
From ancient times, man has recognized the special role of iron in health
and disease. Iron had early medicinal uses by Egyptians, Hindus, Greeks, and
Romans[1]. During the 17th century, iron was used to treat chlorosis (green
disease), a condition often resulting from the iron deficiency[2]. However, it
was not until 1932 that the importance of iron was finally settled by the
convincing proof that inorganic iron was needed for hemoglobin synthesis[3].
For many years, nutritional interest in iron focused on its role in hemoglobin
formation and oxygen transport [4]. Nowadays, although low iron intake and/or
bioavailability are responsible for most anemia in industrialized countries, they
account for only about half of the anemia in developing countries[5], where
infectious and inflammatory diseases (especially malaria), blood loss from
parasitic infections, and other nutrient deficiencies (vitamin A, riboflavin, folic
acid, and vitamin B12) are also important causes[6].

Iron is a fundamental element in human history, from the dawn of

civilization to contemporary days. The ancients used the metal to shape tools, to
forge weapons, and even as a dietary supplement. This last indication has been
handed down until today, when martial therapy is considered fundamental to
correct deficiency states of anemia. The improvement of the martial status is
mainly targeted with dietary supplements that often couple diverse co-factors,
but other methods are available, such as parenteral preparations, dietary
interventions, or real-world approaches. The oral absorption of this metal occurs
in the duodenum and is highly dependent upon its oxidation state, with many
absorption influencers possibly interfering with the intestinal uptake. Bone
marrow and spleen represent the initial and ultimate step of iron metabolism,
respectively, and the most part of body iron circulates bound to specific proteins
and mainly serves to synthesize hemoglobin for new red blood cells. Whatever
the martial status is, today’s knowledge about iron biochemistry allows us to
embrace exceedingly personalized interventions, which however owe their
success to the mythical and historical events that always accompanied this
metal[7].

~1~
2. Types of Iron
2-1 Heme and Non-Heme
The two forms of dietary iron are heme iron and non-heme iron:

 Heme iron is found only in meat, poultry, seafood, and fish, so heme iron is
the type of iron that comes from animal proteins in our diet.

 Non-heme iron, by contrast, is found in plant-based foods like grains, beans,

vegetables, fruits, nuts, and seeds. But don’t make the mistake of assuming
it’s only in plants. Non-heme iron is also found in animal products such as
eggs or milk/dairy, and it also comprises more than half the iron contained in
animal meat[8].

The iron in meat is about 40-45%. The rest of the iron contained in meat
is actually this non-heme form (55-60%). Much of the iron in the diet, however,
is in the non-heme form. About 25 – 35 percent of heme iron is absorbed, yet
this percentage drops to 3 – 20 percent for non-heme iron. This difference is
important because heme iron is found only in animal flesh. For this reason
vegetarians, compared to non-vegetarians, require 1.8 times the amount of iron
when consuming foods that contain only non-heme iron[9].

3. Body iron stores

Most well-nourished people in industrialized countries have 4 to 5 grams
of iron in their bodies (∼38 mg iron/kg body weight for women and ∼50 mg
iron/kg body for men) [10]. Of this, about 2.5 g is contained in the hemoglobin
needed to carry oxygen through the blood (around 0.5 mg of iron per mL of
blood) [11], and most of the rest (approximately 2 grams in adult men, and
somewhat less in women of childbearing age) is contained in ferritin complexes
that are present in all cells, but most common in bone marrow, liver, and spleen.
The liver stores of ferritin are the primary physiologic source of reserve iron in
the body. The reserves of iron in industrialized countries tend to be lower in
children and women of child-bearing age than in men and in the elderly.
Women who must use their stores to compensate for iron lost through
menstruation, pregnancy or lactation have lower non-hemoglobin body stores,
which may consist of 500 mg, or even less.

~2~
 Of the body's total iron content, about 400 mg is devoted to cellular
proteins that use iron for important cellular processes like storing oxygen
(myoglobin) or performing energy-producing redox reactions (cytochromes). A
relatively small amount (3–4 mg) circulates through the plasma, bound to
transferrin[12]. Because of its toxicity, free soluble iron is kept in low
concentration in the body.

Iron deficiency first affects the storage of iron in the body, and depletion
of these stores is thought to be relatively asymptomatic, although some vague
and non-specific symptoms have been associated with it. Since iron is primarily
required for hemoglobin, iron deficiency anemia is the primary clinical
manifestation of iron deficiency. Iron-deficient people will suffer or die from
organ damage well before their cells run out of the iron needed for intracellular
processes like electron transport.

Macrophages of the reticuloendothelial system store iron as part of the

process of breaking down and processing hemoglobin from engulfed red blood
cells. Iron is also stored as a pigment called hemosiderin, which is an ill-defined
deposit of protein and iron, created by macrophages where excess iron is
present, either locally or systemically, e.g., among people with iron overload
due to frequent blood cell destruction and the necessary transfusions their
condition calls for. If systemic iron overload is corrected, over time the
hemosiderin is slowly resorbed by the macrophages.

