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Sophie - Applied Physiology & Pharmacology Year 2 > 51.4 Iron Homeostasis > Flashcards

51.4 Iron Homeostasis Flashcards

1
Q

What is the function of iron in the body?

A

Haemoproteins (hemoglobulin)
Iron-sulphur proteins (electron transport chain)
Redox properties means it acts as a cofactor for many enzymes

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2
Q

Which proteins require iron?

A

Haemoglobulin
Myoglobulin
Cytochrome

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3
Q

List the places where iron is found/stored in the body? How much in each store?

A

1800mg in Red blood cells as Hemoglobulin
1000mg in the liver bound to transferrin (as ferritin)
300mg in bone marrow
600mg in reticuloendothelial macrophages
400mg in other tissues: muscles as myoglobulin, cytochromes in cells
TOTAL = 4000mg

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4
Q

What is the largest store of iron in the body?

A

Red blood cells (Hb) = 1800mg (60%)

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5
Q

What is the total amount of iron in the body at any one time?

A

4000mg (4g)

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6
Q

What is the total dietary uptake of iron?

A

1-2 mg per day

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7
Q

In what form is most dietary iron found as?

A

Fe (III) - but is converted to Fe (II) in the gut

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8
Q

What is the daily loss of iron from the body? How?

A

1-2mg a day from non regulated pathways (skin and enterocyte cell shedding)

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9
Q

What happens to senescent red blood cells? Why?

A

Engulfed by macrophages in the liver and spleen
Do not want to lose all the iron that is contained within the Hb in RBCs

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10
Q

What are the dietary sources of iron?

A

Meat and fish = haem iron
Green vegetables, tofu, beans and pulses = non-haem iron

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11
Q

Describe the recycling of iron in red blood cells that happens daily

A

Red cells become senescent (old and damaged)
Kupffer cells in the liver or macrophages in the spleen engulf red blood cells and broken down to release the haemogloblin
Known as reticuloendothelial system
Hb broken down to release Haem and globulin (used for amino acids)
Haem broken down to iron and bilirubin
Iron binds to transferrin and transported to bone marrow to make more RBC or stored in the liver as ferritin
Recycling of iron means that there is little need for dietary intake

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12
Q

How does hepcidin reduce iron levels?

A

Only regulated step in iron metabolism is IRON UPTAKE and RECYCLING
Hepcidin controls the absorption of iron via ferroportin at the gut mucosal cells.
-Binds to ferroportin, leading to its internalisation and lysosomal degradation to prevent iron release from macrophages and enterocytes
-Redcues the number of active DMT-1 molecules on dudenal enterocytes to reduce iron uptake

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13
Q

How does hypoxia reduce hepcidin production?

A

HIF transcription factor is activated during hypoxic conditions which reduces the transcription of hepcidin in the liver
Thereby stimulating iron uptake into cells during hypoxic conditions (increase RBC so need to more iron into erythroid cells)

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14
Q

How is iron lost from the Gi system?

A

Once ferric iron binds to ferritin it is practically irreversible making it unavaliable for absorption into the plasma and it is instead lost into the faeces when the enterocyte is shed into the lumen

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15
Q

What makes and secretes hepcidin?

A

The liver

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16
Q

What is the suggested sensor for iron levels to control hepcidin secretion by the liver?

A

TfR2 (transferrin receptor 2)

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17
Q

When is hepcidin produced by the liver?

A

In response to elevated iron levels
Also: In response to inflammatory cytokines (anameia of chronic disease)
AIMS TO LOWER IRON UPTAKE

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18
Q

Which factors cause the suppression of hepcidin release?

A

When iron levels are LOW
Erythropoiesis
Hypoxia

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19
Q

Which hormone maintains iron homeostasis?

A

Hepcidin

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20
Q

Which proteins regulate cellular iron homeostasis? How?

A

Iron regulatory proteins (IRPs) control the expression of proteins involved in iron metabolism

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21
Q

What is the role of transferrin?

A

transport of iron

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22
Q

How is iron that is bound to transferrin taken up by target cells?

A

Target cells express surface transferrin receptors (TfR1) which internalise the Fe (III)-transferrin complex by receptor mediated endocytosis

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23
Q

How many ferric iron atoms can be transported by transferrin?

A

Transferrin is a liver-derived glycoprotein with binding sites for two Fe(III) atoms

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24
Q

How much total iron is bound to transferrin?

