1. This document summarizes iron metabolism in the human body, including sources of iron, transport and storage, and clinical aspects of iron deficiency and overload.
2. Iron exists in the body bound to proteins like hemoglobin, myoglobin, cytochromes and iron-requiring enzymes or stored in ferritin and hemosiderin in the liver, spleen and bone marrow. Transferrin transports iron throughout the body.
3. Iron is absorbed in the duodenum and jejunum and either stored in intestinal cells or transported into plasma bound to transferrin. Strict regulation of absorption maintains iron balance in the body.
1. Clinical Biochemistry
SIMS-305
Dr. Ali Raza
Senior Lecturer
Centre for Human Genetics and Molecular Medicine (CHGMM),
Sindh Institute of Medical Sciences (SIMS), SIUT.
1
3. Iron
• Fourth abundant element in the earth’s crust
• Most essential trace elements
• Iron content is 2.3 - 3.8 gm (70 kg)
• 70 % of body's iron is found in the
•Red blood cells as Heamoglobin
•Muscle cells called Myoglobin.
4. Types of Iron Present in Body
Two categories to describe Iron in the body.
A. Essential Iron ( Functional):
• Involved in the normal metabolism of the cells.
B. Storage Iron.
• Ferritin
•Hemosiderin
5. A. Essential Iron
Divided into three groups:
1. Haem Proteins: Haemoglobin and Myoglobin
Other haem proteins : Catalases, Peroxidases
MyoglobinHaemoglobin
6. A. Essential Iron
2. Cytochromes:
Group of organo-iron (carbon-to-iron chemical bond)
compounds in the body Cytochromes
7. A. Essential Iron
3. Iron Requiring Enzymes:
a) Use riboflavin as Coenzyme. Eg: Xanthine Oxidase
b) Require metal (Iron)only as Cofactor. Succinate Dehydrogenase
c) Required for conversion of superoxide radical to free OH–
radical.
.
Succinate dehydrogenase superoxide radical to free OH– radical.
H2O2 can be
quickly oxidize
soluble
ferrous iron to ferric
(Fe+3),
9. Ferritin
• Free iron is Toxic
• bound to ferritin is Nontoxic.
Storage protein of iron and found
• Blood
• Liver
• Spleen
• Bone marrow
• Intestine (mucosal cells).
10. Ferritin
• Apoferritin is the apoprotein form a spherical shell
• Six pores in the shell allow molecules of a certain size
to enter pores
• Pores have catalytic activity, binding of ferrous iron
(Fe++) and
• subsequent oxidation to “ferric oxy hydroxide”
(FeO.OH).
11.
12. Ferritin
• Iron is present as “ferric oxyhydroxy phosphate”
complex in ferritin
• Up to 4500 Fe+++ atoms are found stored in a
ferritin complex.
13. Ferritin molecules
A partially filled ferritin molecule
• with a hydrous Fe (III) oxide microcrystal
growing from a nucleation centre inside
the apoferritin shell
• arrows indicate addition /release of iron
(or phosphate) at the microcrystal
surface.
Release : Last-in first-out’ principle.
A full ferritin molecule
• Containing three microcrystals
• Added ions ,such as phosphate
Represented by full circles,
14. Iron Transport and Utilization
Transferrin : Transport of Fe throughout the body is
accomplished with a specific protein
15. TRANSFERRIN
• Transferrin is a non-haem iron binding
Glycoproteins.
• Apotransferrin is the apoenzyme and Fe is its
prosthetic group.
• It has a molecular weight of 70,000
• it can bind with two atoms of iron in the ferric state
(Fe+++) synergistically in presence of HCO–3 ion.
16. TRANSFERRIN
• Exists in plasma as β1-globulin and is the true carrier
of iron.
• In plasma, transferrin is saturated only to the extent
of 30 - 33 % with iron.
• Prior to binding to transferrin, Fe++ (ous) iron has to
be oxidised to Fe+++(ic) form.
17. Function of Transferrin
• Transport of iron to RE cells, bone marrow to reach the immature RBCs.
• Specific receptors are available on cells surface.
• Transferrin is internalized by receptor mediated endocytosis.
• Within the target cells, iron is released
• apotransferrin is recycled to form new transferrin molecules
18.
19. 2- Haemosiderin
• Derived from Ferritin , Ferritin with partially stripped
shell.
• contains a larger fraction of its mass as Fe than does
ferritin
• Exists as microscopically visible Fe-staining particles.
