This document discusses iron metabolism in the human body. It covers: 1) Molecules involved in iron transport including DMT1, ferroportin, transferrin receptors, hephaestin, transferrin, ferritin, and hepcidin. 2) Steps of iron absorption in the gut and transport through the body. 3) Utilization of iron in erythropoiesis to produce hemoglobin. 4) Disorders of iron metabolism like iron deficiency anemia, hemochromatosis, and atransferrinemia.

1. IRON METABOLISM
IN HEALTH AND
DISEASE
Dr. ANSHUL
15/10/2014

2. 1- Introduction
2- Intake
3- Factors affecting Iron absorption
4- Molecules involved in iron metabolism
5- Steps of iron absorption
6- Iron transport
7- Utilization of iron for erythropoesis.
8- Disorders of iron metabolism.

3. 1- Introduction
• Iron- an important component of all living
organisms.
• Metabolic role –
Oxygen transport.
Energy production by mitochondria (ETC).
• regular source- maintain normal health
• Storage form – ferritin.

4. 2-Intake
• Heme iron and non heme iron.
• Only 10- 15% of ingested iron is absorbed
daily.
• daily iron requirement –
Adult male- 7-10 mg
Adult Female- 7-20 mg.

5. Favored by - Decreased by
Dietary factors : Dietary factors :
-Increased heme iron. - Decreased heme iron.
- Ferrous iron salts. - Ferric iron salts.
Luminal factors : Luminal factors :
- Acidic pH (gastric acidity) - Alkalies (pancreatic secretions)
-Low molecular weight soluble chelates
(vit C, Sugars and amino acids)
-Insoluble iron complexes
(phytates, tannates or phosphates)
Systemic factors : Systemic factors :
- Iron defeciency - Iron overload.
- Increased erythropoesis - Decreased erythropoesis.
- Ineffective erythropoesis - Inflammatory disorders.
-Pregnancy, Hypoxia
Iron absorption-

6. 4-Molecules involved in iron metabolism
1- Protein involved in iron transport across cell
membranes-
Divalent metal-ion transporter-1(DMIT-1)
Ferroportin
Transferrin receptor
2- Reductase and oxidase- facilatate movement
of iron across cell membrane-
Dudenal cytochrome b (Dcyt b).
Ceruloplasmin
Hephaestin

7. 4-Molecules involved in iron metabolism
3- Iron transport in circulation and storage
Transferrin
Ferritin
Hemosiderin
4- Protein controls iron homeostasis by
regulating all above proteins
Hepcidin
5- Functional compound
Hemoglobin, Myoglobin
Cytochrome
Catalase, Peroxidase.

8. 1- Protein involved in iron transport across cell
membranes-
Divalent Metal Transporter-1 (DMT-1)/
Divalent Cation transporter (DCT-1)
• Protein pump coupled apical tranporter of divalent
metal ions.
• Main function- uptake of ferrous form only.
Transport iron across the enterocyte apical plasma
membrane.
necessary for iron assimilation and utilization by
transferrin or transferrin receptor pathway.
• Role in mucosal block as well.

9. 1- Protein involved in iron transport across cell
membranes-
2- Ferroportin
• Iron exporter.
• present at surface of cells that store or transport iron
Basolateral membrane of enterocytes,
Hepatocytres
Phagocytic cells of RES.
• Ferroportin 1- catalyses the exit of divalent metal ions
from epithelial cells into tissues.
• Mutation in gene- Autosomal dominant form of iron
overload- HEMOCHROMATOSIS TYPE IV.
• Inhibited by Hepcidin- retention of iron in
enterocytes,hepatocytes ,macrophage-- ACD

10. 1- Protein involved in iron transport across cell
membranes-
3- Transferrin receptors
Carrier protein for Transferrin.
Import iron in to the cell.
Import the iron by internalizing trnsferrin iron complex- receptor
mediated endocytosis
• Two types TfR 1
TfR 2
• TfR 1- binds diferric transferrin.
- mediates iron delivery to erythroblasts.
• TfR 2- - expressed on hepatocytes and erythroid cells.
binds transferrin with low affinity.
- mutation causes iron overload.
• Truncated portion of TfR shed in blood – measured as serum TfR
conc.

