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Iron Metabolism


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  • Iron is essential for many metabolic processes and forms an important component of all living organisms
  • It exists in both the ferric and ferrous forms
  • Although the earth’s crust consists of about 4% of iron, it is largely unavailable to humans due to the insolubility of ferric iron
  • Iron deficiency is the commonest cause of anaemia all over the world
  • This is because excess loss of iron from haemorrhage is common and the body has limited ability to absorb iron

DISTRIBUTION OF BODY IRON

  • 50mg/kg in adult male
  • 40mg/kg in adult female
  • Most (about 2/3/) contained in haemoglobin
  • Much of the rest in storage proteins, ferritin and haemosiderin
  • 450ml (1 unit) of whole blood contains about 200mg of iron

 

 

 

 

Amount of iron in average adult

Male(mg)

Female(mg)  

Percentage of total

Haemoglobin

2400

1700

65

Ferritin and haemosiderin

1000(300-1500)

300(0-1000)

30

Myoglobin

150

120

3.5

Haem enzymes(e.g. Cytochromes, catalase etc)

20

15

0.5

Transferrin bound iron

4

3

0.1

 

  • Haemoglobin
  • Myoglobin serves as oxygen reserve in muscles
  • Cytochrome a, b and c, succinate dehydrogenase and cytochrome oxidase – form an electron transport pathway responsible for the oxidation of intracellular substrates and the simultaneous production of adenosine triphosphate
  • Cytochrome P450 – hydroxylation reactions (including drug detoxification by the liver)
  • Cyclo-oxygenase – prostaglandin synthesis
  • Catalase and lactoperoxidase – peroxide breakdown
  • Tryptophan pyrrolase – oxidation of tryptophan to form formylkynurenine
  • Iron sulphur proteins – xanthine oxidase, reduced nicotinamide adenine dinucleotide dehydrogenase and aconitase
  • Iron is also necessary for the function of ribonucleotide reductase an important enzyme in DNA synthesis

IRON STORAGE PROTEINS

 

Body iron is stored mainly as ferritin and haemosiderin

  • These are found mainly in RE[1] cells of the liver, spleen and bone marrow which gain iron from broken down red cells
  • Also in parenchymal liver cells which normally gain iron from transferrin

FERRITIN

  • It is the primary storage iron protein with MW 465 000
  • It is a water soluble protein-iron complex with an apoprotein shell and a ferric hydroxyphosphate core
  • 20% of its weight is iron and can contain up to 4,000 atoms of iron
  • Not visible by light microscopy

HAEMOSIDERIN

  • Insoluble protein-iron complex
  • 37% of its weight is iron
  • Formed by the partial digestion of ferritin aggregates by lysosomal enzymes
  • Visible by light microscopy when stained by the Prussian blue (Perls’) reaction

TRANSFERRIN

  • A single chain polypeptide (mol. Wt. = 79 500) present in plasma and extravascular fluid
  • It has a plasma half-life of 8-11 days
  • It is synthesized predominantly by the liver, synthesis being inversely related to iron stores
  • Transferrin can bind up to 2 atoms of ferric iron
  • Most transferrin iron is gotten from broken down red cells
  • Only a small proportion is from dietary iron
  • It delivers iron to tissues that have transferrin receptors

Transferrin Receptors

  • The uptake of iron from transferrin required that the protein can be attached to specific receptors on the cell surface (TfR1)
  • TFR1 (CD71) is expressed in largest number in the erythroblast
  • It is a transmembrane protein
  • 2 subunits bind one transferrin molecule and thereafter undergoes receptor mediated endocytosis
  • TFR2 also binds transferrin and together with TFR-1 and HFE[2] is involved in regulation of Hepcidin synthesis

Serum transferrin receptors is increased in iron deficiency

NORMAL IRON BALANCE

  • Amount at birth depends on the blood volume and Hb conc.
  • Birth weight is very important
  • Maternal iron level has very little effect on foetal iron
  • 80 mg/kg at full term
  • Neonatal iron reserve is utilized for growth
  • There is virtually no iron store from 6 months to 2 years
  • Gradually accumulates during childhood to around 5 mg/kg
  • In men, there is further increase between 15 and 30 years to about 10-12 mg/kg (total up to approximately 1g)
  • Iron stores remain lower in women (average 300 mg) until menopause
  • It would take 4 years or more for a man to deplete body iron stores and develop iron deficiency anaemia solely due to lack of dietary intake or malabsorption

DIETARY IRON

  • In the form of simple inorganic salts or iron-amino acid complexes
  • Daily intake of a normal adult on a mixed western diet contains 10-20mg iron of which 10% (1-2mg) or less is absorbed
  • Amount absorbed from diet normally balances losses (in stools mainly)

Sources of Dietary Iron

  • Red or organ meat (liver, kidney)
  • Cereals (fortified with iron)
  • Egg yolk
  • Green vegetables
  • Fruits
  • Milk (cow milk has low iron content)

