Minerals

lecture 1
Iron

DR FHSHAH
 Learning Objectives

What is iron.

Total iron content &Daily requirements.

Body distribution and storage .

Types of iron present in body.

Ferritin ,Apoferritin, hemosiderin

&transferrin.
 Learning objectives

What are sources of iron.

Factors regulating iron absorption.

Functions of iron

Iron deficiency anemia.

Iron overload, primary and secondary

hemochromatosis & hemosiderosis.
 IRON

Iron is one of the most essential trace elements

in the body.
 In spite of the fact that iron is the fourth most
abundant element in the earth’s crust, iron
deficiency is one of the most important prevalent
nutritional deficiencies in world.

 The reasons for this are numerous and, in many

cases, not well understood..
 Total iron content

Total iron content in a human of 70 kg body

weight varies approximately from 2.3 gm to
3.8 gm.

Average iron content of

Adult males is about 3.8 gm and

of females about 2.3 gm.

 Types of Iron Present in Body

 There are two broad categories that are used to

describe iron in the body.
They are:

A. Essential (or functional) iron

B. Storage iron.

 A. Essential Iron

Essential or functional iron is one which is

involved in the normal metabolism of the cells.

They are mainly divided into three groups:

1. Haem Proteins

 1. Haemoglobin and Myoglobin

 These are haem proteins, which are proteins with

 an iron porphyrin prosthetic group attached to the

 protein globin.

 They are most abundant of the essential

(or functional) iron compounds in the body.
 Other HEME proteins are

Catalases:
A haem containing enzyme.

 It contains four haem groups and is found in

blood, bone marrow, mucous membrane, liver and
kidney. Its molecular weight is 225, 000.

It destroys hydrogen peroxide, H2O2, formed

in the tissues and molecular O2 is evolved in the
reaction
 CATALASES

The reaction is inhibited by CN–, F– and H2S.

Peroxisomes are found in liver and they are rich

in aerobic dehydrogenases and catalases.

 • Peroxidases

It is typically a plant enzyme, but it is also found in

 milk, erythrocytes, leucocytes and lens

 fibres.

Its molecular weight is 44,100 and its

prosthetic group is protohaem which is only
loosely bound to apoprotein.
 Example:

Typical example is glutathione peroxidase

which also catalyses destruction of H2O2, but it

 works in conjunction with reduced glutathione, G

-SH.
 Catalase and Glutathione peroxidase

Both catalase and glutathione peroxidase catalyses

 the destruction of H2O2 and forms H2O and O2.

• Catalase can directly act on H2O2, but

 glutathione peroxidase cannot, it requires

 reduced glutathione.
.
 H2O2

The reason is Km of catalase for H2O2 is

much greater than that of glutathione
peroxidase.

• To scavenge small amounts of H2O2 formed in

 cells like RB cells and lens fibres, glutathione

 peroxidase becomes the active enzyme

 2. Cytochromes

: A second group of organo-iron compounds

in the body are the cytochromes.

Cytochromes are chiefly found in mitochondria

.
 3. Iron Requiring Enzymes

: A third group of iron containing compounds is the

iron-requiring enzymes.
a. This group contains enzymes that also use
riboflavin as coenzyme.
Examples are:
Xanthine oxidase,
Cytochrome C reductase,
 Acyl-CoA dehydrogenase,
 NADH reductase.
 Iron Requiring Enzymes

b. Other enzymes in this group that require the metal

only as cofactor:

Succinate dehydrogenase,

Aconitase,

 Ribonucleotide reductase
 Haber’s reaction.

c. Fe++ is required for conversion of O2- -

superoxide radical to free OH– radical. This is called

 as Haber’s reaction.
 B. Storage Iron

Storage iron is present in two major compounds.

They are:

1. Ferritin

2. Haemosiderin.
 1. Ferritin

Free iron is toxic and catalyses the conversion of O2

to hydroxy OH– oxy radicals.

 Iron bound to ferritin is nontoxic.

