This document summarizes iron metabolism. It discusses daily iron requirements, absorption and transport of iron, iron storage, and regulation of iron levels. It also covers iron deficiency anemia and iron overload disorders like hemochromatosis. Iron is absorbed in the duodenum and transported bound to transferrin. It is stored primarily in the liver as ferritin or hemosiderin. Iron levels are regulated by the liver peptide hepcidin which controls intestinal iron absorption and macrophage iron recycling by degrading the iron exporter ferroportin.

1. Iron metabolism
Specific objectives-
• Daily requirement
• Absorption, Transport, storage
• Regulation
• Related diseases
•Deficiency –anemia
•Excess –Hemochromatosis

2. OVERVIEW
•One of the most important trace element
•Also toxic to the body.
• Total content of iron in human body = 3-4 gm.
About 65% of total iron in Hb (2.5gm)
5% of total iron in Myoglobin & other enzymes = (300mg)
25% of total iron in Ferritin & hemosiderin =(1000mg).
Labile pool-80 mg
Daily requirement
• For adults= 20 mg/day
• Pregnant & lactating lady= 40 mg/day.
Transfer of iron & calcium from mother to fetus occur - last
trimester of pregnancy - should take iron & calcium rich diet.

3. 11/18/2023 3
Sources (exogenous & endogenous)
Exogenous- from diet:2 forms of iron
Heme iron— from non-veg. source
Non heme iron— from plant source
Rich sources—non vegetarian sourcesMeat [2mg/100gm]
Good sources–leafy vegetables[20mg/100gm] pulses [10mg/100gm]
Poor sources –Milk [0.1mg/100gm]
Iron found in plant sources - bound with proteins or organic acids
(Phytates & Oxalates) - unavailable for absorption
Internal (Endogenous)source of iron
Destruction of old RBCs Hb heme & destruction of other
heme proteins.
Per day 200 billion RBCs are destroyed (40 ml blood = 6gm Hb),
can give 25 mg iron.
Each gram of Hb contains 3.4 mg iron.

4. Heme containing proteins
 Hemoglobin
 Myoglobin
 Tryptophan
pyrrolase
 Cytochrome,
 Catalase - etc
Iron sulfur complexes protein—
 Complex I, II & III of ETS,
 Xanthine oxidase
 Aconitase
 Succinyl Dehydrogenase.
Non heme [non ironsulfur]
Iron proteins—
 Transferrin
 Lactoferrin
 Some enzymes
 (Homogentisate
oxidase),
 Ferritin, Hemosiderin
Functions of Iron:
It exerts its action through
its compounds
Iron containing compounds

5. 11/18/2023 5
Absorption of iron
1. Iron is absorbed - upper part of duodenum.
2. Approximately 1mg of iron is absorbed / day & same amount
is lost through feces. [Nonheme iron only 5% absorbed, heme
iron 30% absorbed; overall bioavailability is10%]
3. Iron is absorbed either in the ferrous or Heme form.
4. Bioavailability of the diet is more important factor than iron
content of the diet.

6. 11/18/2023 6
Factors affecting iron absorption
1. Gastric acid, vitamin C, Cysteine, FERRIC REDUCTASE
(duodenal Cyt b)  ferric iron ferrous form.
2. Phytic acid (in cereals), Oxalic acid (in leafy vegetables) and
Tannic acid (of Tea) forming insoluble iron complex
inhibit
3. Ca++, Zn++, Pb, Cu, PO4
–  competitor for iron absorption.
4. Resection of duodenum (partial or total Gastrectomy) reduces
surface area for absorption.
5. Achlorhydria, celiac sprue also reduce iron absorption.
6. Presence ferric reductase/Duodenal cytochrome b enzyme on
the brush border of duodenal enterocyte converts ferric to
ferrous.
7. 7. Limitation of absorbing capacity of enterocytes for iron

7. 11/18/2023 7
Mechanism of iron absorption
(Mucosal block theory)
• Heme is directly absorbed by a transporter on luminal surface
of enterocytes- heme transporter (HT). Inside enterocytes
cytoplasm, ferrous iron is released from heme by heme oxidase
(HO)/Heme oxygenase.
• Non heme iron is converted into ferrous form inside GIT lumen
by various factors and ferrous iron is absorbed by Divalent Metal
Transporter (DMT)
•Ferrous iron has 2 fates (depend on demand of iron) :
•either converted into Ferritin
•passes into portal vein - a channel—ferroportin at basolateral
surface of cell -Before reaching in portal circulation ferrous iron
is again changed into ferric iron- transported by a carrier protein
Transferrin. Transferrin carries iron to different target tissues

8. Mechanism of iron absorption
(Mucosal block theory)
DMT=DIVALENT METAL TRANSPORTER
HT= HEME TRANSPORTER
HO= HEME OXIDASE/OXYGENASE
FP= FERROPORTIN
HP= HEPHAESTIN
TF=TRANSFERRIN
DCYT-b= DUODENAL CYTOCHROME b
•Once Ferritin is formed remain stored inside enterocyte
usually not be utilized further, it is thrown out when cells shed
out in fecal matter.

