Iron Metabolism

1. Iron Metabolism
- A short talk

2. Distribution
• It is by mass the most common element on
Earth.
• Total Body Iron 3600 mg
• Hemoglobin Fe (70%) 2200 mg
• Ferritin & Hemosiderin 1000 mg
• Myoglobin Fe 300 mg
• Others (cytochromes; enzymes) 100 mg

3. Flavoproteins
Hemeproteins
Fe-sulfur
Nzms
Other Fe
Nzms
Other Fe
Proteins
Fe-Containing
Proteins
Transferrin
&
Others
Ferritin
&
Hemosiderin
Other NzmsHeme
Flavoproteins
Hemoglobin
Other Nzms
Iron
Activated
Nzms
2Fe-2S
4Fe-4S
Nzms
Myoglobin Cytochromes Other Nzms
Function

4. Intake & Excretion
• Intake -15-20 mg of iron daily.
• Only 10% ie 1.5-2 mg of dietary iron absorbed
• Adult-20mg/d
• Children-20-30 mg/d
• Pregnant-40mg/d
• 85% of foods are of Non Heme iron(Fe3+)
• Excretion:-Only small amounts of iron are lost daily as
shedding of hair, skin, gastrointestinal cells & via urine.
Sources:-meat, liver, fish, eggs, green vegetables, cereals
Jaggery

5. Preterm babies & Fe deficiency
• Transfer of iron and calcium from mother to
fetus occurs mainly during last trimester of
pregnancy
• During first 3 months of life, iron intake is
negligible & during this time child is
dependent on iron reserve
• Premature babies are at risk of iron deficiency
anemia.

6. Role of Iron
1. O2 transport by hemoglobin
2. Eectron transport chain & cellular respiration
3. Cell proliferation & differentiation
4. Oxidation & reduction reactions
• In the skin:- Elastin function
Oxygenation & Nutrition
• Fe deficiency:-
Pallor,Itching,Glossitis,Koilonychia,Hairloss

7. Deficiency Signs
Koilonychia
“Spoon Nails”
Glossitis
Angular Stomatitis

8. • 25 mg Fe needed for rbc production
• 2mg Fe lost via excretion
• So,25+2 mg Fe needs to be replaced
• 25 mg Fe from Recycling from senescent rbc’s
• 2 mg Fe from absorption from our intestine

10. Heme Iron
• 2200 mg ie 70% of Total body iron –Locked in
heme
• Lies in the centre of porphyrin ring
• Porphyrin consists of 4 pyrrole rings
• Total 6 binding sites
• 4 with Nitrogen,1 with Globin
• Last one can bind with water/O2

12. Myoglobin
• Myoglobin is an Fe and O2-binding protein
found in the muscle tissue
• The binding of O2 by myoglobin is unaffected
by the O2 pressure in the surrounding tissue.
• Myoglobin is often cited as having an "instant
binding tenacity" to O2 given its
“hyperbolic oxygen dissociation curve”

13. As a part of enzymes
• Certain enzymes also contain heme as part of
their prosthetic group….catalase,peroxidases
• Examples of iron-sulphur proteins are the ….
……………….ferredoxins, NADH dehydrogenases

14. Absorption
• Promotors
– Amino Acids
– Animal Proteins(for heme)
– Ascorbic Acid
– Hydrochloric Acid
– Organic Acids
– Sugars
– Mucin
• Inhibitors
– Carbonates
– Calcium (for heme)
– Egg yolk phosvitin
– Fiber
– Oxalates
– Phosphates
– Phytates
– Plant polyphenols
– Soy proteins
Iron uptake phase
- Duodenal lumen to Duodenal mucosa

16. • The Fe3+ Fe2+ by acids in stomach &
ascorbic acid(Vit C), cysteine and –SH groups of
proteins.
• An enzyme in brush border of enterocyte reduces
Fe 3+ to Fe2+ Eg:-Duodenal cytochrome B
(DcytB)
• DMT1 transports Fe2+ inside
• Fe2+ to Fe3+ by Ferroxidase and Fe3+ combines
with Apoferritin to form Ferritin
• Hephaestin, a copper-containing protein, which
oxidizes Fe2+ back to Fe3+ .

17. • The ferritin stores are gradually built up, but
most are lost when the mucosal cells are shed.
• The export of iron by FPN depends on two
multicopper oxidases …Hephaestin on the
basolateral membrane of enterocytes &
ceruloplasmin (Cp) in the circulation
• Hephaestin converts Fe+2 Fe+3 for
incorporation of iron into transferrin (Tf).

19. • There is no pathway for iron excretion from
the body therefore the total body iron level is
regulated only at the level of iron absorption
from the small intestine

20. Hepcidin –The key regulator
• Produced by the hepatocytes
• Hepcidin negatively regulates the Fe uptake by
transferrin
• Large hepatic adenomas–Overexpress hepcidin
will lead to refractory microcytic anemia
• HFE, TfR2 and HJV mutations of which all result in an
iron overload phenotype.