A

300 μg/dL

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25
Q

Describe the mechanism for iron absorption in the duodenum.

A
  • Fe2+ crosses the apical membrane by the divalent cation transporter DCT1 (dependent on the H+ gradient generated by the acidity of the duodenum lumen)
  • Any Fe3+ in the lumen is reduced to Fe2+ by iron reductase on the apical membrane, so it can be taken up by DCT1
  • Haem can also be taken up by a haem transporter on the apical membrane, after which it is converted to Fe2+ by haem oxidase
  • Fe2+ can now enter one of two pathways:
    • Absorptive pathway
      • A complex of two proteins (hephaestin and ferroportin) transports the Fe2+ into the blood -> The hephaestin converts the Fe2+ into Fe3+
      • In the blood, the Fe3+ is bound to transferrin for transport
    • Storage pathway
      • Fe2+ binds to ferritin in the cytoplasm, where it is stored
      • When needed, the Fe2+ can be mobilised and taken to the hephaestin/ferroportin complex for transport into the blood
26
Q

What oxidation state of iron does tranferrin bind and how many irons does it bind?

A
  • Fe3+
  • It binds two irons
27
Q

How does serum tranferrin change in response to iron deficiency?

A

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

28
Q

What is usually a good measure of iron availability?

A

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

29
Q

How is iron taken up into cells from the blood?

A
  • Target cells (e.g. erythroid cells) express the cell surface transferrin receptors TfR1
  • These bind the Fe3+-transferrin complex and lead to the formation of a clathrin-coated pit.
  • An endosome is then formed, which is acidified to release the iron.
  • The iron is stored using ferritin or converted into haemoglobin
30
Q

When is hepcidin produced and what are the main actions?

A
  • Hepcidin is produced when the liver senses elevated iron levels (via sensing transferrin-iron complexes)
  • It opposes the release of iron from macrophages and enterocytes

(You can think of hepcidin as an equivalent of insulin, but for iron)

31
Q

What proteins are responsible for INTRACELLULAR iron homeostasis?

A

IRPs (iron-regulatory proteins)

32
Q

How do IRPs (iron regulatory protein) work when intracellular iron levels drops?

A

When cellular iron levels are low, IRPs:

  • Inhibit translation of ferritin
  • Stabilise transferrin receptor mRNA

Thus, they encourage iron uptake.

33
Q

What are the main indicators of iron status?

A
  • Haemoglobin and mean cell volume
  • Serum ferritin
  • Serum iron and transferrin
  • Serum transferrin saturation
  • Soluble transferrin receptor
34
Q

What type of anaemia is a hallmark of iron deficiency anaemia?

A

Hypochromic microcytic anaemia

(Hypochromic = Lacking colour, Microcytic = Small RBCs)

35
Q

What are some causes of iron deficiency?

A
  • Inadequate dietary intake
  • Malabsorption (e.g. coeliac disease)
  • Excessive use of iron (e.g. pregnancy, growth)
  • Hookworm infection (common worldwide)
  • Blood loss:
    • Blood donation
    • Menstrual loss in young women
    • Gastrointestinal bleeding
36
Q

What are some causes of iron overload?

A
  • Primary genetic disease (haemochromatosis)
  • Alcoholic cirrhosis
  • Excessive oral intake of iron
  • Repeated blood transfusions
  • Excessive (ineffective) erythropoiesis
37
Q

Describe the mechanism for iron absorption in the duodenum.

A
  • Fe2+ crosses the apical membrane by the divalent cation transporter DCT1 (dependent on the H+ gradient generated by the acidity of the duodenum lumen)
  • Any Fe3+ in the lumen is reduced to Fe2+ by iron reductase on the apical membrane, so it can be taken up by DCT1
  • Haem can also be taken up by a haem transporter on the apical membrane, after which it is converted to Fe2+ by haem oxidase
  • Fe2+ can now enter one of two pathways:
    • Absorptive pathway
      • A complex of two proteins (hephaestin and ferroportin) transports the Fe2+ into the blood -> The hephaestin converts the Fe2+ into Fe3+
      • In the blood, the Fe3+ is bound to transferrin for transport
    • Storage pathway
      • Fe2+ binds to ferritin in the cytoplasm, where it is stored
      • When needed, the Fe2+ can be mobilised and taken to the hephaestin/ferroportin complex for transport into the blood
38
Q

What is the purpose of storing iron using ferritin in enterocytes?