It is the storage protein of iron and found in

 blood, liver, spleen, bone marrow and intestine

 (mucosal cells).
 Apoferritin

Apoferritin is the apoprotein with a molecular

 weight of 550,000.

Apoferritin is an interesting compound in that it

is composed of 24 monomeric units, each

 having molecular weight of 18,000, that form a

 spherical shell.
 Apoferritin

There are six pores in the shell that allow

molecules of a certain size to enter and exit the shell.

The pores have been shown to have catalytic

activity, most notably the binding of ferrous iron
(Fe++) and its subsequent oxidation to “ferric oxy
hydroxide” (FeO.OH).
 FERRITIN

Bound form of iron with ferritin is more soluble and

iron is present as “ferric oxyhydroxy
phosphate” complex in ferritin and it is reddish
brown in colour.

Up to 4500 Fe+++ atoms are found stored in

a ferritin complex
 Haemosiderin

Evidence suggests that haemosiderin is derived

from ferritin and is ferritin with partially stripped
shell.

Haemosiderin contains a larger fraction of its mass

as Fe than does ferritin and exists as microscopically
visible Fe-staining particles.

 Haemosiderin

Haemosiderin is usually seen in states of

 iron overload or when Fe is in excess, when

 the synthesis of apoferritin and its uptake of Fe are

 maximum.
 Haemosiderin

Haemosiderin is rather insoluble.

Fe in haemosiderin is available for formation of

Hb,

 but mobilisation of iron is much slower from

haemosiderin than ferritin.
Distribution of iron in the body is shown in the
Table
 Haemosiderin

Haemosiderin is usually seen in

states of iron overload or when Fe is in

 excess, when the synthesis of apoferritin and its

 uptake of Fe are maximum.

 TRANSFERRIN

Transferrin is a non-haem iron binding

glycoproteins.

Apotransferrin is the apoenzyme and Fe is

its prosthetic group.

 It has a molecular weight of 70,000 and it can

bind with two atoms of iron in the ferric
state (Fe+++) synergistically in presence of HCO3
ion.
 TRANSFERRIN

It exists in plasma as β1-globulin and is the true

 carrier of iron.
 TRANSFERRIN

In plasma, transferrin is saturated only to the extent

 of 30 per cent to 33 per cent with iron.

Prior to binding to transferrin, Fe++ (ous) iron has

 to be oxidised to Fe+++(ic) form.

.
 TRANSFERRIN

Ceruloplasmin and ferroxidase II are

required for this conversion.

Note: In copper deficiency, this conversion cannot

 occur and haemopoietic system will not be getting

 required amount of Fe for inclusion in Hb synthesis

 Function of Transferrin

Major function of transferrin is transport of

iron to RE cells, bone marrow to reach the
immature red blood cells.
Specific receptors are available on cells surface.
Transferrin is internalised by receptor mediated
endocytosis.
Within the target cells, iron is released and
apotransferrin is recycled to form new transferrin
molecules .
 Next lecture
 DIETARY SOURCES OF IRON

I. Exogenous: Foods rich in iron include:

a. Animal Sources:
1.Meat,
2. Fish,
3. Liver,
4.Spleen,
5.Red marrow are very rich sources (2.0 to 6.0 mg/100
gm).
6.Also found in shellfish.
.
 Iron Sources

b. Vegetable Sources:

 Cereals (2.0 to 8.0 mg/100 gm) are the major rich
source.

 Legumes,

 Molasses,

 Nuts, amaranth leaves.

 Dates are other good sources
 II. Endogenous

Fe is utilised from ferritin of RE system and

 intestinal mucosal cells.

Fe obtained from “effete” red cells are also re

 utilised.
 FACTORS REGULATING ABSORPTION

Normally, the loss of iron from the body of a

man is limited to 1 mg per day.

Menstruating women lose iron with menstrual
blood.

Around 10 to 20 mg of Fe is taken in the diet and

only about 10 per cent is absorbed.
 FACTORS REGULATING ABSORPTION

The greatest need of iron is during infancy and

adolescence.

The only mechanism by which total body stores of

iron is regulated is at the level of absorption.