11. Transferrin receptors
• Serum TfR concentration- directly
proportional to rate of erythropoesis.
- differentiates iron deficiency anemia from
anemia of chronic disorders.
Iron deficiency anemia- Increase in sr TfR
Anemia of chronic disorders-decreased in Sr Tfr.

12. 2- Reductase and oxidase- facilatate movement of iron
across cell membrane-
1- Duodenal cytochrome B ( Dcyt B)
• Dihaem protien, member of cytochrome B 561
family of ascorbate dependant reductases.
• Site – intestinal brush border and solubilises
dietary iron for absorption by reducing ferric
to ferrous iron.
• Rapidly downregulated on receiving large
doses of oral iron – molecular mechanism in
mucosal block.

13. 2- Reductase and oxidase- facilatate movement of iron
across cell membrane-
2- Hephaestin
• Dr. Christopher D Vulpe, university of California in
1999.
• Membrane bound homologue of ceruloplasmin, acts as
a multicopper ferroxidase.
• Accessory protein required for transfer of iron across
the basolateral membrane and for binding to
transferrin,
• Oxidises ferrous to ferric form so that it can be carried
by transferrin.
• Location – enterocytes of villus only, not crypt cells.
• Deficiency of copper- Iron deficiency anemia.

14. 3-Molecules involves in Iron transport in
circulation and storage
1 Transferrin
 Transport form of iron.
 Structure- 678 amino acid glycoprotein.
 one or two molecules of ferric iron bind to one
molecule of transferrin  mono/ diferric forms.
 Synthesized as apoferritin in liver+ iron 
transferrin.
 Rate of synthesis – inversely proportional to iron
stores.

15. 3-Molecules involves in Iron transport in
circulation and storage
2- Ferritin
• Discovered by Lanfberger in 1937.
• Spherical protein shell- store 4500 iron atoms
& transport to area where required.
Primary storage compound of iron, readily
available for erythropoesis.
• Structure- Multimer (24 subunit polypeptide to
form hollow sphere)
• Two monomers L (light type) ferritin
H (heavy type) ferritin

16. • Light type - basic ferritin, contains 174 amino acids.
- L monomers have 15 hydrophilic sites which are responsible for
binding iron readily and tightly.
- therefore responsible for low turnover of iron and thus suitable for
storage.
- liver, spleen and serum.
• Heavy type - acidic ferritin, contains 182 amino acids.
- seven hydrophobic sites, takes up and releases iron readily.
- heart, kidney, placenta, monocytes, lymphocytes and
erythrocytes.
• Ferrtin level- parallel concentration of iron stores.
• Ferritin – acute phase reactant – not reliable indicator

17. 3-Molecules involves in Iron transport in
circulation and storage
3. Hemosiderin
• Heterogeneous aggregate of carbohydrate, lipid ,protein & iron.
• formed by degradation of ferritin.
High levels of cellular iron (Ferritin)
Ferritin form aggregates
Taken up by lysosomes and degraded
Hemosiderin

18. Hemosiderin
• Contains 50 % of iron by weight.
• Macrophage of bone marrow, spleen and kupffer
cells of liver.
• At lower iron stores - ferritin predominate.
• At higher stores- Hemosiderin predominate
• Storage form of hemosiderin estimation- Bone
marrow tissue section. (Graded 0-IV)

19. 4- Protein controls iron homeostasis by
regulating all above proteins
• Hepcidin
Master iron regulating hormone – inhibiting activity of
genes involved in intestinal iron absorption and
transport.
Negative regulator of iron absorption/transfer.
Hepcidin synthesis controlled by –
hypoxia/anaemia
Infection /inflammation-

20. Hepcidin
Infection or inflammation
CYTOKINE IL 6
INCRESED HEPCIDIN SECREATION
1- DECREASE IRON ABSORPTION
2- IRON RETENTION IN MACROPHAGES-
as majority of iron for erythropoiesis is recycled
ANEMIA OF CHRONIC DISEASE

21. 5- Functional compound
1- Hemoglobin
• Discovered by Hunefeld in 1840.
• Max Perutz – molecular structure of hemoglobin by
X ray crystallography in 1959.
• Made of 2 pairs of globin chain bearing a heme
molecule.
• Heme molecule has central ferrous iron to which
oxygen is attached loosely.
• Contains most of the body iron, ideal for carrying
oxygen.
• Each molecule of hemoglobin contains 0.34% of
iron by weight. 1 ml of packed red cells contain 1
mg iron.

