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

1. Reduction of dietary iron (ferric form) to ferrous form (Fe2+)
   * Also promoted by presence of dietary ascorbic acid
2. 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)