A

It means that it has not yet technically been absorbed, which is advantageous because it means that this iron can either be fully absorbed or shed with the enterocytes (depending on the iron levels in the body).

39
Q

What transporter is used to take up Fe2+ from the duodenum lumen?

A

DCT1 (divalent cation transporter 1)

40
Q

How is any Fe3+ in the duodenum lumen absorbed?

A
  • It is reduced to Fe2+ by iron reductase on the apical membrane
  • Then it is taken up by DCT1
41
Q

How is haem in the duodenum lumen absorbed?

A
  • It is taken up by a haem transporter on the apical membrane
  • Then it is converted to Fe2+ by haem oxidase.
42
Q

What transporter moves iron from enterocytes into the blood?

A

A complex of two proteins (hephaestin and ferroportin).

(Ferroportin is the one mentioned in the spec, while hephaestin is responsible for converting Fe2+ into Fe3+)

43
Q

What are two important iron binding proteins/glycoproteins and what is the function of each?

A
  • Ferritin -> Storage of iron in enterocytes
  • Tranferrin -> Transport of iron in the blood around the body
44
Q

Why may females have larger daily losses of iron?

A

Blood loss during menstruation takes daily loss to 2mg/day (doubles)

45
Q

Why is an excess of iron dangerous in the body?

A

Iron can be toxic through its participation in FENTON reactions (e.g. Fe2+ + H2O2 Fe3+ + OH· + OH- ) which generate FREE RADICALS

46
Q

Which trasnsporter do macrophages and enterocytes use to export iron from their cells?

A

FERROPORTIN

47
Q

Which enzyme converts Fe 3+ to Fe 2+ and why?

A

DCYTB (duodenal cytochrome b reductase) on the brush border
Fe 3+ is not a substrate for DMT-1

48
Q

When can plasma ferritin not be a good indicator for iron stores? (normally circulates in the blood)

A

DURING INFECTION
Ferritin levels increase as it is an acute phase protein so you cannot accurately tell how much iron there is because ferritin no longer reflects how much iron is in the body

49
Q

What valency must iron be in to be taken up by enterocytes?

A

Fe (II)
Must be reduced

50
Q

What valency is ferrous iron?

A

Fe 2+ (II)

51
Q

What valency is ferric iron?

A

Fe 3+ (III)

52
Q

What protein inside of cells allows for iron storage? What is function of this protein outside of cells?

A

Ferritin can store up to 4500 iron atoms in a crystalline core
Ferritin is an ACUTE PHASE protein (means its concentration increases during inflammation

53
Q

What must happen to exported ferrous iron before it can be absorbed into the blood?

A

Must be oxidised to ferric iron so it can bind to apotransferrin (transferrin without iron bound to it)

54
Q

What is the histological hallmark of iron deficiency anaemia?

A

Hypochromic microcytic anaemia
Paler and smaller

55
Q

What is haemosiderin?

A

Another iron storage molecule but it tends to be harmful as it can overload and deposit inside of tissues which causes damage

56
Q

What happens when intracellular iron levels rise?

A

IRPs are inactivated = increased ferritin expression and reduces transferrin receptor expression and a protective shift towards iron storage and reduced iron uptake.

57
Q

What happens to serum levels of transferrin during iron deficiency?

A

Serum transferrin concentration rises in response to iron deficiency, and is often quantified as ‘total iron-binding capacity’
= makes sure you can scavenge all the iron avaliable

58
Q

What are the two fates of Fe2+ once it has entered duodenal enterocytes?

A

-Leaves via the basolateral membrane using ferroportin transporter
-Oxidised (Fe 3+) and bound to cytoplasmic protein apoferritin to form Ferritin

59
Q

If haem enters a cell, how is iron liberated from haem?

A

Haem oxidase liberates fe2+ from haem

60
Q

How does vitamin C aid in iron absorption into the body?

A

Ascorbate (vit C) reduces Fe 3+ to Fe 2+

61
Q

Describe the steps involved in the cellular liberation and uptake of iron bound to transferrin. Which cell is likely to be the target cell?

A

ERYTHROID CELLS (will become RBCs)
Fe(III)-transferrin complex binds to TfR1
Enter the cell by receptor mediated endocytosis into a vesicle
Acidic conditions breaks down the complex
Fe 3+ is reduced to Fe 2+ and transported out by DMT-1 for storage as ferritin (Fe 3+) or incorporation into haem molecules

Sophie - Applied Physiology & Pharmacology Year 2 (32 decks)

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