Meat is a better source of iron than vegetables

IRON ABSORPTION

  • Depends not only on the amount of iron in the diet, but also and more importantly on the bioavailability of the iron, as well as, body’s need for iron
  • Iron is maximally absorbed from the jejunum, probably because the increasingly alkaline environment leads to the formation of insoluble ferric hydroxide complexes
  • Factors such as acids and reducing agents which help keep iron in the ferrous form in the gut lumen favour iron absorption
  • Much of dietary iron is non-haem iron derived from cereals with a lesser component of haem iron from meat and fish

Iron is released from protein complexes by acid and proteolytic enzymes in the stomach and small intestine, and haem is liberated from haemoglobin and myoglobin

  • Both haem and inorganic iron are absorbed in the apical membrane of duodenal enterocytes
  • Non-haem iron is released from food as Fe3+ and reduced by the brush border ferrireductase, duodenal cytochrome b1 (Dcytb) to Fe2+
  • The Ferrous iron (Fe2+) is then transported across the apical membrane by DMT-1 (divalent metal transporter)
  • Haem iron is initially bound by haem receptors at the brush border membrane and released intracellularly by haem oxygenase
  • Inside absorptive enterocytes, there are 2 alternative pathways depending on body’s need for iron
  • The iron is either stored in ferritin and eventually lost from the body when the cells are exfoliated or it is transported across the basolateral membrane into the portal plasma
  • Basolateral iron transport is mediated by ferroportin 1
  • Hephaestin, a ferroxidase at the basal surface converts the Fe2+ to Fe3+ prior to binding to transferrin in the portal plasma

 

 

 

HEPCIDIN

  • Hepcidin is the major hormonal regulator of iron homeostasis
  • A product of HAMP gene synthesized in the liver
  • A small polypeptide consisting of 25 amino acids
  • It inhibits iron release from duodenal enterocyte and macrophages by binding to ferroportin causing its degradation in lysosomes
  • It is bound to α-2 macroglobulin and is cleared by the kidneys
  • It is also an acute phase protein
  • Increased production is induced by inflammation via IL-6
  • It inhibits:
    • Iron absorption in the intestine
    • Iron transport across the placenta
    • Iron release from macrophages
  • Hepcidin levels increases in iron overload and inflammatory conditions
  • Levels are decreased in iron deficiency, hypoxia and increased erythropoietic activity  Synthesis is controlled by 3 proteins:
    • HFE[3]
    • Hemojuvelin ü Transferrin receptor 2

Regulation of Iron Absorption

  • This is the mechanism by which the body controls its iron content
  • The body has extremely limited capacity to excrete iron
  • Regulated both at the stage of mucosal uptake and at the stage of transfer to the blood stream
  • The small intestine is highly sensitive to repletion or depletion of iron stores
  • Hepcidin plays vital role in regulation of iron absorption
  • Rapid correction of imbalance by decreasing or increasing absorption occurs
  • The amount of iron absorbed is regulated according to the body’s need by changing the levels of DMT-1[4] and Ferroportin
  • DMT-1 levels is regulated by the IRP/IRE binding mechanism
  • Ferroportin is regulated by the Hepcidin
  • In iron deficiency, there is increased expression of DMT-1 so there is increased transfer of iron from the gut lumen into the enterocytes. The reverse is the case in overload
  • Low hepcidin level in iron deficiency increases ferroportin levels and allow more iron to enter portal plasma. The reverse is the case in overload

 

Regulation of Ferritin, DMT, TFR1 Synthesis

  • Levels of Ferritin, TfR1[5], ALA-S and DMT-1 are linked to iron stores
  • Iron overload causes increased synthesis of ferritin and ALA-S with decreased TFR1 and DMT-1
  • Iron deficiency causes decreased synthesis of ferritin and ALA-S with increased TFR1 and DMT-1
  • The synthesis of these proteins is regulated at the level of RNA translation by a protein, named iron regulatory protein (IRP)
  • IRP binds to iron responsive elements (IREs) on the Ferritin, TfR1, ALA-S and DMT-1 mRNA molecules
  • The mRNAs encoding TfR1 and DMT-1 contain 5 IREs in their 3’ untranslated regions (UTRs)
  • The mRNAs encoding ferritin and ALA-S contain a single IREs in their 5’ untranslated regions (UTRs)
  • Iron deficiency increases ability of IRP to bind to IRE
  • Iron overload decreases ability of IRP to bind to IRE
  • When cellular iron levels are low, IRE-IRP interactions inhibit translation of ferritin and ALA-S, but increase translation of TfR1 and DMT-1 by preventing degradation of their mRNA
  • When iron levels are high, the IRP no longer binds to the IREs
  • Ferritin and ALA-S synthesis can thus proceed, while TfR1 and DMT-1 synthesis is reduced

 