22. Discovery of HEPCIDIN (2000)
Increased expression of hepicidin leads to
Decrease iron absorption and release.
Mutation :Hemochromatosis
Increased expression:Iron deficiency
Hepicidin mRna expression is increased by
erythropoetin,hypoxia & inflammation.
Hepcidin-ferroportin complex is degraded in
lysosomes & Fe locked up inside
enterocytes,macrophages & hepatocytes.

23. Other Factors
• Hypoxia-inducible factor (HIF)-mediated
signaling plays a critical role in regulating iron
absorption
• Iron regulatory proteins (IRPs) are essential for
intestinal iron absorption.They regulate DMT1 &
Ferroportin
• Intestinal Fe absorption coordinately regulated by
 HIF-2……..Hypoxia
 IRP…………Enterocyte iron levels
 Hepcidin..Bodily iron levels

24. Ferritin
Fe stored as mineral –ferric oxyhydroxyhydroxide phosphate [(FeOOH)8 (FeO-OPO3H2)].
Upto 4500 Fe atoms can be stored inside a single ferritin molecule

25. Ferritin
• Bulk of Fe storage –Liver, RE cells, Sk muscle
• Excess iron –get deposited as Hemosiderin
• It lies adjacent to the ferritin
Expression of ferroportin
Degradation of ferritin in proteasomes
& export of cytosolic iron

27. Transferrin
• Transferrin is a protein involved in the
transport of iron.
• Each Transferrin binds to 2 Fe3+
• Normal Transferrin saturation - 30-50%
• Most cells have transferrin receptors (CD 71)
to which Fe laden transferrin binds.

28. • Fe-Transferrin complex gets into the cell via
endocytosis.
• In rbc, the endocytotic vacuole fuses with a
lysozyme.
• In the acid pH, the iron (Fe++) is released from
transferrin and transported to mitochondria
• where it is incorporated into heme, the ferrous
iron complex of protoporphyrin IX.

31. Methemoglobin/Ferrihemoglobin:-
Fe3+
• This Fe 3+ cant bind with O2
• Methylene blue leukomethylene blue
Methemoglobin reductase reduces in the
presence of NADPH
• Leukomethylene blue reduces methemoglobin
oxyhemoglobin. Fe3+ Fe 2+
• Methylene blue use when MetHb levels >20 or
who have lower levels but are symptomatic
• 1- 2 mg/kg (0.1- 0.2 ml/kg of 1% solution)
intravenously infused over 5 minutes.
• Rapid effect within 30 minutes.

32. Iron Deficiency Anemia
• C/F-
• Anemia,Angular stomatitis,Cheilitis,
Glossitis,Atrophied filiform papillae,
suceptibility for bacterial & fungal infections.
• Plummer-Vinson syndrome-Dysphagia along
with cheilitis,glossitis & koilonychia
Dry skin, lips thin, smaller mouth opening

33. Anemia of chronic disease
1) Inflammation increases hepcidin synthesis
2) Hepcidin decreases iron export from
macrophages
3) Iron is locked up inside the macrophages
4) Iron is locked up in enterocytes, and does not
enter the body

34. Hemochromatosis (Bronze Diabetes)
• Total body iron >15g
• Middle aged men,Juveniles
• C/F:-Bronze pigmentation-Face,Dorsum of
hands,Extnesor forearm,Genitalia
• Diabetes,Cirrhosis,Cardiomegaly,Arrhythmia,
CCF,Hypogonadism,Arthropathy
• Patho:-Fe deposition in macrophages, around
blood vessels & sweatglands
Increased melanin causes hyperpigmentation

35. Type of HH Gene Protein Gene
mapping
Type of
inheritance
Classic
hemochromatosis
(HFE1) – later onset
HFE
7 exons
HFE
(non-classical
MHC class-I
protein)
6p21.3 Autosomal
recessive
Juvenile hemochromatosis:
HFE2A
HFE2B
HJV
4 exons
HAMP
(LEAP1)
3 exons
Hemojuvelin
(hemojuvelin
precursor)
Hepcidin
antimicrobial
peptide
1q21
19q13
Autosomal
recessive
Autosomal
recessive
Hemochromatosis,
type 3 (HFE3) – later onset
TfR2
18 exons
Transferrin
receptor 2
7q22 Autosomal
recessive
Hemochromatosis,
type 4 (HFE4)
(ferroportin disease)
FPN1
8 exons
Ferroportin1
(iron-regulated
transporter-1)
2q32 Autosomal
dominant

36. Take Home Messages
If suspected: measure transferrin saturation
and ferritin.
Elevated transferrin saturation – genetic testing
High ferritin – consider phlebotomy
Classical hemochromatosis:1:200 Incidence
C282Y homozygosity
Low penetrance .So the clinical disease much less
frequent

37. Take Home Messages
Suspect:
Unexplained cardiomyopathy
Hypogonadism: delayed puberty
Look for very high transferrin saturation and
hyperferritinemia
Juvenile Hemochromatosis:
Rare but much more lethal if diagnosis missed

38. References
• Iron Metabolism in Humans:An Overview
By Sarika Arora & Raj Kumar Kapoor ESI PGIMS
• Hemochromatosis by Gillian Lockitch.

39. Thank You &