• Haemosiderin is usually seen in states of iron
overload or when Fe is in excess
20. 2. Haemosiderin
• E.g: the synthesis of apoferritin and its uptake of Fe
are maximum.
• Haemosiderin is rather insoluble.
• Fe in haemosiderin is available for formation of Hb
• Mobilisation of iron is much slower from
haemosiderin
21. DIETARY SOURCES OF IRON
I. Exogenous: Foods rich in iron include:
a. Animal Sources: Meat, fish, liver, spleen, red marrow (2.0
to 6.0 mg/100gm).
b. Vegetable Sources:
Cereals (2.0 to 8.0 mg/100 gm) are the major rich source.
Legumes, molasses, nuts, amaranth leaves.
Dates are other good sources.
II. Endogenous: Fe is utilised from ferritin of RE system
and intestinal mucosal cells.
Fe obtained from “effete” red cells are also reutilised.
22. ABSORPTION OF IRON AND
FACTORS REGULATING ABSORPTION
• Around 10 to 20 mg of Fe is taken in the diet and only
about 10 per cent is absorbed
• The only mechanism by which total body stores of
iron is regulated is at the level of absorption.
• Garnick proposed a “mucosal block theory” for iron
absorption.
23. Mucosal Block Theory
1. Soluble inorganic salts of iron are easily absorbed
from the small intestine.
• HCl present in gastric juice liberates free (Ferric) Fe3+
from non-haem proteins.
• Vitamin C and glutathione reduce Fe3+ to
Fe2+(Ferrous), which is more soluble form of iron.
• Vitamin C and amino acids can form iron-ascorbate
and iron-amino acid are readily absorbed.
24. Mucosal Block Theory
2. Gastroferrin, a glycoprotein in gastric juice is believed
to bind iron
• facilitate uptake in duodenum and jejunum.
3. The absorption of iron from intestinal lumen into
mucosal cells takes place as Fe2+.
25. Events in Absorption of iron
Iron in the Fe3+ state is reduced
to Fe2+ by “Ferrireductase” on
enterocytes, by vitamin C
Transfer of iron (Fe2+) from the apical
surfaces of enterocytes into their
interiors is performed by Divalent
metal transporter
Stored as “ferritin”
Passage of Fe2+ across the basolateral
membrane is carried out by Iron regulatory
protein 1
Most of Fe2+ required to be absorbed is
transferred to plasma by a Fe2+ transporter
(FP).
IREG1 may interact with the copper containing
protein called “hephaestin”
• Hephaestin have a ‘ferroxidase’ activity
• important in the release of iron from cells as Fe3+,
• the form in which it is transported in the plasma by transferrin.
26. Events in intestinal mucosal cells (Enterocyte):
• Enterocytes in the proximal duodenum are responsible
for absorption of iron.
• Incoming iron in the Fe3+ state is reduced to Fe2+
by “Ferrireductase” present on the surface of
enterocytes, helped by vitamin C present in the foods.
• Transfer of iron (Fe2+) from the apical surfaces
of enterocytes into their interiors is performed by
a proton-coupled divalent metal transporter (DMT1).
• DMT1 protein is not specific for iron as it can transport
a wide variety of divalent cations.
27. Events in intestinal mucosal cells (Enterocyte):
• Once it is inside, it can either be stored as “ferritin”
or transferred across the busolateral membrane into the
plasma where it is carried bound to transferrin.
• Passage of Fe2+ across the basolateral membrane
is carried out by another protein called iron regulatory
protein 1 (IREG 1).
• Most of Fe2+ required to be absorbed is transferred
to plasma by a Fe2+ transporter (FP).
• Fe2+ in the enterocytes also come from “haem” by
the action of “haem oxidase” enzyme on haem.
28. Events in intestinal mucosal cells (Enterocyte):
• IREG1 may interact with the copper containing
protein called “hephaestin”
• Hephaestin have a ‘ferroxidase’ activity
• important in the release of iron from cells as Fe3+,
• the form in which it is transported in the plasma by
transferrin.
29. Overall regulation of iron absorption
• Exerted at the level of the enterocyte
• Absorption of iron is blocked if sufficient amount
taken up,
• for body need—so called dietary regulation exerted
by “mucosal block” (Garnick’s hypothesis).
30. Other Factors
(a) Source of Fe has marked effect on absorption:
Haem iron
• comes from animal products (Hb, myoglobin),
• efficiently absorbed (about 20 - 30%).