 Garnick proposed a “mucosal block theory”

for iron absorption.
 “Mucosal block theory”

 It is exerted at the level of the enterocyte where

further absorption of iron is blocked if sufficient

 amount taken up, for body need—so called dietary

 regulation exerted by “mucosal block”

 (Garnick’s hypothesis).
 ABSORPTION

(a) Source of Fe has marked effect on

absorption:
• Haem iron which comes mainly from animal
products and is from Hb and myoglobin, is
efficiently absorbed (about 20 to 30%).

• Non-haem iron, which is present in plants,

though ingested in larger amount than haem iron,
are inefficiently absorbed (only 1 to 5%).
 ABSORPTION

(b) The absorption of non-haem iron is influenced

by the:

• Composition of the diet

• pH of the intestinal milieu, and

• State of health of the individual

 1. Composition of the Diet

 The composition of the diet exerts a profound effect

on non-haem iron absorption.
Dietary factors that increase iron absorption
are
the presence of Vitamin C (ascorbic acid),

Glutathione, and

 some form of meat, fish or poultry (all contain an

 unknown “meat factor”).
 :
Foods that inhibit non-haem iron absorption to
some extent are

 Tea (diminishes absorption by > 60%)

Coffee (reduced absorption by > 35%)

Phytates, found in corn, soya products, grains,

and bran (producing insoluble complex)

Oxalates found in spinach and chocolates

 Some dietary fibres may also bind the iron or
decrease gastrointestinal transit time.
 2. pH of Intestinal Milieu

• HCl secreted in gastric juice liberates Fe3+ from

non-haem iron and serves to increase solubility
of dietary non-haem iron.
pH of duodenum is most conducive for
absorption.
Rate of absorption further decreases down
the intestines as the pH becomes more
alkaline.
At high alkaline pH, the ingested iron is precipitated.
 3. State of Health of the Individual

• Healthy adults absorb about 5 to 10 per cent

of dietary iron, which is approx. 1 to 2 mg of iron.

• Iron-deficient adults absorb 10 to 20 per cent of

the dietary iron equivalent to 3 to 6 mg of Fe.
 4.MEDICAL CONDITIONS

Individuals having
1)Achlorhydria or achylia gastrica

2)and in persons having resection of gut, partial

or total gastrectomies, iron absorption is

diminished and they are at risk of iron deficiency.

 5.INTESTINAL CONDITIONS

• Intestinal epithelia normally are desquamated and

again regenerated.
 Significant quantity of iron as ferritin is lost
during desquamation.

 Parasitic infection, viz. Ankylostoma duodenale

produces Fe loss as the parasites suck blood and
thrive on it.
 Iron Transport and Utilisation

Transport of Fe throughout the body is accomplished

 with a specific protein called transferrin.

Transferrin transports Fe from the GI tract to the

 bone marrow for Hb synthesis and to all other cells

 as required.
 TRANSFERRIN

Transferrin can transport a maximum of two atoms

of iron as Fe3+ per molecule.

 Normally, in plasma/serum transferrin is

about 33 per cent saturated with Fe.
 ROLE OF RECEPTORS

As discussed above, cell surface specific

receptors are available for the iron-transferrin
complex.

Tissues having high uptake, e.g. liver, have a larger
number of receptors present.

 The number of receptors decreases when a

person is replete with iron and increases
with depletion.
 TRANSPORT

Iron is transported to bone marrow where it is

 required for Hb synthesis.

 IMPORTANCE OF TRANSPORT

Fe2+ is incorporated in protoporphyrin IX with

the help of the enzyme “ferrochelatase”.

Iron is also transported into cells where it is used for

both oxidative phosphorylation and as an enzyme
cofactor.
 RECYCLING

A small amount of Fe is released each day from

‘effete’ red cells, which are destroyed by phagocytes,
but this released Fe2+ is recycled into new Hb in the
erythroblasts.

A small amount of released Fe is also stored as

ferritin.
 IRON TURNOVER

The turnover of iron in an adult in 24 hours

has been calculated to be 35 to 40 mg.