22. Structure of hemoglobin molecule

23. 5- Functional compound
2- Myoglobin
• Discovered by John Kendrew in 1958.
• Monomer, structurally similar to hemoglobin.
• Present in all muscles, primary oxygen carrying pigment of
muscle tissue.
• Myoglobin in serum – sensitive marker of muscle injury
Structure of myoglobin

24. 5- Steps of iron absorption
• Site- duodenum and jejunum.
• 3 stages –
1) reduction and uptake of solubilised iron
through apical membrane.
2) intracellular processing and transport to
basolateral membrane.
3) transfer of iron through basolateral
membrane into portal circulation.

25. 1) Reduction and uptake of solubilised iron through
apical membrane-
• D cyt B, ferric reductase, converts ferric to ferrous form.
• ferrous form is soluble and has more efficient
mechanism of absorption.
• Heme and non heme iron have different mechanisms of
absorption.
• Heme iron enters enterocytes via heme receptor and
then degraded to free iron, bilirubin and carbon
monoxide by heme oxygenase.
• Ferrous ion uptake is mediated through DMT 1.

26. 2) Intracellular processing of iron :
- Iron transported is either stored in the enterocyte-Ferritin
or transported across the basolateral membrane.
3) Transfer of iron through basolateral membrane into
portal circulation:
- Active process against electric gradient.
- Basolateral membrane transporter is ferroportin.
- Hephaestin, an accessory protien, transfers iron across the
basolateral membrane and binds to transferrin as it converts
ferrous to ferric form.

27. Iron absorption

28. 6-Iron transport :
• Transferrin transports iron in ferric form and
delivers it to various tissues.
• Immature red cells posses high affinity
receptors for transferrin .
• Unbound iron leaves plasma rapidly and is
taken up non specifically by the tissues.

29. 7-Utilization of iron for erythropoesis :
- 80 to 90% of iron entering the cell is taken up by
mitochondria for heme synthesis and rest stored as ferritin.
Cytochrome C reduces ferric to ferrous
iron for heme synthesis -matrix.
Passively transported - inner leaflet.
Ferric iron bound to receptors - outer
membrane of mitochondria.

30. Body Iron content :
Compartment Iron content Percentage
Hemoglobin 2 gm 67
Storage iron 1 gm 27
Myoglobin 0.13 gm 3.5
Labile pool 0.08 gm 2.2
Tissue iron 0.008 gm 0.2
Transport iron 0.003 gm 0.08

31. Iron excretion :
• Iron loss - faeces, exfoliating skin, urine.
• Males -1 mg/day
• Mensturating females - 2 mg/day.
• Persons with marked iron overload - 4 mg/day

32. 8-Disorders of iron metabolism :
• Iron deficiency anemia
Etiology:
Parasitic infestation- Helminths- tape worm,flukes,round worm
Blood loss- menorrhagia, peptic ulcer disease.
Dietary iron deficiency
Iron malabsorption- Celiac disease, IBD, post surgical reesction
Increased demand- Menstruation, pregnancy, infancy.
- Intravascular hemolysis and hemoglobinuria
- Dialysis treatment of chronic renal diseas

33. • Clinical features :
- fatigubility, irritability, headaches and paraesthesias.
- Pica
- Restless legs in elderly.
- Clinical signs- Pallor, Koilonychia, angular chelitis.

34. • Lab investigations :
- Hb estimation
- Peripheral smear study
- Bone marrow picture
- Serum iron concentration – decreased
- TIBC and transferrin saturation – increased
- Serum ferritin – decreased
- Serum transferrin receptor concentration – increased.
• Management :
- Dietary therapy
- Iron preparations (oral and parentral)
- Blood transfusions.