4. Iron Distribution in the Human Body

The adult human body contains approximately 3–5 g of iron (45–55
mg/kg of body weight in adult women and men, respectively), with more than
two-thirds (∼2 g) incorporated in the hemoglobin of developing erythroid
precursors and mature red blood cells. The remaining body iron is mostly found
in a transit pool in reticuloendothelial macrophages (∼600 mg) or stored in
hepatocytes (∼1000 mg) within ferritin, an iron storage protein. A smaller
fraction is found in muscles within myoglobin (∼300 mg), while only a
minuscule amount (∼8 mg) is constituent of other cellular iron containing
proteins and enzymes. A healthy individual absorbs daily 1–2 mg of iron from
the diet, which compensates nonspecific iron losses by cell desquamation in the
skin and the intestine (Fig.1). Furthermore, menstruating women
physiologically lose iron from the blood. Recycling of iron via
reticuloendothelial macrophages provides the amount of iron required for

~3~
erythropoiesis (30 mg/day). Iron bound to plasma transferrin corresponds to less
than 0.1% of total body iron, but represents, in kinetic terms, the most active
pool.

Fig. 1 Iron distribution in human body

5. Iron Functions in the Body

Iron performs many important functions in the body. It is primarily
involved in the transfer of oxygen from the lungs to tissues. However, iron also
plays a role in metabolism as a component of some proteins and enzymes.

Iron is toxic to the body in its free state. It is associated with proteins
either through ligand binding or by being incorporated into a porphyrin group -
a ring-shaped molecule. A complex of the ferrous form of iron and
protoporphyrin IX is known as heme. Heme iron is found in proteins connected
with oxygen transport, including hemoglobin and myoglobin. Non-heme iron
can be found in proteins connected with oxidative phosphorylation and in iron
storage proteins like transferrin and ferritin[13].

~4~
6. Hemoglobin and Myoglobin
6 – 1 Hemoglobin
Hemoglobin is a protein in red blood cells responsible for carrying
oxygen to the tissues from the lungs[14]. Myoglobin is a protein found in
muscles that is used for storage of oxygen to the muscle cells[15].

6 – 2 Myoglobin
Hemoglobin is the oxygen transport system found in the red blood cells
of all vertebrates and some invertebrates. In humans, hemoglobin is made up of
four globular protein subunits. The four subunits form a pocket that binds a
heme group. About 65 to 80 percent of the body’s iron is in the blood in the
form of hemoglobin.

Oxygen binds to the iron atom within the hemoglobin molecule in the
lungs to form oxyhemoglobin. This occurs in the capillaries of the lung alveoli.
It is released at its destination in the cells. Hemoglobin carries CO2 back to the
lungs to be exhaled as waste, but CO2 binds to the protein portion of the
hemoglobin molecule, not to the bound iron in the heme group.

Like hemoglobin, myoglobin binds iron within a heme group. However,

structurally, it is much simpler, consisting of a single polypeptide chain of 154
amino acids. It is found only in cardiac myocytes and oxidative skeletal muscle.
Myoglobin is an oxygen storage protein. In marine mammals, it provides an
oxygen supply for extended periods when the animal is diving under water. At
those times, myoglobin releases oxygen to sustain aerobic metabolism in the
muscle. In humans, myoglobin levels have been shown to be increased at high
altitudes[16].

Fig. (2) Structure of human hemoglobin and Myoglobin

~5~
7. Sources of Iron
7 – 1 Food

The richest sources of heme iron in the diet include lean meat and
seafood[17]. Dietary sources of non-heme iron include nuts, beans, vegetables,
and fortified grain products. In the United States, about half of dietary iron
comes from bread, cereal, and other grain products[18]. Breast milk contains
highly bioavailable iron but in amounts that are not sufficient to meet the needs
of infants older than 4 to 6 months[19].

In the United States, Canada, and many other countries, wheat and other flours
are fortified with iron[20]. Infant formulas are fortified with 12 mg iron per
liter[21].

Heme iron has higher bioavailability than non-heme iron, and other
dietary components have less effect on the bioavailability of heme than non-
heme iron. The bioavailability of iron is approximately 14% to 18% from mixed
diets that include substantial amounts of meat, seafood, and vitamin C (ascorbic
acid, which enhances the bioavailability of non-heme iron) and 5% to 12% from
vegetarian diets. In addition to ascorbic acid, meat, poultry, and seafood can
enhance non-heme iron absorption, whereas phytate (present in grains and
beans) and certain polyphenols in some non-animal foods (such as cereals and
legumes) have the opposite effect. Unlike other inhibitors of iron absorption,
calcium might reduce the bioavailability of both non-heme and heme iron.
However, the effects of enhancers and inhibitors of iron absorption are
attenuated by a typical mixed western diet, so they have little effect on most
people’s iron status[22].