9. 11/18/2023 9
Hephaestin
Heme Oxidase
Divalent
Metal
Transporter
Heme Transporter
Ferroportin
PV
Apoferritin

10. 11/18/2023 10
• Thus, duodenum mucosa has mechanism to prevent entry of
excess iron in circulation by making it into Ferritin—(relatively)
unavailable form. This mechanism is called as Mucosal block
/Ferritin curtain.
• In stool, unabsorbed iron (85-90%) + iron present in
shed out enterocytes.
Recycling of iron in macrophages
Iron is released from Heme by action of Heme oxygenase.0/ heme
oxidase.
Released iron comes into cytoplasm from reticulo endothelial
system by NRAMP1 (natural resistance associated macrophage
protein).
From cytoplasm of macrophage to systemic circulation by
ferroportin.
In circulation it is transported by Transferrin.

11. Fe++
Hb
Heme
Biliverdin
Fe++
Fe+++
FP
Blood
Macrophage
TF
Microsome

12. 11/18/2023 12
Transport and delivery of iron
•Transferrin (Tf) is 76KD β1-globulin, glycoprotein - carry
2molecules of ferric iron.
•Synthesized in liver
Concentration - in plasma 300mg/dl.
100ml of plasma can carry 300μg of iron, this called as
Total Iron binding capacity of the plasma.
• Iron that present in Tf is called as serum Iron, 120µg/dl in
men; 100µg/dl in women
•Transferrin transports as well delivers iron to target cells - bone
marrow.

13. 11/18/2023 13
Iron is delivered to the target tissues by receptor mediated
Endocytosis
2 types of transferrin receptors on surface of target tissues—TfR1
& TfR2
Acidic pH inside the Lysosome causes release of iron from receptor
Iron [++] is released into cytoplasm by DMT-1
Excess iron is stored as Ferritin particularly, in liver cells.

14. 11/18/2023 14
Blood
TF
Lysosome
TF
TFR
TFR
TF
TF

15. TfR1 TfR2
Affinity for Tf High Low
Present in All cells hepatocytes
function To deliver iron Iron sensor
• Glycosylation of transferrin is impaired in chronic
alcoholism resulting in increased circulating level of
carbohydrate deficient transferrin [CDT].marker for chr alc
• Soluble transferrin receptor [sTfR] -some proportion of TfR1
is released from erythroid cells into blood circulation.
Marker for iron def anemia

16. Storage of Iron
2 storage form of Iron—Ferritin & Hemosiderin,
stored in liver , spleen, & bone marrow
Ferritin-is predominant storage form
Ferritin = Apoferritin (24subunits)+ 3000-4500 ferric atoms
Very little amount of Ferritin in human plasma, can be measured
by immunoassay method, useful to know body iron stores [50-
200 µg/dl].
•Mol. Wt 440KD
•2 types of subunit-H &L
•All units form a shell
•H type has Ferroxidase activity converts-
iron to ferric form
•Iron is in soluble form,can be easily
retrieved—on demand.

17. Hemosiderin-derivative of Ferritin (partially degraded protein
shell of Ferritin) found in macrophage (not present in blood).
It can store more iron than Ferritin
Mobilization of iron is very slow.
Regulation of Iron metabolism
•The overall regulation of iron is complex and not well
understood.
• Controlled by 2 regulatory system
One for Systemic Iron Homeostasis
Another for intracellular Iron Homeostasis

18. 11/18/2023 18
Iron metabolism disorders
Iron deficiency anemia
Most common nutritional disorder.
60-80% of pregnant women of India are anemic, 15% of all
maternal death is due to anemia.
Causes
1. Nutritional deficiency of iron—inadequate intake of iron.
2. Increased requirement—repeated pregnancy, major surgery,
growing phase.
3. Impaired absorption—Sprue, Gastrectomy, achlorhydria,
Malabsorption.

