Prepared by

IRON DEFICIENCY ANEMIA Darien Liew Daojuin

23 June 2017
ANEMIA
Anaemia is present when
there is a decrease in Hb
in the blood below the
reference level for the
age and sex of the
individual
INTRODUCTION
Iron deficiency is the most common cause of anaemia in the world,
affecting 30% of the worlds population.
Although iron is abundant, most is in the insoluble ferric (Fe3+) form,
which has poor bioavailability. Ferrous (Fe2+) is more readily
absorbed.
IRON METABOLISM
A normal western diet contains 10-20mg of heme iron (animal
sources). Vegetables contain inorganic iron. About 20% of heme iron is
absorbable (vs. 1-2% of non-heme iron).

Heme iron Hemoglobin, myoglobin,

cytochromes, cytochrome
oxidase, catalase
Non-heme iron containing Transferrin, ferritin,
proteins hemosiderin

Total body iron content (TBIC) is about 2.5g in women and as high as
6g in men. TBIC can be divided into functional and storage
compartments.
IRON METABOLISM
80% of functional iron is found in hemoglobin.
The remaining 20% consists of myoglobin, iron containing enzymes
(catalase, cytochromes).

The storage pool (15%-20% of TIBC) contains hemosiderin and

ferritin.
IRON ABSORPTION
ROLE OF HEPCIDIN

Iron absorption is regulated by hepcidin, a small circulating peptide

that is synthesized and released from the liver in response to increases
in intrahepatic iron levels.
Hepcidin inhibits iron transfer from the enterocyte to plasma by
binding to ferroportin and causing it to be endocytosed and
degraded.
As a result, as hepcidin levels rise, iron becomes trapped within
duodenal cells in the form of mucosal ferritin and is lost as these cells
are sloughed. Thus, when the body is replete with iron, high hepcidin
levels inhibit its absorption into the blood.
Conversely, with low body stores of iron, hepcidin synthesis falls and
this in turn facilitates iron absorption.
IRON ABSORPTION
ROLE OF HEPCIDIN

By inhibiting ferroportin (causing itself to internalise and degrade),

hepcidin not only reduces iron uptake from enterocytes but also
suppresses iron release from macrophages, which are an important
source of the iron that is used by erythroid precursors to make
hemoglobin.
This is important in the pathogenesis of anemia of chronic diseases as
well inflammatory mediators (IL-6) result in increased hepcidin
production.
IRON ABSORPTION
APICAL MEMBRANE

Luminal nonheme & heme iron is mostly in the insoluble Fe3+ (ferric)
state and must first be reduced to Fe2+ (ferrous) iron by
ferrireductases, such as b cytochromes and STEAP3.
Fe2+ iron is then transported across the apical membrane by divalent
metal transporter 1 (DMT1).
IRON ABSORPTION
IRON ABSORPTION
ABSORPTION OF INORGANIC IRON

Absorption of inorganic iron is enhanced by ascorbic acid, citric acid,

amino acids, and sugars in the diet, and inhibited by tannates (found
in tea), carbonates, oxalates, and phosphates.
The absorption of non-heme iron is variable and often inefficient,
being inhibited by substances in the diet that bind and stabilize Fe3+
iron and enhanced by substances that stabilize Fe2+.
Frequently, less than 5% of dietary nonheme iron is absorbed. In
contrast, about 25% of the heme iron derived from hemoglobin,
myoglobin, and other animal proteins is absorbed.
IRON TRANSPORT
Iron in the dudoenal cell cytoplasm has 2 fates
1. Transport to the blood
2. Storage as mucosal iron

Fe2+ iron destined for the circulation is transported from the cytoplasm
across the basolateral enterocyte membrane by ferroportin. This is
followed by oxidation of Fe2+ iron to Fe3+ iron, which is carried out
by the iron oxidases hephaestin and ceruloplasmin.
Fe3+ iron then binds rapidly to the plasma protein transferrin, which
delivers iron to red cell progenitors in the marrow.
DMT1 AND FERROPORTIN
Both DMT1 and ferroportin are widely distributed in the body and
are involved in iron transport in other tissues as well.
For example, DMT1 also mediates the uptake of functional iron
(derived from endocytosed transferrin) across lysosomal membranes
into the cytosol of red cell precursors in the bone marrow, and
ferroportin plays an important role in the release of storage iron from
macrophages.
 PLASMA TRANSFERRIN
Iron in the body is recycled between
the functional and storage pools. It is
transported in plasma by transferrin,
which is synthesized in the liver.
In normal individuals, 1/3 of total
transferrin contains iron, yielding
serum iron levels that average 120
g/dL in men and 100 g/dL in
women. The major function of plasma
transferrin is to deliver iron to cells,
including erythroid precursors, which
require iron to synthesize hemoglobin.
Erythroid precursors possess high-
affinity receptors for transferrin that
mediate iron import through receptor-
mediated endocytosis.
STORAGE OF IRON
FERRITIN

Iron can either be stored as ferritin (2/3 of total iron storage

compartment) or hemosiderin (remaining 1/3).
Ferritin is a ubiquitous protein-iron complex that is found at highest
levels in the liver, spleen, bone marrow, and skeletal muscles.
In the liver, most ferritin is stored within the parenchymal cells; in other
tissues, such as the spleen and the bone marrow, it is found mainly in
macrophages.
Hepatocyte iron is derived from plasma transferrin, whereas storage
iron in macrophages is derived from the breakdown of red cells.
Intracellular ferritin is located in the cytosol and in lysosomes, in which
partially degraded protein shells of ferritin aggregate into
hemosiderin granules.
STORAGE OF IRON
HEMOSIDERIN