Several food sources of iron are listed in Table 2. Some plant-based foods
that are good sources of iron, such as spinach, have low iron bioavailability
because they contain iron-absorption inhibitors, such as polyphenols[23].

7 – 2 Dietary supplements

Iron is available in many dietary supplements. Multivitamin/multimineral

supplements with iron, especially those designed for women, typically provide
18 mg iron (100% of the DV). Multivitamin/multimineral supplements for men
or seniors frequently contain less or no iron. Iron-only supplements usually
deliver more than the DV, with many providing 65 mg iron (360% of the DV).

~6~
 Frequently used forms of iron in supplements include ferrous and ferric
iron salts, such as ferrous sulfate, ferrous gluconate, ferric citrate, and ferric
sulfate[24]. Because of its higher solubility, ferrous iron in dietary supplements
is more bioavailable than ferric iron[25]. High doses of supplemental iron (45
mg/day or more) may cause gastrointestinal side effects, such as nausea and
constipation[26]. Other forms of supplemental iron, such as heme iron
polypeptides, carbonyl iron, iron amino-acid chelates, and polysaccharide-iron
complexes, might have fewer gastrointestinal side effects than ferrous or ferric
salts[27].

The different forms of iron in supplements contain varying amounts of

elemental iron. For example, ferrous fumarate is 33% elemental iron by weight,
whereas ferrous sulfate is 20% and ferrous gluconate is 12% elemental iron.
Fortunately, elemental iron is listed in the Supplement Facts panel, so
consumers do not need to calculate the amount of iron supplied by various
forms of iron supplements[28].

Approximately 14% to 18% of Americans use a supplement containing

iron[29]. Rates of use of supplements containing iron vary by age and gender,
ranging from 6% of children aged 12 to 19 years to 60% of women who are
lactating and 72% of pregnant women[30].

Calcium might interfere with the absorption of iron, although this effect
has not been definitively established[31]. For this reason, some experts suggest
that people take individual calcium and iron supplements at different times of
the day[32].

8. Human Requirements of Iron

During early infancy, iron requirements are met by the little iron
contained in the human milk. The need for iron rises markedly 4-6 months after
birth and amounts to about 0.7-0.9 mg/day during the remaining part of the first
year. Between 1 and 6 years of age, the body iron content is again doubled. Iron
requirements are also very high in adolescents, particularly during the period of
growth spurt. Girls usually have their growth spurt before menarche, but growth
is not finished at that time. In boys there is a marked increase in hemoglobin
mass and concentration during puberty. In this stage, iron requirements increase

~7~
to a level above the average iron requirements in menstruating women[33]
[ Table 1].

The average adult stores about 1-3 g of iron in his or her body. A fine
balance between dietary uptake and loss maintains this balance. About 1 mg of
iron is lost each day through sloughing of cells from skin and mucosal surfaces,
including the lining of the gastrointestinal tract[34]. Menstruation increases the
average daily iron loss to about 2 mg per day in premenopausal female adults.
The augmentation of body mass during neonatal and childhood growth spurts
transiently boosts iron requirements[35].

Age Male Female Pregnancy Lactation

Birth to 6 months 0.27 mg* 0.27 mg*
7–12 months 11 mg 11 mg
1–3 years 7 mg 7 mg
4–8 years 10 mg 10 mg
9–13 years 8 mg 8 mg
14–18 years 11 mg 15 mg 27 mg 10 mg
19–50 years 8 mg 18 mg 27 mg 9 mg
51+ years 8 mg 8 mg

Table ( 1 ): Recommended Dietary Allowances (RDAs) for Iron[36]

9. Iron Absorption
Iron absorption is affected by the iron status of the individual, the type of
food eaten, vitamin C intake and other factors in the diet. The healthy body
absorbs around 18% of the available iron from a typical western diet (which
includes animal foods) and about 10% from a vegetarian diet. People with a low
reserve of iron will absorb more iron than those with sufficient stores. This is
the body’s way of trying to maintain adequate levels of iron while protecting
against iron toxicity.

Dietary iron absorption occurs mostly at the duodenum and the upper
portions of the jejunum. The body has no effective means of excreting iron and
thus the regulation of absorption of dietary iron plays a critical role in iron
homeostasis. Multiple steps are involved in iron absorption, including the
reduction of iron to a ferrous state, apical uptake, intracellular storage or
~8~
transcellular trafficking, and basolateral release. Dietary iron is found in heme
(10%) and nonheme (90%) forms and their absorption occurs under
different mechanisms.