  • Dietary factors
  • Luminal factors
  • Mucosal or systemic factors

FAVOURED BY ↓ REDUCED BY ↓

DIETARY FACTORS

  • Increased haem iron  Decreased haem iron
  • Increased animal food  Decreased animal food  Ferrous iron salts         Ferric iron salts

 

LUMINAL FACTORS

  • Acid pH e.g. gastric HCl
  • Low MW soluble chelates e.g. vit. C, sugars, amino acids
  • Alkalis e.g. pancreatic secretions
  • Insoluble iron complexes e.g. phytates, tannates in tea

 

SYSTEMIC/MUCOSAL FACTORS

  • Iron deficiency  Iron overload
  • Increased erythropoiesis  Decreased erythropoiesis
  • Ineffective E  Inflammatory disorders
  • Pregnancy
  • Hypoxia

 

IRON UPTAKE

  • Iron is transported in the plasma bound to transferrin
  • Each molecule of transferrin can bind 2 atoms of iron
  • Uptake of iron requires transferrin receptors
  • Transferrin receptors are present in high concentration in cells with a high iron requirement
  • Transferrin receptors are found on;
    • Erythroblasts and reticulocytes
    • Placenta
    • Other body cells

Number of receptors in any given cell increases with an increase in proliferation

  • Cell transferrin receptors have the highest affinity for diferric transferrin
  • The transferrin-receptor complex is taken up by a process of receptor mediated endocytosis
  • The iron is released and apotransferrin and receptor are recycled to the plasma and cell membrane respectively

IRON REQUIREMENT

  • Varies with age and sex, to compensate for losses and growth
  • Highest in pregnant and lactating women and in adolescents
  • In children and adolescents for losses and growth
  • In adults for losses alone
  • Losses mainly in urine, feaces and sweat
  • Also menses in females

Daily Dietary Iron Requirements per 24 Hours

  • Male: 1mg
  • Adolescence: 2-3mg
  • Female (reproductive age): 2-3mg
  • Pregnancy: 3-4mg
  • Infancy: 1mg
  • Maximum bioavailability from normal diet is about 4mg

EXCRETION OF IRON

  • Amount of iron lost from the body per day is small, between 0.5mg and 1.0mg under normal physiological conditions
  • Rate of loss approximates that taken in the diet
  • Almost all this iron loss occurs mainly from the GIT by way of faeces
  • Other routes of losses are from;
    • Excretion in the urine and sweat
    • Loss of hair and nails and
    • Exfoliation of skin and dermal appendages

DIAGNOSTIC METHODS OF INVESTIGATING IRON METABOLISM

  • Storage iron
    • Serum ferritin
    • Bone marrow iron
  • Iron supply to tissues
    • Serum iron
    • Serum iron binding capacity
    • Serum transferrin receptors
    • Red cell protoporphyrin
    • Red cell ferritin
    • Percentage of hypochromic cells

SERUM FERRITIN

  • Correlates well with iron stores in healthy individuals
  • Normal is 15-300 µg/L
  • Higher in men than premenopausal women
  • Values below 15 µg/L are specific for storage iron depletion but normal value does not exclude it
  • Above 300 does not usually indicate iron overload because ferritin synthesis is influenced by factors other than iron
  • It is an acute phase protein

BONE MARROW IRON

  • Staining of bone marrow for iron gives indication of RE[6] iron as well as erythroblast iron
  • In iron deficiency anaemia, both RE and erythroblast iron are ABSENT

SERUM IRON

  • Gives a measure of iron supply to tissues
  • Shows a diurnal rhythm in normal subjects
  • Values lower in the morning than evening
  • In iron deficiency and overload, values stabilize at low and high levels respectively

TOTAL IRON BINDING CAPACITY (TIBC)

  • Gives a measure of iron supply to tissue
  • Serum transferrin saturation (Serum iron/TIBC) × 100

ü < 15% is insufficient to support normal erythropoiesis

  • Rise in TIBC is characteristic of iron deficiency
  • Reduced serum iron with normal or reduced TIBC is a characteristic response to infection and inflammation

SERUM TRANSFERRIN RECEPTOR

  • Reflects both the number of erythroid precursors and iron supply to the bone marrow
  • Increased in erythropoiesis from any cause results in high serum concentration
  • Increased in IDA[7] but not in anaemia of CD[8]
  • Provides a valuable indicator of deficiency of body iron stores in anaemia of chronic disease

RED CELL PROTOPORPHYRIN

  • Protoporphyrin combines with iron to form haem
  • In iron deficiency, there is accumulation of protoporphyrin in the red cell

 

[1] Reticuloendothelial

[2] High Iron Gene

[3] High Iron Gene

[4] DMT – Divalent Metal Transporter

[5] Transferrin receptor

[6] Reticuloendothelial

[7] Iron Deficiency Anaemia

[8] Anaemia of Chronic Disorders