Iron
[Ref: KB2:p198-201]
Major forms of dietary iron
- Iron bound in haem
- Iron (mostly ferrric) bound to organic ligands in food
NB:
- Some food may have high content of iron, but also contain other substances that bind to iron and prevent its absorption
* e.g. Oxalate in spinach
- Absorption may also be reduced by alkali, chelating agents such as phytates and phosphate
Absorption of iron
- Location
= Iron is absorbed from duodenum and upper jejunum
- Typically, 5-10% of dietary iron is absorbed
= 1-2 mg/day
- 20-25 mg of iron is used in haemoglobin
* Most of the iron is recycled from Hb breakdown
Absorption of iron ions into enterocyte
Involves both:
- Ferrireductase
* Converts any free ferric iron (Fe3+) into the ferrous form (Fe2+)
- Divalent metal transporter 1 (DMT1)
* Transports ferrous iron and some other divalent metal ions across the apical membrane
NB:
- Transferrin is not involved
- Possible alternative pathway (mobbilferrin-integrin pathway) for ferric ion
Absorption of haem into enterocyte
- Dietary Hb and myoglobin are broken down releasing haem
- Haem is soluble in alkaline duodenal content
* But insoluble at pH < 6
- Absorption of intact haem involves a haem receptor
* Independent of ferrireductase-DMT1 pathway
- Haem is then broken down within enterocyte
* By haem oxygenase
* Ferrous ion released
From enterocyte
Iron in enterocyte can then be stored in cell or transported into blood
Storage
Iron (in ferric form) binds to apoferritin
--> Ferritin
--> Stored in enterocyte
Transport into blood
- Iron (in ferrous form) is transported by ferroportin (aka Ireg1)
- Transport process is coupled with hephaestin (a ferrioxidase)
* Contains copper
* Converts ferrous iron into ferric form
--> Iron (now in ferric form) binds to transferrin in blood
From blood into body cells
Transferrin binds to transferrin receptors
--> Endocytosis
--> Iron release within the cell and transferrin returned intact to ISF
Role of gastric acid in iron absorption
Low pH is important because it facilitates two things
- Reduction of dietary iron (ferric form) to ferrous form (Fe2+)
* Also promoted by presence of dietary ascorbic acid
- Formation of soluble chelates
* Ferric iron can bind with some substances (e.g. certain amino acids) forming soluble chelates
pH and solubility
- In ferrous form, iron is more soluble
--> Soluble up to pH of 7.5
- In ferric form, iron precipitates when pH > 3
--> Cannot be absorbed in duodenum (pH of 4-7)
* Unless soluble chelates are formed
Regulation of iron store
Also see Iron distribution
- Iron is very chemically active and potentially toxic
- Can bind non-specifically to many proteins and impair their function
- There is no physiological control mechanism for EXCRETION of iron from body
--> Control of iron content is solely by regulation of absorption
Lost of iron from body
- Menses in females
- Blood loss
- Cell sloughing
Loss is relatively minor and unregulated
Main loss is in faeces as desquamated epithelial cells of the gut
= 0.5 to 1g day
Regulation of absorption
Control of iron absorption occurs at the enterocytes
--> i.e. mucosal block (aka mucosal intelligence)
* Full details are not known
If iron store is low
--> Plasma level of transferrin is high and saturation is low
--> More iron is passed from ferritin in mucosal cells to transferrin in blood
If iron store is adequate
--> Normal saturation
--> Iron remain in the enterocyte
--> Iron is lost when the cell is shed
Thus,
- Net amount absorbed from the enterocyte into the blood is controlled
* By ferritin and transferrin levels and transferrin saturation
Proteins related to iron transport
Ferritin
- Major storage form of iron in body
- A complex of apoferritin and iron (ferric form, Fe3+)
- A single ferritin molecule can carry as many as 4000 molecules of iron
* Almost 50% of its weight can be iron
* Under normal condition, about 23% of ferritin weight is iron
- When cellular iron level increase, iron can bind to the mRNA and increase synthesis of apoferritin
Transferrin
- Beta1-globulin
* Produced in liver
- Each protein molecule has 2 binding sites for ferric iron (Fe3+)
- Normally about 1/3 saturated
- Halflife = 8-10 days
* [PK1:p240]
Haemosiderin
- Insoluble cellular iron store composed of partially degraded ferritin
- Occurs when iron store is high, mostly in liver
Role of liver
= Major site of ferritin storage
When there is a demand for iron
- Transferrin saturation falls and transferrin synthesis increases
- Iron (Fe3+) is released from ferritin and converted to Fe2+
--> Ferrous iron binds to a transporter protein and crosses the cell membrane
--> Caeruloplasmin (a copper-containing ferrioxidase) converts into ferric form
--> Ferric form can bind to transferrin in the blood
Other notes
- Iron in both deoxyHb and oxyHb are reduced form (ferrous, Fe2+)
- When the haem iron is oxidised to ferric form (Fe3+)
--> Methaemoglobin (MetHb)