Iron absorption can vary significantly from person to person and also
from meal to meal: coffee or tea taken with a meal can reduce absorption by as
much as 50 percent. Individuals can absorb anywhere from < 1 percent to > 50
percent of the iron in their diet. Dietary factors that can reduce non-heme iron
absorption include phytates (found in grains, legumes, and rice); soy protein and
soy fiber; oxalates (found in spinach); and tannic acid (found in teas and
coffee). Calcium (found in dairy products) can reduce the absorption of both
non-heme and heme iron. In order to maximize iron uptake, foods high in non-
heme iron should be eaten at the same time as those that are a good source of
vitamin C, such as orange juice, tomatoes, bell peppers, strawberries,
cantaloupe, or broccoli. Absorption of non-heme iron can also be enhanced by
the presence of heme iron. For example, a stew made with beans, tomatoes, and
a small amount of meat, for example, would maximize the iron potential of both
the meat and the beans[37].

9 – 1 Iron Absorption Process

Iron absorption is a two-step process:

First, iron ions are absorbed from the intestinal lumen into mucosal cells.
Ferrous iron is better absorbed than ferric iron because ferric iron precipitates
out of solution at around pH 7 or under normal physiologic conditions[38].
However, both forms can be absorbed if they are ionized[39]. Because iron
must be ionized to be absorbed, metallic iron and iron oxide (rust) are not
generally of concern when they are ingested[40].

Most iron absorption occurs in the duodenum and upper jejunum, but in
animals with iron toxicosis, the iron seems to be well-absorbed along all parts of
the intestinal tract[41]. A diet high in sugar and vitamin C increases iron
absorption, while a high-phosphate diet reduces iron absorption[42]. But in
acute overdoses, the iron seems to be absorbed in a passive, concentration
dependent fashion, similar to how most other metals are absorbed.

Second, iron is transferred to ferritin or into circulation bound to

transferrin proteins. Transferrin is an alpha1-globulin produced in the liver[43].
Complexed with transferrin, iron is distributed to other iron storage locations in

~9~
the body. A unique feature of iron metabolism is the almost complete absence
of iron excretion. Any iron lost from hemoglobin degradation is rapidly bound
to transferrin and transported to the bone marrow for the resynthesis of
hemoglobin[44]. Consequently, little iron is lost in the urine and feces. In
addition, iron loss is not notably increased even after iron overdoses[45]. Most
iron loss is through the exfoliation of gastrointestinal mucosal cells in all
mammals and through menstrual blood loss[46]. While anywhere from 2% to
15% of the iron ingested is absorbed, only about 0.01% of the iron body burden
is eliminated every day[47].

9 – 2 Iron uptake and utilization in liver

The liver is a major storage organ of iron, in which excess iron is stored
as ferritin and hemosiderin. In addition to these proteins, an additional fraction
of free iron is present in the form of the labile iron pool (LIP) within cells. The
LIP is biologically active in intracellular metabolism via oxidation–reduction
reactions, cell proliferation, and cell signaling, but is toxic if present in excess.
As shown in ( Fig. 3) [48], hepatocytes have essentially two pathways for
uptake of iron from the circulation: Tf-bound iron (Fe2-Tf) at physiological iron
concentrations, and NTBI in iron overload conditions[49].

Fig. (3) The two hepatocytes pathways for uptake of iron from the circulation:

Tf-bound iron (Fe2-Tf) and NTBI[50]

~ 10 ~
9 – 3 Nutrients Affecting Absorption
9-3-1 Improving Iron Absorption
There are, however, a number of ways to improve iron absorption.

 Foods rich in vitamin C can enhance the absorption of iron. Good sources
of vitamin C include citrus fruits and juices, tomatoes, strawberries,
melons, dark green leafy vegetables and potatoes. To have an effect, these
foods must be eaten at the same meal as the iron source.
 Include animal protein (haem) with plant (non-haem) sources of iron,
such as meat with beans – for example, beef and kidney beans in a chilli
con carne, also improves absorption. Not only will more total
iron be eaten, but the percentage of non-heme iron that is absorbed will
be greater.
9-3-2 factors may decrease the availability of iron:
 The tannins in both tea and coffee adversely affect iron availability.
Coffee and tea consumption at the time of a meal can significantly
decrease iron absorption. Tea can cause iron absorption to drop by 60
percent and coffee can cause a 50 percent decrease in iron uptake.

 Phytates in some legumes and grains, phosphates in cola drinks, some

proteins in soybeans, and calcium and fiber may also interfere with iron
absorption. These may be important factors if the diet is already low in
iron. Vitamin A helps release iron from iron stores in the body and makes
it more available for the body to use. Vitamin A deficiencies, therefore,
may manifest as iron deficiencies. The use of vitamin A and iron
supplementation may help relieve iron deficiency more than iron alone. If
there is concern for iron deficiency, it is important to talk with a doctor
before beginning iron supplementation.