Iron in hemosiderin is chemically reactive and turns blue-black when

exposed to potassium ferrocyanide, which is the basis for the Prussian
blue stain.
With normal iron stores, only trace amounts of hemosiderin are found
in the body, principally in macrophages in the bone marrow, spleen,
and liver, most being stored as ferritin.
In iron-overloaded cells, most iron is stored in hemosiderin; E.g.
hemochromatosis.
ETIOLOGY
Iron deficiency can result from
1. dietary lack
2. impaired absorption
3. increased requirement
4. chronic blood loss
To maintain normal iron
balance, about 1mg of iron
must be absorbed from the
diet everyday.
Each day 0.5mg to 1mg is lost
in the feces, urine and sweat.
Menstruating women lose 30-
40mL of blood/month, an
average of 0.5-0.7 mg of
iron/day.
ETIOLOGY
Impaired absorption Increased requirement
Chronic diarrhea Growing infants, children and
Fat malabosorption adolescent
Gastrectomy Premenopausal women
Multiple pregnancies

Iron deficiency in adult man and

postmenopausal women must be
attributed to GI bleeding until
proven otherwise.
PATHOGENESIS
At the outset of chronic blood loss or
other states of negative iron balance,
reserves in the form of ferritin and
hemosiderin may be adequate to
maintain normal hemoglobin and
hematocrit levels as well as normal
serum iron and transferrin saturation.
Progressive depletion of these
reserves first lowers serum iron and
transferrin saturation levels without
producing anemia. In this early stage
there is increased erythroid activity in
the bone marrow.
Anemia appears only when iron
stores are completely depleted and is
accompanied by lower than normal
serum iron, ferritin, and transferrin
saturation levels.
MORPHOLOGY
CLINICAL FEATURES
CLINICAL FEATURES
INVESTIGATION
Useful tests include
a complete blood count (CBC);
a peripheral smear;
Iron studies serum iron, total iron-
binding capacity (TIBC), and serum
ferritin;
evaluation for hemosiderinuria,
hemoglobinuria, and pulmonary
hemosiderosis;
hemoglobin electrophoresis and
measurement of hemoglobin
A2 and fetal hemoglobin;
reticulocyte hemoglobin content.
Other laboratory tests
stool testing,
incubated osmotic fragility testing,
measurement of lead in tissue, and
bone marrow aspiration
These are useful for establishing the
etiology of iron deficiency anemia
and for excluding or establishing a
diagnosis of 1 of the other
microcytic anemias.
INVESTIGATION
IRON STUDIES
Serum Iron and Total Iron-Binding Capacity
The serum iron level represents
the amount of circulating iron
bound to transferrin.
The TIBC is an indirect measure
of the circulating transferrin.
The normal range for the serum
iron is 50150 g/dL; the
normal range for TIBC is 300
360 g/dL.
Transferrin saturation, which is
normally 25%50%, is obtained
by the following formula: serum
iron 100 TIBC.
Iron deficiency states are
associated with transferrin
saturation levels <20%.
There is a diurnal variation in the
serum iron.
A transferrin saturation % >50%
indicates that a disproportionate
amount of the iron bound to
transferrin is being delivered to
nonerythroid tissues. If this
persists for an extended time,
tissue iron overload may occur.
INVESTIGATION
IRON STUDIES
Serum Ferritin
Free iron is toxic to cells, hence iron is
either stored as ferritin or hemosiderin, or
it is bounded to transferrin.
Apoferritin binds to free ferrous iron and
stores it in the ferric state.
As ferritin accumulates within cells of the
RE system, protein aggregates are formed
as hemosiderin. Iron in ferritin or
hemosiderin can be extracted for release
by the RE cells, although hemosiderin is
less readily available.
Under steady-state conditions, the serum
ferritin level correlates with total body
iron stores; thus, the serum ferritin level is
the most convenient laboratory test to
estimate iron stores.
INVESTIGATION
The sequence of events (left to right) that occur with gradual depletion of body stores of iron. Serum ferritin and
stainable iron in tissue stores are the most sensitive laboratory indicators of mild iron deficiency and are particularly
useful in differentiating iron deficiency from the anemia of chronic disorders. The percentage saturation of transferrin
with iron and free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron.
Subsequently, a decrease in the hemoglobin concentration occurs because iron is unavailable for heme synthesis. Red
blood cell indices do not become abnormal for several months after tissue stores are depleted of iron.
DIFFERENTIAL DIAGNOSIS
 TREATMENT
1. Treat underlying cause
2. Oral iron therapy
3. Ascorbic acid
4. Parenteral iron
replacement (if oral iron
tablet is not well
tolerated)
5. Blood transfusion (for
patients with cardiac
instability)
TREATMENT
Treatment guidelines from the American College of Physicians (ACP)
for adult patients with anemia and iron deficiency include the
following :
A restrictive red blood cell transfusion strategy is recommended for hospitalized
patients with coronary heart disease, with the trigger hemoglobin threshold lowered
to 7-8 g/dL (recommendation: weak; quality of evidence: low)
Erythropoiesis-stimulating agents are not recommended for patients with mild to
moderate anemia and either congestive heart failure or coronary heart disease
(recommendation: strong; quality of evidence: moderate)
TREATMENT
IRON THERAPY
REFERENCES
http://www.aafp.org/afp/2013/0115/p98.html
http://bestpractice.bmj.com.ezproxy.lib.monash.edu.au/best-
practice/monograph/94/treatment/details.html
http://emedicine.medscape.com/article/202333-overview
Harrisons Principles of Internal Medicine, 19 Edition
Kumar and Clark, 8th Edition
Davidsons Principles and Practice of Medicine, 22nd Edition