 FERRITIN

Plasma “transferrin iron pool” is in equilibrium with

the iron in storage forms ferritin and haemosiderin.

 Ferritin in storage form of Fe occurs in

reticuloendothelial system (RES),
viz. liver,
 spleen and bone marrow and also in
intestinal mucosal cells.
 Mobilisation of Iron

When Fe is mobilised from ferritin, the storage form,

the sequence is as follows:
• First call: From ferritin of RE system (liver, spleen
and bone marrow)
• Second call: From ferritin of intestinal mucosal
cells.
• Thirdly: Absorbed iron from intestines.
Before Fe is released from ferritin to blood, Fe3+ of
ferritin is first reduced to Fe2+.
 Iron Requirements

Requirement of iron varies according to age, sex,

weight and state of health.

An adult male requires approx. 10 mg/day and adult
female 20 mg/day.

 Pregnancy and lactation demands more: Pregnant

women require 10 mg/day and lactating mothers 25 to 30
mg/day.

Children require 10 to 15 mg/day.

 Iron Requirements

Note
1. In the last trimester of pregnancy, the fetus
sequesters Fe from the mother at an average rate of
3 to 4 mg/day.

 At birth, the infant’s iron stores average 75 mg/ kg

body wt.

 A premature infant will not have had time to

build its stores sufficiently.
 Iron requirements in Infants

The iron content of breast milk is relatively high

and human milk is more efficiently absorbed.

3. As the infant begins to take solid foods, iron availability

decreases and supplementation has to be made to
maintain an acceptable level in infants.

4. During childhood, iron needs are not excessive. But

if intake is less, then often iron deficiency can develop.
 Fe requirements

5. Iron need in adolescence increases

tremendously. The growth spurt results in an
increase in red blood cell mass that necessitates an
increase of 25 per cent in total body iron.

 In adolescent girls, the burden is more due

to menstruation, which increases iron loss
markedly.

.
 Iron in women

6. Adult women face the risk of iron deficiency due

to pregnancies.
Each pregnancy extracts about 1000 mg
of iron which exceeds the normal iron stores.
Menorrhagia can occur in approx. 10 per cent of all
women and entails extra loss of Fe.
Hence iron must be supplemented in such cases to
avoid iron deficiency anaemia
 Diseases and Iron

7. Iron status of adult males and postmenopausal

women tends to increase throughout life and

 normally iron deficiency should not be a problem.

, etc.
 DISEASES ARE CAUSE OF IRON DEFICIENCY

But certain chronic diseases at this age group,

if not treated, can lead to iron deficiency.
 They are: Chronic infections including
 Tuberculosis
• Malignancies
• Chronic aspirin ingestion
• Peptic ulcers
• Rheumatoid arthritis and
• Parasitic infections
 A. IRON DEFICIENCY

: Three stages of iron deficiency are:

1. Iron storage depletion

2. Iron deficiency

3. Iron deficiency anaemia.

 1. Iron Storage Depletion

: This phase is not usually recognisable by the

patient and normally does not elicit a medical
examination.
Serum ferritin decreases during this phase and is the
only good indication of possible iron deficiency.

 Many women of child bearing age remain in

this phase for years without being identified.
 2. Iron Deficiency

: In this phase, iron stores are almost exhausted.

Biochemically the
serum ferritin is low↓ and
transferrin saturation is low↓.
Erythrocyte protoporphyrin↑ increases, as
erythropoiesis is slowed down due to nonavailability of
Fe which cannot be incorporated in protoporphyrin IX.
Haemoglobin concentration falls↓ to the lowest
limit of normal.
 3. Iron Deficiency Anaemia

: Iron deficiency anaemia is manifested as

 hypochromic microcytic anaemia. At this

 phase:
Serum ferritin level shows slow decline↓
Transferrin saturation continues to fall↓ and
 Erythrocyte protoporphyrin increases to
upper limit of normal↑.
 How to diagnose

To classify as iron deficiency anaemia,

a low Hb plus a documented abnormal serum
ferritin or other iron test must be present.