~ 11 ~
10. Iron-deficiency
Iron deficiency is defined as a condition in which there are no
mobilizable iron stores and in which signs of a compromised supply of iron to
tissues, including the erythron, are noted[51]. Iron deficiency is the most
common nutritional disorder in the world. It’s important to have good amounts
of iron in our diets at any age, but there are some phases when low intakes can
affect us more. The highest probability of suffering iron deficiency is found in
those parts of a population that have inadequate access to foods rich in
absorbable iron during stages of high iron demand. These groups correspond to
children, adolescents, and women of reproductive age, in particular during
pregnancy[52].

For example, iron is a key mineral for a healthy growth and development,
which is why it’s particularly important during infancy, childhood and
adolescence. Moreover, from the onset of menstruation to menopause, people
need extra amounts of iron-rich foods in their diets to compensate for the
monthly losses of iron during menstruation.

10 – 1 Iron deficiency without anemia

Iron deficiency can exist with or without anemia. Some functional
changes may occur in the absence of anemia, but the most functional deficits
appear to occur with the development of anemia[53]. Iron is found in the body
in two forms, as functional iron (iron that serves a metabolic function) and as
storage iron. When a person has depleted their stores of iron, they are said to be
“iron deficient.” When the depletion progresses, the hemoglobin concentration
in red blood cells falls below the normal range (the 95 percentile for age). At
this point, the person is classified as having anemia. Iron deficiency can exist
with or without anemia[54] [55].

The continuum from iron deficiency to iron deficiency anemia has a host
of associated consequences, depending on the severity of iron depletion.
Iron deficiency, without anemia, has few discernable outcomes but it has been
shown to reduce work capacity, particularly in regards to endurance. As iron
deficiency progresses to anemia, further consequences become more evident
including changes in behavior and intellectual performance, reduced
resistance to infection, increased susceptibility to lead poisoning, loss of

~ 12 ~
appetite, tachycardia, and cardiomegaly. Symptoms of iron deficiency are
shown in fig. (4).

Symptoms of iron deficiency[56]

Iron depletion and deficiency progresses through several stages[57]:

1. Mild deficiency or storage iron depletion: Serum ferritin concentrations

and levels of iron in bone marrow decrease.

2. Marginal deficiency, mild functional deficiency, or iron-deficient

erythropoiesis (erythrocyte production): Iron stores are depleted, iron
supply to erythropoietic cells and transferrin saturation decline, but
hemoglobin levels are usually within the normal range.

3. IDA: Iron stores are exhausted; hematocrit and levels of hemoglobin

decline; and the resulting microcytic, hypochromic anemia is
characterized by small red blood cells with low hemoglobin
concentrations.

~ 13 ~
 Iron values in the body are measured by blood analysis of specific proteins
that regulate its transport and storage[58]:

1. Sideremia, which measures the amount of circulating iron bound to

transferrin;

2. Transferrinemia, which measures the amount of transferrin, protein that

transports iron to the organs and tissues;

3. Saturation of transferrin, which indicates the percentage of saturated

transferrin, i.e. that is binding iron compared to the total. The optimal
values are between 20% and 50%;

4. Ferritinemia, which measures the amount of ferritin, protein responsible

for iron storage in the liver, muscles, and bone marrow.

10 – 2 Anemia
Anemia is defined as the condition with a decreased number of RBCs in
the blood, or RBCs have less than the normal amount of hemoglobin. According
to the World Health Organization, iron deficiency anemia is one of the most
common nutrient deficiencies in the world. It can be caused by a low dietary
intake of iron, poor iron absorption, or excessive blood loss. Signs of anemia
include: constantly feeling weak and tired; short attention span; irritability;
decreased performance at work or school; delayed cognitive development in
infants and young children; decreased immune function leading to increased
illness; swollen and red tongue (glossitis), and difficulty maintaining body
temperature. Several groups are at an increased risk for iron deficiency
including children and adolescents, pregnant women, women of child-bearing
age, athletes, and older adults[59].

In the case of Anemia, Iron supplementation is necessary. Conventional

oral iron therapy is limited in many patients because of dose dependent side
effects, insufficient absorption, lack of compliance and limitation in various
inflammatory conditions. Liposomal iron is a technologically designed,
innovative form of iron which due to its differential delivery system ensures
higher absorption and bioavailability, greater tolerability and least gastro-
intestinal side effects unlike conventional oral iron preparations[60].

~ 14 ~
 In young children, prolonged iron deficiency anemia has been associated
with motor and cognitive deficits and an inability to concentrate. These
symptoms are not always reversed with iron supplementation. In pregnant
women, iron deficiency anemia has been associated with adverse effects for
both the mother and fetus, including increased perinatal complications,
premature delivery, and low birth weight.

10-2-1 Symptoms of iron deficiency anemia

 Fatigue/extreme tiredness
 Tired more quickly than normal with exercise
 Pale skin
 Feeling lightheaded or dizzy
 Cravings for non-food items such as ice.
Severe anemia may cause:
 Fainting.
 Chest pain.
 Angina.
 Heart attack.

