Iron Metabolism

- A short talk

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

Flavoproteins

Hemeproteins

Fe-sulfurNzms

Other FeNzms

Other FeProteins

Fe-Containing Proteins

Transferrin&

Others

Ferritin&

Hemosiderin

Other NzmsHemeFlavoproteins

Hemoglobin

Other Nzms

IronActivated

Nzms

2Fe-2S4Fe-4SNzms

Myoglobin Cytochromes Other Nzms

Function

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

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.

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

Deficiency Signs

Koilonychia“Spoon Nails”

Glossitis

Angular Stomatitis

• 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

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

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”

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

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

• 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+ .

• 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).

• 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

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.

Discovery of HEPCIDIN (2000)Increased expression of hepicidin leads toDecrease iron absorption and release.Mutation :HemochromatosisIncreased expression:Iron deficiencyHepicidin mRna expression is increased by

erythropoetin,hypoxia & inflammation.Hepcidin-ferroportin complex is degraded in

lysosomes & Fe locked up inside enterocytes,macrophages & hepatocytes.

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

Ferritin

Fe stored as mineral –ferric oxyhydroxyhydroxide phosphate [(FeOOH)8 (FeO-OPO3H2)].

Upto 4500 Fe atoms can be stored inside a single ferritin molecule

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

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.

• 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.

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 methemoglobinoxyhemoglobin. 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.

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

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

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

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

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

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

References

• Iron Metabolism in Humans:An Overview

By Sarika Arora & Raj Kumar Kapoor ESI PGIMS

• Hemochromatosis by Gillian Lockitch.

Thank You &