35. Disorders of iron storage :
1- Hemosiderosis–
Iron overload disorder resulting in accumulation of hemosiderin
1 Transfusion hemosiderosis
2 Idipathic pulmonary hemosiderosis-
Good pasture’s syndrome, Wegener’s granulomatosis
2- Hemochromatosis –
• first described by Troiser in France and later by Von
recklingausen.
- Clinical presentation- iron induced injury to various organs.
Classification – 1) hereditary hemochromatosis.
2) secondary hemochromatosis.

36. • Causes of secondary hemochromatosis –
A) Parentral iron overload.
B) Ineffective erythropoesis with increased erythroid activity.
C) Increased oral iron intake.
D) Congenital atransferrinemia.
E) Chronic liver disease.
• Hereditary hemochromatosis :
• Pathogenesis –
- Hemochromatosis gene, HFE is located on short arm of
chromosome 6.
- Crypt cells with mutant HFE lack the facilitating effect on
TfR –dependent iron uptake, thus decreasing the regulatory
iron pool in the crypt cell – Excessive iron uptake.

37. Excessive iron causes toxicity on host tissue by –
- Iron catalysed free radicals reactions- Lipid peroxidation .
- Interaction of reactive oxygen species of iron with DNA lethal
injury to DNA, predisposing to HCC.
- Stellate cells located in perisinusoidal space of Disse, undergo
numerous phenotypic changes like- , increased collagen synthesis
and fibrosis.

38. • Histopathology
- Deposition of hemosiderin in liver, pancreas, myocardium,
pitutary, adrenal gland, thyroid and parathyroid, joints and
skin.
- Cirrhosis.
- Pancreatic fibrosis.
• Laboratory investigations :
- Biochemical determination of hepatic iron concentration.
normal ≤ 1000 micro gm/ gm dry weight of liver.
Hereditary hemochromatosis – more than 10,000 micro gm/gm.
Fibrosis/ cirrhosis – more than 22,000 micro gm/gm dry weight

39. • Clinical features :
- More common in males, evident after 40 years of age.
- Hepatomegaly, skin pigmentation, diabetes mellitus and
atypical arthritis.
- Hypogonadism
- Death due to cirrhosis/ cardiac disease/ hepatocellular
carcinoma.
• Treatment :
- Regular phlebotomy.

40. Disorders of iron transport :
1-Congenital atransferrinemia :
- Pathogenesis : atransferrinemia
decreased delivery of iron to marrow
Marked increase in iron
absorption from intestinal
mucosa
Decreased hemoglobin
synthesis
Severe iron overload Anemia

41. • 2-Congenital aceruloplasminemia :
- Ceruloplasmin converts ferrous to ferric form.
- Ferrous form iron can traverse cell membranes but cannot
bind to transferrin and thus cannot be delivered to
erythroblasts.
- Liver, pancreas, CNS and retina.
- Dementia, dystonia, dysarthria, DM and retinal
degeneration

42. Other related conditions :
• Congenital cataract with hyperferritinemia :
Inheritance is AD.
- Mutation in iron responsive element (IRE)- unregulated
apoferritin synthesis.
- Plasma iron concentration, TIBC and tranferrin saturation are
normal but S.Ferritin concentration is increased.
Unregulated synthesis of a protien within lenses causes
adverse colloid osmotic effect  congenital cataract.
• Superficial hemosiderosis of CNS :
- Due to recurrent subarachnoid hemorrhage with deposition
of iron in meninges.
- associated with ataxia and other CNS manifestations.

43. References:
• Mc Kenzie Shirlyn,William J Lynn.Clinical laboratory
haematology,2nd ed,USA;Pearson;2010.pg165-200.
• Bain J Barbara,Bates Imalda,Latten A
Michael.Dacie and Lewis Practical
haematology,11th ed,China:Elsevier ;2012.p69-125.
• Kumar V, Abbas A K, Fausto N,Aster editors. J C.
Robbins and Cotrans pathological basis of disease,
8th edition.USA:Elsevier;2010. p619-645.
• Greer John P. et al .Wintrobes clinical
hematology,11th ed,USA;Lippincott Williams and
wilkins;2003,p1779-1800.