Fig. (5) Symptoms of anemia

~ 15 ~
10 – 3 Infants, Children and Adolescents

The greatest need for iron is during growth or periods of blood loss.
Young children and adolescents have increased needs because of the growth
taking place during these periods. Infants—especially those born preterm or
with low birth weight or whose mothers have iron deficiency—are at risk of
iron deficiency because of their high iron requirements due to their rapid
growth[61]. Full-term infants usually have sufficient iron stores and need little
if any iron from external sources until they are 4 to 6 months old[62].

Very young children are at particular risk for iron-deficiency anemia due
to their rapid growth rate. In addition, children’s diets may rely heavily on milk
products, which, while providing an excellent source of calcium, are not good
sources of iron and can replace foods that provide iron[63].

Iron deficiency is seen more frequently in those children whose diets do

not include meats (even though they may consume eggs or dairy products) as
compared to omnivorous children. Care should be taken to ensure that foods
containing available iron are included in the diet.

10 – 4 Pregnant and Menstruating Women

During pregnancy, plasma volume and red cell mass expand due to
dramatic increases in maternal red blood cell production[64]. As a result of this
expansion and to meet the needs of the fetus and placenta, the amount of iron
that women need increases during pregnancy. Iron deficiency during pregnancy
increases the risk of maternal and infant mortality, premature birth, and low
birth weight[65].

Because adequate intakes of iron are crucial for both the woman and her
fetus, the RDA for iron during pregnancy is 27 mg/day. Iron is needed during
pregnancy to replace iron lost in the course of daily activities, to allow for the
needed expansion of the red blood cell mass, to provide iron to the placenta and
fetal bone tissues, and to replace iron from blood lost during delivery[66].

10 – 5 Athletes

An active female athlete involved in a rigorous training program has an

increased risk for iron deficiency anemia. Iron deficiency is common with or
without anemia, decreases performance for the athlete, and often is not detected
on a standard blood test. The capacity to transport oxygen to the cells of the

~ 16 ~
muscle via myoglobin is impaired (energy production is limited), which is vital
for competition. Male endurance athletes and vegetarian athletes may also be at
an increased risk for iron deficiency. To ensure optimum iron stores, athletes
should eat meals or snacks that contain adequate quantities of iron-rich foods
and, in some cases, see a physician for a recommended iron supplement. See
fact sheet 9.362, Nutrition for the Athlete, for more information.

10 – 6 Restrictive Diets (vegetarians, vegans)

Vegans and vegetarians also need to pay extra attention to their iron
intake, as our bodies absorb less iron from plant-based foods than that from
animal sources. If that’s the case, consult a registered dietitian/nutritionist or
check your national dietary guidelines to plan a diet that includes enough
sources of iron to meet your daily needs.

10 – 7 People with heart failure

Approximately 60% of patients with chronic heart failure have iron

deficiency and 17% have IDA, which might be associated with a higher risk of
death in this population[67]. Potential causes of iron deficiency in people with
heart failure include poor nutrition, malabsorption, defective mobilization of
iron stores, cardiac cachexia, and use of aspirin and oral anticoagulants, which
might result in the loss of some blood in the gastrointestinal tract[68].

11. Causes of iron deficiency

Iron deficiency results from depletion of iron stores and occurs when iron
absorption cannot keep pace over an extended period with the metabolic
demands for iron to sustain growth and to replenish iron loss, which is primarily
related to blood loss[69]. The primary causes of iron deficiency include low
intake of bioavailable iron, increased iron requirements as a result of rapid
growth, pregnancy, menstruation, and excess blood loss caused by pathologic
infections, such as hook worm and whipworm causing gastrointestinal blood
loss[70] and impaired absorption of iron[71]. The frequency of iron deficiency
rises in female adolescents because menstrual iron losses are superimposed with
needs for rapid growth[72]. Other risk factors for iron deficiency in young
women are high parity, use of an intrauterine device, and vegetarian diets[73].

Nutritional iron deficiency arises when physiological requirements cannot

be met by iron absorption from the diet[74] Dietary iron bioavailability is low in

~ 17 ~
populations consuming monotonous plant-based diets with little meat. In many
developing countries, plant-based weaning-foods are rarely fortified with iron,
and the frequency of anemia exceeds 50% in children younger than 4 years[75].

When iron stores are depleted and insufficient iron is available for
erythropoiesis, hemoglobin synthesis in erythrocyte precursors become
impaired and hematologic signs of iron deficiency anemia appear.