Non-haem iron
• comes from plants
• Inefficiently absorbed (only 1 to 5%).
31. (b) The absorption of non-haem iron is influenced by:
• Composition of the diet
• pH of the intestinal milieu
• State of health of the individual.
32. Composition of the Diet effect on non-haem iron
absorption
• Dietary factors increase iron absorption are
vitamin C
glutathione
meat factor
• Foods that inhibit non-haem iron absorption are:
– Tea (diminishes absorption by > 60%)
– Coffee (reduced absorption by > 35%)
– Phytates
– Oxalates
33. 2. pH of Intestinal Milieu
• Gastric HCl liberates Fe3+ from non-haem iron
• Increase solubility of dietary non-haem iron.
• pH of duodenum is most conducive for absorption.
• Rate of absorption further decreases
• down the intestines as the pH becomes more alkaline.
• At high alkaline pH, the ingested iron is precipitated.
34. 3. State of Health of the Individual
• Healthy adults absorb about 5 to 10 % of dietary iron, approx.
1 - 2 mg of iron.
• Iron-deficient adults absorb 10 - 20 % of the dietary iron
equivalent to 3 to 6 mg of Fe.
35. Iron Requirements
Requirement of iron varies according to
• age
• gender
• weight
• state of health.
Adult male = 10 mg/day
Adult female = 20 mg/day.
Children = 10 to 15 mg/day.
37. A. IRON DEFICIENCY:
Three stages of iron deficiency are:
1. Iron storage depletion
2. Iron deficiency
3. Iron deficiency anaemia.
38. 1. Iron Storage Depletion:
• This phase is not usually recognizable by the patient
and normally does not elicit a medical examination.
• Serum ferritin decreases during this phase
is the only good indication of possible iron deficiency.
• Many women of child bearing age remain in this phase
for years without being identified.
39. 2. Iron Deficiency:
• Iron stores are almost exhausted.
• Biochemically the serum ferritin is low↓ and
transferrin saturation is low↓.
• Erythrocyte protoporphyrin↑ increases, as
erythropoiesis is slowed down due to non availability
of Fe which cannot be incorporated in protoporphyrin
IX.
• Hb concentration falls↓ to the lowest limit of normal.
40. 3. Iron Deficiency Anaemia:
• Iron deficiency anaemia is manifested as hypochromic
microcytic anaemia.
At this phase:
• Serum ferritin level shows slow decline↓
• Transferrin saturation continues to fall↓
• Erythrocyte protoporphyrin increases to upper limit of
normal↑.
41. B. IRON OVERLOAD
Iron stores may increase due to:
• Excessive absorption, or
• Parental iron therapy or
• Repeated transfusions.
• Cells start to fill with excess of haemosiderin↑.
• Both reticuloendothelial cells and parenchymal cells sequester
iron.
42. Types: Two broad types of iron overload
1. Haemochromatosis:
When iron overload is associated with injury to cells.
2. Haemosiderosis:
Iron overload without cell damage is called
haemosiderosis.
Editor's Notes
Organoiron chemistry is the chemistry of iron compounds containing a carbon-to-iron chemical bond.
Cytochromes are proteins containing heme as a cofactor. Cytochromes function as electron transfer agents in many metabolic pathways, especially cellular respiration.
They are classified according to the type of heme and its mode of binding. Four varieties are recognized by the IUBMB, cytochromes a, cytochromes b, cytochromes c and cytochrome d.
Hydrogen peroxide can be used to quickly oxidize soluble ferrous iron to ferric (Fe+3), forming a rapidly settling ferric hydroxide floc.
a colorless crystalline protein capable of storing iron in bodily cells especially of the liver by combining with iron to form ferritin.
Bound form of iron with ferritin is more soluble
Hemosiderin or haemosiderin is an iron-storage complex. The breakdown of heme gives rise to biliverdin and iron.[1][2] The body then traps the released iron and stores it as hemosiderin in tissues.[3] Hemosiderin is also generated from the abnormal metabolic pathway of ferritin.[3]
It is only found within cells (as opposed to circulating in blood) and appears to be a complex of ferritin, denatured ferritin and other material.[4][5] The iron within deposits of hemosiderin is very poorly available to supply iron when needed.
Pregnancy and
lactation demands more: Pregnant women require 10
mg/day and lactating mothers 25 to 30 mg/day.