Note: It is imperative to determine iron levels in all

patients with anaemias, since there are disorders
such as thalassaemias that may be present and
misdiagnosed as iron deficiency
 Iron Overload

Iron overload can also be an important clinical

concern. Iron stores may increase due to:
• Excessive absorption, or
• Parental iron therapy or
• Repeated transfusions.
Cells start to fill with excess of haemosiderin↑.
Both reticuloendothelial cells and parenchymal cells
sequester iron.
 Types:

Two broad types of iron overload are seen:

1. Haemochromatosis: When iron overload is
associated with injury to cells.

2. Haemosiderosis: Iron overload without cell

damage is called haemosiderosis.
 1. HAEMOCHROMATOSIS

Haemochromatosis can be of two types:

1. Primary hereditary haemochromatosis
(Idiopathic)
2. Secondary haemochromatosis.

Note:
Early diagnosis of haemochromatosis is
essential.
.
 Untreated Haemochromatosis

can lead to
 Liver,
Pancreatic and cardiac impairment,
Diabetes mellitus, and hepatic carcinoma.
• A helpful screening test is: Serum transferrin
saturation.

Patients with serum transferrin saturation > 62 per

cent may have haemochromatosis
 a. Primary (Idiopathic) Haemochromatosis

• Inherited disorder

• Autosomal recessive

• Massive accumulation of iron, mainly as ferritin

 and haemosiderin, in visceral organs, principally

 liver and skin.

 • Classic “triad” for diagnosis

1. Micronodular cirrhosis with marked

brown pigmentation.
2. Diabetes mellitus and
3. Skin pigmentation called as “Bronze
diabetes”.

4• Deposition of iron in myocardium can

cause cardiomyopathy and heart failure.
 Accumulation

Excess iron accumulates in the cytoplasm of

parenchymal cells with possible “free” radical
generation, leading to lysosomal disruption
and cell damage.
• Increased risk of hepatocellular carcinoma
• Haemochromatosis “gene” is linked to HLAA3,
with a frequency of 1:200.
.
 Postulated Mechanisms for the Disease

:
1.Hereditary defect in regulation of iron
absorption by the duodenum and jejunum.

2.A defect in immediate postabsorptive

excretion of iron.

3.A genetic inability of phagocytes to take up

iron with loss of their regulatory control signals over
iron absorption
 Suggested scheme of events that take place in primary

idiopathic haemochromatosis .

• Mutations in HFE gene located on chromosome 6p21.3

↓
• Leading to abnormalities of structure of encoded HFE
protein
↓
• Loss of regulation of iron in small intestine
↓
• Results to accumulation of iron in various tissues particularly
in pancreatic islets, liver, heart, muscle, and skin.
↓
• Excessive iron damages the tissues leading to cirrhosis
liver, diabetes mellitus, damage to cardiac muscles, skin
pigmentation (bronzed diabetes).
 b. Secondary Haemochromatosis

Due to ineffective erythropoiesis as in

 1. Thalassaemia,

 2.Erythrogenesis imperfecta or

 3. With repeated blood transfusion/transfusion

overload or

4. Patients with haemodialysis.

 CONSEQUENCES

It exhibits more even distribution of iron between

macrophages and hepatocytes.

Long-term accumulation of Fe in hepatocytes leads

to hepatocellular necrosis and secondary
scarring and rarely a micronodular cirrhosis
develop
2. SIDEROSIS OR HAEMOSIDEROSIS

• Bantu siderosis: Bantus in Africa cook their food

in iron pots. This causes enhanced absorption of Fe
leading to Bantu siderosis. Their PO4 intake is
usually low as they consume plenty of corn.

 Low PO4 aggravates increased Fe

absorption.
Note: Fe deficiency anaemia is not found in
pregnant Bantu women.
• Repeated blood transfusions, thalassaemia and

hereditary haemolytic anaemias may also result in

 this condition.
.
 • Idiopathic pulmonary haemosiderosis

Chronic episodic haemorrhages of the lungs of

 unknown etiology result in prominent haemosiderin

 deposition and fibrosis