12. Iron overload

The body is able to substantially reduce the amount of iron it absorbs
across the mucosa. It does not seem to be able to entirely shut down the iron
transport process. Also, in situations where excess iron damages the intestinal
lining itself (for instance, when children eat a large quantity of iron tablets
produced for adult consumption), even more iron can enter the bloodstream and
cause a potentially deadly syndrome of iron overload. Large amounts of free
iron in the circulation will cause damage to critical cells in the liver, the heart
and other metabolically active organs.

Iron toxicity results when the amount of circulating iron exceeds the
amount of transferrin available to bind it, but the body is able to vigorously
regulate its iron uptake. Thus, iron toxicity from ingestion is usually the result
of extraordinary circumstances like iron tablet over-consumption[76] rather than
variations in diet. The type of acute toxicity from iron ingestion causes severe
mucosal damage in the gastrointestinal tract, among other problems.

Excess iron has been linked to higher rates of disease and mortality. For
example, breast cancer patients with low ferroportin expression (leading to
higher concentrations of intracellular iron) survive for a shorter period of time
on average, while high ferroportin expression predicts 90% 10-year survival in
breast cancer patients[77]. Similarly, genetic variations in iron transporter genes
known to increase serum iron levels also reduce lifespan and the average
number of years spent in good health[78]. It has been suggested that mutations
that increase iron absorption, such as the ones responsible for hemochromatosis
(see below), were selected for during Neolithic times as they provided a
selective advantage against iron-deficiency anemia[79]. The increase in
systemic iron levels becomes pathological in old age, which supports the notion
that antagonistic pleiotropy or "hyperfunction" drives human aging[80].

~ 18 ~
 Chronic iron toxicity is usually the result of more chronic iron overload
syndromes associated with genetic diseases, repeated transfusions or other
causes. In such cases the iron stores of an adult may reach 50 grams (10 times
normal total body iron) or more. The most common diseases of iron overload
are hereditary hemochromatosis (HH), caused by mutations in the HFE gene,
and the more severe disease juvenile hemochromatosis (JH), caused by
mutations in either hemojuvelin (HJV) [81] or hepcidin (HAMP). The exact
mechanisms of most of the various forms of adult hemochromatosis, which
make up most of the genetic iron overload disorders, remain unsolved. So,
while researchers have been able to identify genetic mutations causing several
adult variants of hemochromatosis, they now must turn their attention to the
normal function of these mutated genes.

13. Iron Toxicity

Iron overload induces organ damage in liver, heart, pancreas, thyroid, and
the central nervous system. The main cause of this organ damage is due to the
presence of excess iron[82].

Because intestinal absorption of iron is regulated by iron stores, iron

toxicity is rare. However, there are some conditions in which excess iron is
absorbed by the body:

• Consuming large quantities of alcohol may increase the absorption

of iron.
• Hemochromatosis, a genetic disorder, causes the body to absorb too much
iron from food that is consumed. Once iron is absorbed, it is only
excreted through blood loss. Excess iron will build up in tissues and
organs. If too much iron accumulates in the body, this may increase the
risk for developing certain types of cancer and may eventually lead to
death.

• An overdose of iron supplements can cause toxicity in adults and children.

However, in children as little as 20 to 60 mg of iron/kg body weight can
cause toxicity and death. It is important to keep iron supplements away
from children and tightly closed. The tolerable upper limits for iron as set
by the Institute for Medicine and the National Academy of Sciences is 40
mg/day for children under the age of 14 and 45 mg/day for anyone 14 years

~ 19 ~
 of age or older. This limit is set as the largest amount of iron a person can
consume without risk of negative side effects.
14. Iron and Diseases
The central importance of iron in the pathophysiology of disease is
derived from the ease with which iron is reversibly oxidized and reduced. This
property, while essential for its metabolic functions, makes iron potentially
hazardous because of its ability to participate in the generation of powerful
oxidant species such as hydroxyl radical[83]. Oxygen normally accepts four
electrons and is converted directly to water. However, partial reduction of
oxygen can and does occur in biological systems. Thus, the sequential reduction
of oxygen along the univalent pathway leads to the generation of superoxide
anion, hydrogen peroxide, hydroxyl radical, and water[84]. Superoxide and
hydrogen peroxide appear to be the primary generated species. These species
may then play a role in the generation of additional and more reactive oxidants,
including the highly reactive hydroxyl radical (or a related highly oxidizing
species) in which iron salts play a catalytic role in a reaction. This reaction is
commonly referred to as the metal catalyzed Haber-Weiss reaction:

14 – 1 Heart Disease

Heart disease risk seems to be greater in societies that eat high amounts
of red meat versus those that eat minimal amounts. The amount of iron stored
in the body can influence a person’s potential to develop heart disease. Excess
iron is associated with the formation of free radicals, unstable molecules in the
body, which may injure vessels supplying blood to the heart. It has also been
suggested that the incidence of heart disease rises dramatically in women once
menstruation stops due to increased amounts of iron in the blood.

