IRON METABOLISM

AND DISEASE
Micronutrients :
(intake does not exceed 100 mg daily)

Daily intake Body stores

Zinc 10 mg 2200 mg
Copper 2.5 mg 70 mg
Iron 1-2 mg 4000 mg
Manganese 10 mg
Molybdenum 10 mg
Cobalt 1.5 mg
Chromium 1.5 mg
Functions

As Haemprotein

Hemoglobin: more than one half of total body iron (2.5

grams)

Cytochromes: of the mitochondrial respiratory chain

(100 mg of iron)

Myoglobin: about 0.3 grams Fe, muscle oxygen storage

protein

Cytochrome: P450: most abundant hemeprotein of the

liver (about 1 mg)
detoxifies foreign compounds
 Non - heme iron proteins

• Ferritin - iron storage protein

• Haemosiderrine -iron storage protein

• Transferrin: iron transport protein

• Iron-sulfercontaining enzymes : NADH
dehydrogenase & Succinate
dehydrogenase
Iron metabolism balance:
Total: 3 - 4 grams

Hemoglobin: about 2.5 g

Daily RBC production: needs 30 mg

Daily dose in food: 10 mg

Daily uptake from diet: 1- 2 mg

 Clinical Relevance

Irondeficiency anaemia affects the

whole body

Excess free iron can lead to serious

organ damage
Hemoproteins: contain iron in the form of heme

Heme: iron inserted in a tetrapyrrole ring

 Hem
Porphyrin
Focus on RBCs:

Figure 16-7a, b: Bone marrow

 Recommended daily allowance

 Adult male -10 mg/day

 Adult female pre menopuasal – 20mg/day
 Adult female post menopuasal – 10mg/day
 Pregnant and lactating women – 40mg/day

Infancy/childhood – rapid growth

At birth, enough iron stores for 4-5 months
Milk is poor source of iron
Iron supplementation recommended
Source of oral Iron
Non Haem:
◦ Cereals, legumes ,Green leafy vegetables and fruits
◦ 10% bioavailability
◦ Absorption enhanced by ascorbic acid ,amino acids and
other dietary reducings substances (maintains Fe2+).
◦ Inhibited by tanins, phytates (chappatis).
Haem:
◦ Meat, fish,liver,sppleen and kidney are rich sources.
◦ 30% bioavailability
Ironreleased from complexes by acid, proteases
Binds to mucin and travels to small bowel.
 Only 1-2 mg of iron is taken up daily from the diet
Only 1 mg (in men) of iron is lost daily from the body by
nonspecific pathways

(sloughing off of dead cells, eg . Epethelial cells of skin

and enterocytes)

In women, additional 30 mg of iron is lost monthly

by menstruation
 The basic rule about body iron regulation:

• There is no special pathway for iron excretion

• The amount of total body iron is determined

only at the level of iron uptake from the
duodenum
 A normal adult possesses 3 to 5 gm of iron

And this small amount is utilised again and again in

body.

Iron has uniqe metabolsm in body and is called one way

metabolism.

Iron metabolism in the body is a closed system,

with little intake and little loss
ONE WAY METABOLISM

Iron is not like other vitamins or most other organic and

inorgnic substances, which are either inactivated or excreted
during their physiological function
 IRON ABSORPTION

Iron kept soluble and in ferrous state by

gastric acid, organic acids in diet
Absorbed mainly in duodenum
Quantity absorbed regulated by enterocyte
Multiple proteins involved in control of iron
transport
Haem iron enters the enterocyte through
different process than inorganic iron
 Factors affecting Iron Absorption

• State of iron store in the body:

↑ in deficiency & ↓when iron overload

• Rate of erythropoiesis:

• The content of the diet : substances that form soluble

iron complexes eg, ascorbic acid and glutathion like
reducing sub in diet ↑ absorption,
• While sub that form insouble comlexes ,like phytates ,
oxalates , phosphates and tannates ↓absorption

• Nature of GI Secretions and chemical state of

iron
 Chemical forms of iron:

Ferric (3+) iron: insoluble at physiological pH

Ferrous (2+) iron:dangerous if free, forms free radicals

Since free iron is insoluble or toxic, it must be

bound to proteins
ABSORPTION OF IRON

Enterocyte Gut
Fe+++
Ferritin
Fe++
Tf-Fe++ Fe++
+
Fe++

Haem
Tf
 Intestinal iron uptake

Dmt1 Ferroportin
Fe2+ Fe2+ Fe2+
e-

Fe3+ DcytB
Fe3+ Transferrin

Heme Heme
Hephaestin
Hcp1
Ferritin

apical basolateral

Dmt –divalent mteal transporter duodenal cytochrome b1

 Import

 Luminal (absorptive) side:

