Iron homeostasis

Question 1

What are dietary sources of iron?

Answer 1

• meat and fish contain ham iron

- green veg, tofu, beans and pulses are rich in non-ham iron

Question 2

What is the total dietary uptake of iron?

Answer 2

1-2mg/day

Question 3

What transition state is most dietary iron found in?

Answer 3

Fe(III) and then converted to Fe(II) in the gut

Question 4

What is iron involved in in the body?

Answer 4

• cofactor of Hb
• component of iron-sulfur proteins in the ETC → cytochromes
• acts as a co-factor in many enzymes, facilitating redox reactions - catalase and peroxidase

Question 5

When can iron be toxic?

Answer 5

can be toxic in excess, participating in intracellular ‘Fenton Reactions’ (e.g. reacting with hydrogen peroxide to produce 2OH-) which can generate harmful free radicals and cause tissue damage

Question 6

What exclusively takes up iron?

Answer 6

Duodenum

Question 7

Describe excretion of iron

Answer 7

the body has no pathway for iron excretion, so absorption is the key regulatory step in controlling body iron
(unless mensuration)

Question 8

What may happen to iron following uptake?

Answer 8

May be stored as ferritin in enterocytes (and subsequently lost via cell shedding) or absorbed via the ferroportin transporter (in the BL membrane)

Question 9

What promotes iron uptake and how?

Answer 9

vitamin C - converts it to harm iron

Question 10

What transition state must iron be in before uptake into enterocytes by DMT-1?

Answer 10

FeII

Question 11

Which are the only cells that ferroportin is found in?

Answer 11

enterocytes and splenic reticuloendothelial macrophages involved in RBC turnover

Question 12

Discuss transition states require for iron export from enterocyte

Answer 12

Must be converted to Fe(III) by hephaestin

Question 13

How does iron then travel in the plasma?

Answer 13

Bound to transferrin

Question 14

Describe transferrin

Answer 14

Liver-derived glycoprotein with binding sites for two Fe(III)

Serum transferrin concentration rises in response to iron deficiency and is often quantified
as ‘total iron-binding capacity’

Free serum iron levels are variable, and alone rarely a good index of iron status

Transferrin saturation (serum iron/TIBC x 100) is usually around 20-30%, and is often used
as an index of iron availability

Question 15

What do target cells of transferrin express? Describe

Answer 15

Cell surface transferrin receptors TfR1 which can bind and internalise the Fe(III)-transferrin complex
Liver cells also expression TfR2 with may be important in sensing iron availability

Question 16

Give an example of a target cell for the transferrin complex

Answer 16

Erythroid cells

Question 17

What is the key protein for intracellular iron storage and detoxification?

Answer 17

Ferritin

Question 18

What is plasma ferritin a good indicator of? WHat is bad about it?

Answer 18

Plasma ferritin is
sometimes a good indicator of body iron stores but is also an ‘acute phase reactant’, so levels rise
with inflammation or infection.

Question 19

What can smaller amounts of iron be stored in cells as?

Answer 19

insoluble haemosiderin

- this can be bad and is often implicated in fibrosis in tissues

Question 20

Describe hepcidin

Answer 20

• The peptide hormone hepcidin is produced in the liver in response to elevated iron levels. It
  opposes the release of iron from enterocytes and macrophages

-Hepcidin inactivates ferroportin – leading to its internalisation and lysosomal degradation

Question 21

Describe other influences on hepcidin

Answer 21

1) Erythropoiesis
By an unknown mechanism, erythropoiesis per se seems to suppress hepcidin production,
independent of iron levels. This can cause problems in patients with excessive but
ineffective erythrocytosis (e.g. thalassaemia), in whom profound hepcidin suppression can
produce tissue iron overload

2) Hypoxia
Hypoxia also reduces hepcidin production, partly by stimulating erythropoiesis and
causing iron deficiency, but (perhaps) also directly through the HIF family of TFs.

3) Inflammation
Several inflammatory cytokines, particularly IL-6, stimulate hepcidin production by the
liver. This may reflect an evolutionary desire to deprive invading microbes of iron, and
probably explains the ‘anaemia of chronic disease’

Question 22

What do iron-regulatory proteins (IRPs) do?

Answer 22

Cellular iron homeostasis

Coordinate cellular iron uptake and storage by controlling expression of important proteins according to iron levels

e.g. when iron levels are low, ferritin mRNA translation is inhibited and transferrin receptor
mRNAa is stabilised, to encourage iron uptake.

When cellular iron rises, IRPs are inactivated, leading to increased ferritin expression, reduced
transferring receptor expression, and a protective shift towards iron storage and reduced iron
uptake.

Question 23

What are clinical indices of iron status?

Answer 23

• Hb and mean cell volume
• Serum ferritin
• Serum iron and transferrin
• Serum transferrin saturation
• Soluble transferrin receptor

Question 24

What is a hallmark of iron deficiency anaemia?

Answer 24

Hypochromic (loss of colour) microcytic (smaller cells) anaemia

Question 25

Possible causes of iron deficiency

Answer 25

1) Inadequate dietary intake
2) Malabsorption (e.g. coeliac disease)
3) Excessive use of iron (e.g. pregnancy, growth)
4) Hookworm infection
5) Blood loss: blood donation, menstrual loss in young women, GI bleeding