Fig. (6) Iron and Cardiovascular disease

~ 20 ~
 However, there is no conclusive evidence that excess iron increases
coronary heart disease, so it is not recommended to eliminate red meat or other
iron rich foods from the diet[85].

It has been known for some time that iron deficiency predisposes to
pulmonary arterial hypertension (PAH). In this condition, the vasculature in the
lungs is constricted and remodeled, and this puts pressure on the right side of
the heart. For some time it was thought that PAH is caused by anemia, a
condition in which iron deficiency is the underlying mechanism.

Fig. (7) iron deficiency and Cardiovascular diseases

Consequently, the only consideration given to iron deficiency in the

clinical setting has been in the context of correcting anemia[86].

14 – 2 Diabetes

There is suggestive evidence that iron plays a pathogenic role in diabetes

and its complications such as microangiopathy and atherosclerosis. Reliable and
sensitive methods need to be developed to precisely measure the free/catalytic
iron that participates in oxidative injury. Iron chelation therapy may present a
novel way to interrupt the cycle of catalytic iron–induced oxidative stress and

~ 21 ~
tissue injury and consequent release of catalytic iron in diabetes and to prevent
diabetes-related complications[87].

Excessive iron stores may play a role in type 2 diabetes. Patients with
hemochromatosis have an increased risk for type 2 diabetes and some studies
have shown elevated iron levels in patients with type 2 diabetes.

Fig. (7) Illustration of the relationships of iron deficiency or overload with diabetes,
[88]
insulin resistance and diabetic complications .

Yet, there is not enough scientific evidence to prove a link between iron
and type 2 diabetes, and reducing iron intake to treat or decrease the risk of
developing diabetes is not recommended[89].

14 – 3 Restless Leg Syndrome

Restless leg syndrome (RLS) is a neurological movement disorder.

People with RLS experience an uncomfortable sensation in their arms and legs
that result in the need to move and effects sleep patterns. Iron supplementation
relieves the need to move in some patients with RLS. The mechanisms
behind iron’s benefit to RLS sufferers are not well understood, but they may be
linked to iron insufficiencies in spinal fluid or parts of the brain.

~ 22 ~
Conclusions
 Iron is an essential metal for the body, while excess iron accumulation
causes organ dysfunction through the production of reactive oxygen
species.
 Iron is an essential nutrient which is required: as hemoglobin in red blood
cells for transporting oxygen from the lungs to the tissues; in the form of
myoglobin for storage and use of oxygen in muscles; and as a component
of a number of enzymes which are essential for many metabolic and
synthetic functions.
 Iron is vital for almost all living organisms by participating in a wide
variety of metabolic processes, including oxygen transport, DNA
synthesis, and electron transport.
 The adult human body contains approximately 3–5 g of iron (45–55
mg/kg of body weight in adult women and men, respectively)
 Ferritin is the protein within the body that stores iron and releases it
through channels in a controlled fashion. Ferritin can control the amount
of available iron in the body, preventing iron disorders like anemia and
iron overload.

 Dietary iron is found in both animal and plant products. Iron is present in
foods as heme or non-heme iron. Heme iron is found almost exclusively
in foods of animal origin. Non-heme iron is found in animal and plant
tissues, fortified foods and supplements.
 Iron concentrations in body tissues must be tightly regulated because
excessive iron leads to tissue damage, as a result of formation of free
radicals.
 The liver is a major storage organ of iron, in which excess iron is stored
as ferritin and hemosiderin.
 Certain foods and drinks affect how much iron your body absorbs.
 Iron deficiency is when the stores of iron in your body are too low.
 Common causes of iron deficiency include not getting enough iron in
your diet, chronic blood loss, pregnancy and vigorous exercise.
 Some people become iron deficient if they are unable to absorb iron.
 Iron deficiency can be treated by adding iron-rich foods to the diet.
 If you have iron deficiency anemia, your GP (doctor) may recommend
that you take iron supplements.

~ 23 ~
 The free irons, non-transferrin-bound iron, and labile plasma iron in the
circulation, and the labile iron pool within the cells, are responsible for
iron toxicity.
 The characteristic features of advanced iron overload are failure of vital
organs such as liver, heart, pancreas, thyroid, and the central nervous
system in addition to endocrine dysfunctions.
 Iron plays a role in the development of several cardiovascular diseases
including HF and atherosclerosis.
 Iron overload is associated with diabetes risk, iron deficiency is
associated with another major risk factor for diabetes, obesity.
 Iron plays a pathogenic role in diabetes and its complications such as
microangiopathy and atherosclerosis.
 The way our body absorbs these two types of iron is very different:
 Heme iron is more easily absorbed and is, therefore, a large source of
dietary iron for people both with and without hemochromatosis.
 Non-heme iron is usually less readily absorbed than heme iron.
Especially in people without hemochromatosis, non-heme iron tends not
to be a big source of dietary iron.

~ 24 ~
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