◦ DMT1 (aka Nramp2):
 Absorbs Non-Haem Fe2+
 Fe3+ must be reduced by DcytB (duodenal cytochrome
b1, located in brush border) to Fe2+.
 Concentrated towards apex of villus.
 Downregulated during crypt progression in Fe
overload, upregulated in Fe deficiency.
◦ Haem receptors (apical haem receptor 1)
 Accept and absorb Haem iron
 Released intracellularly by Haem oxygenase
Export
Basolateral Membrane:
◦ Ferroportin 1 (aka Ireg1, MTP1)
 Single chain glycoprotein multiple membrane spanning
receptor.
 Present only in mature enterocytes, not crypts. Also liver
Kupffer cells: role in scavenging iron from RBC.
 Via IRP/ IRE system, upregulated by amount of available
iron.
◦ Haphaestin:
 Transmembrane bound ferric oxidase, converting Fe2+
to Fe3+ for loading to Tf.
 Creates a concentration/ electrochemical gradient of
Fe2+ across the basolateral membrane.
 May have transporter function.
Iron Metabolism - Transport
• Major iron transport protein is transferrin.
• Each gram of transferrin will bind 1.4 mg
of iron.
• Total transferrin present in plasma to bind
253-435 mcg of iron/dL of plasma – Total
iron-binding capacity (TIBC)
• Serum iron concentration is 70 – 201
mcg/dL – 95% is complexed with transferrin
• Transferrin bound iron in plasma delivered to
body cells according to cellular iron
requirements
Note:
Only 20% of plasma bound iron derived from gut.
Most plasma iron is derived from breakdown of
senescent red cells.
• Hemoglobin from degrading RBC is degraded in
liver, spleen – iron is released.
• 85% of this iron is recycled – delivered to
bone marrow bound to transferrin
 Transferrin

 Transports iron in the blood

 Contains only 2 atoms of iron

 Transferrin is the only source of iron for hemoglobin

 Transferrin saturation is clinically useful

for iron metabolism studies
(iron-saturated Tf / total Tf)
 Transferrin saturation:

Normal about 30-50 %,

Transferrin saturation under

15 %=
Iron deficiency
 Transferrin uptake

Transferrin receptor

Transferrin

Transferrin receptor

Cells which need iron express high number of

transferrin receptors on their surface
Transferrin - TfR interactions

Each TfR can bind two Tf molecules, which are

endocytosed through clathrin coated pits.
A proton pump generates acidity in the endosome,
facilitating release of Fe from Tf.
DMT-1 transporter exports Fe from endosome.
Iron metabolism - Storage
Major storage depot is liver
• Stored as ferritin and hemosiderin

Ferritin: primary storage compound for

body’s need
• Readily released for heme synthesis
• Small amounts found in blood – parallels
the storage iron in the body
 Ferritin: iron storage protein
In men, contains up to 1 gram of iron

Reflects the amount of BODY IRON STORES

men: 20-275 μg/litre

women: 5-200 μg/litre

15 μg/litre and less: insufficient iron stores

Hemosiderin
• Major long term storage
form of iron
• Slow release
• Estimation of hemosiderin
made on bone marrow
tissue sections
Iron absorption regulation
Increased
◦ Low dietary iron
◦ Low body iron stores
◦ Increased red cell production
◦ Low haemoglobin
◦ Low blood oxygen content
Decreased
◦ Systemic inflammation
◦ High serum iron and body stored ferritine
 Increased Iron Uptake
Low dietary iron
Signal from body to gut(intracellular
sensors, IRE/IRP) in response to increased
needs
↓
Leads to increased activity of:
◦ DCytB and DMT1
Caused by local factors in gut
 IRON DEFICIENCY
Commonest cause of anaemia worldwide
Cause of chronic ill health
May indicate the presence of important
underlying disease eg. blood loss from
tumour
 CAUSES OF IRON DEFICIENCY
Increased physiologic demand
eg. pregnancy, lactation, rapid
growth
Blood loss from GI tract, uterus,
haemoglobinuria
Malabsorption
Diet

colon cancer
 2. CLINICAL FEATURES IRON
DEFICIENCY

Symptoms eg. fatigue, dizziness, headache

Signs eg. pallor, glossitis, angular
cheilosis, koilonychia, Plummer Vinson
syndrome

Koilonychia Glossitis
 CLINICAL FEATURES OF IRON
DEFICIENCY
Plummer Vinson
Syndrome :
Angular Cheilosis Oesophageal Web
or Stomatitis

                  

                       
 LABORATORY DIAGNOSIS: IRON
DEFICIENCY

Microcytic hypochromic anaemia

Often pencil cells and target cells on
blood film
Decreased serum ferritin
Decreased serum iron, increased TIBC,
decreased % transferrin saturation
Absent bone marrow haemosiderin :
(rarely required for diagnosis )
 Hypochromic
microcytic red cells
Hypochromic
microcytic red
cells
Pencil Cell
DIFFERENTIAL DIAGNOSIS: IRON DEFICIENCY
ANAEMIA
IRON OVERLOAD
 WHEN DOES IRON BECOME A
PROBLEM?

Normally 2.5 – 3.5g of iron in the

body.

Tissue damage when total body iron

is 7 – 15 g
CAUSES OF IRON OVERLOAD

Hereditary haemochromatosis
Multiple transfusions
Liver disease
Prolonged use medicinal iron
Ineffective erythropoiesis
African Iron Overload
 HEREDITARY
HAEMOCHROMATOSIS

Most common cause of iron

overload in North America
Most cases due to mutations of the
HFE gene
Results in increased inappropriate
iron absorption from gut
CLINICAL DIAGNOSIS
Commonly made on basis of
biochemical changes : increased
serum ferritin or % transferrin
saturation
May have non-specific
symptoms/signs such as fatigue or
arthropathy
Discovered as part of family screening
Rarely fullblown picture : cirrhosis,
diabetes, cardiomyopathy, skin
THANK YOU