19. 11/18/2023 19
4. Blood loss
• Menstrual blood loss—about 30 mg iron lost in each
cycle.
• Parturition (during normal delivery)—750 mg lost.
• Hookworm infestation—0.3ml blood is sucked per worm
• Chronic blood loss—hemorrhoids, nephritis, peptic ulcer
disease, gastric carcinoma, menorrhagia etc.
• Acute blood loss—road traffic accidents
Stages of Iron Deficiency
Iron deficiency anemia progress through 3 stages-
1. Negative Iron balance
2. Iron deficient erythropoiesis
3. Iron deficiency anemia

20. Stages of Iron Deficiency
Intestinal absorption of Iron is insufficient to meet the
body’s demand (negative iron balance)
Progressive depletion of Iron store low serum ferritin, TIBC
incr
Iron deficient erythropoiesis RBC protoporphyrin ↑[ZPP, free
erythrocyte protoporphyrin]
Iron deficiency anemia  low Hb, Hypochromic , microcytic
blood picture
Mobilization of Iron from iron
store (ferritin)
Hb synthesis is impaired

22. 11/18/2023 22
Pallor
•Fatigueness
• decreased exercise capacity
•breathlessness [low O2 carrying
capacity]
•Pica(in children).
•Palpitation
•Tachycardia
Clinical features—sign/symptoms
•Severe and prolonged iron deficiency may lead to
Koilonychia (spooning of nails)
•Plummer-Vinson syndrome — atrophy of gastric and intestinal
mucosa presents with dysphasia,soreness of mouth &
esophageal web.
• Acute severe cases represent with pulmonary edema  heart
failure death.

23. 11/18/2023 23
Laboratory findings
• Low hemoglobin concentration <13gm/dl in males; <11gm/dl
for females.
• Blood smear shows- Microcytic Hypochromic picture
• Serum iron concentration (<50μg/dl).
• TIBC increased(>300-360μg/dl)
• Serum Ferritin low (50-200μg/dl)
• Soluble transferrin receptor increased (4-9μg/L)
• Cellular Iron content decreased—reflected by high value of
ZPP in RBC.

24. 11/18/2023 24
Normal smear
Microcytic
Hypochromic
smear

25. 11/18/2023 25
Iron overload disorder
Hemochromatosis—excessive accumulation of iron in liver &
pancreas etc.
Reasons
Genetic Defect (abnormal HFe gene) causing excessive iron
absorption—Hereditary hemochromatosis.
Parenteral administration of iron—secondary hemochromatosis.
Sign Symptoms:
Cirrhosis, Diabetes mellitus, skin pigmentation (bronze
diabetes).
Total iron content >50gm.
Plasma Ferritin level increased >500µg/dl

27. 11/18/2023 27
Hemoglobin & disorders, Iron metabolism &
disorders, vitamin B12 & Folic acid, Blood buffers &
pH regulation, Metabolism occurring in RBC-
Glycolysis, HMP shunt, Glutathione

28. Regulation of Iron metabolism
•The overall regulation of iron is complex and not well
understood.
• Controlled by 2 regulatory system
One for Systemic Iron Homeostasis
Another for intracellular Iron Homeostasis
Systemic Iron homeostasis
• Entry of Iron in systemic circulation is regulated by Iron
exporter-ferroportin [mucosal block phenomenon]
• there is no regulation for iron excretion (per day excretion 1-
1.5 mg through skin, intestine, urine etc)
• Activity of Ferroportin is influenced by Hepcidin

29. 11/18/2023 29
Hepcidin
25 AA polypeptide
Synthesized in liver
blood
 Decreases iron
absorption and
prevents recycling of
Iron from macrophage
-triggering degradation
of Ferroportin.
Expression - regulated
by systemic iron,
hypoxia, inflammation,
erythropoiesis,
 Hepatocytes act as
iron sensor cell
Hepcidin
Ferroportin
Negative
regulators
Anemia, Hypoxia
Erythropoietic
signals
Positive
regulators
Increased
serum iron
Inflammation
Decreased iron
in circulation
Increased iron in
circulation

30. Iron Sensor
• Iron sensing complex on the surface of Hepatocytes
• Constitute of HFE protein, TFR1, TFR2.
• HFE protein occupies TFR-1 where TF-Fe binds, therefore
TF-FE competes with HFE for binding to TFR1
• Mechanism-
When TF-Fe level high, HFE is replaced from TFR1 and then it
binds to TFR2 (on surface on Hepatocytes)
HFE—TFR2—TF-FE complex is formed
Triggers an intracellular signalling cascade
Up regulation of expression of Hepcidin gene (HAMP)
Increased synthesis of Hepcidin less Iron absorption

32. 11/18/2023 32
IRE-BP
IRE-BP
Intracellular iron homeostasis
cellular iron metabolism is controlled through iron-regulatory
proteins [IRP], acts as intracellular Iron sensor.
•When iron level is high in cell IRP not binding to mRNA 
Translation of Ferritin is increased & translation of TfR
decreased.

33. •When iron content is low IRP binds to iron responsive
elements (IRE) of mRNA of TfR and ferritin Increased
translation of TfR & decreased translation of ferritin.
IRP (IRE-BP) is sensitive to intracellular iron levels {not
with ferritin level} and are induced by low Iron levels