MEH 8 - Iron Metabolism + Microlytic Anaemias Flashcards
What is microcytic anaemia?
What are the 2 ways in which microcytic anaemia can occur? - Describe some causes for both of these ways.
- A reduced rate of Hb synthesis w/erythrocytes smaller than normal. (Microcytic + hypochromic)
1) Reduced Haem Synthesis - e.g.: Anaemia of chronic disease, Iron deficiency, Lead poisoning + Sideroblastic anaemia.
2) Reduced Globin Chain Synthesis - e.g.: alpha and beta thalassaemia
Use TALIS (thalassaemia, anaemia of chronic disease etc) to remember causes of microcytic anaemia.
What 2 main things is Iron (Fe2+) required for?
Why is iron potentially very toxic for cells?
Can the body excrete irom?
1) Oxygen carriers - e.g.: Hb or myoglobin
2) Co-factor in enzymes - e.g.: CYP450, krebs cycle enzymes etc.
- Fe2+ can participate in Fenton reaction which produces free radicals leading to oxidative stress.
- Body doesn’t have a mechanism for excreting Fe2+ so need complex regulatory systems to absorb, transport + utilise iron.
What 2 oxidation states can iron exist in?
Which type of iron is absorbed from the diet?
1) Fe2+ (ferrous iron) - reduced form (OILRIG)
2) Fe3+ (ferric iron) - oxidised form
- Dietary iron consists of haem (Fe2+) and non-haem (mixture of Fe2+ + Fe3+). Ferric iron must be reduced to ferrous iron to be absorbed.
How much Iron is required in diet per day?
Where does absorption of iron occur?
Name some good dietary sources of haem + non-haem iron.
- 10-15mg/day
- Duodenum + Upper Jejunum
- Haem Iron = Liver, kidney, beef steak, chicken, salmon
- Non-Haem = Fortified cereals, raisins, beans, figs, oats
Describe in its entirety, the process of dietary iron absorption.
1) Dietary iron passes into SI from stomach within chyme, any ferric iron reduced to ferrous via ferric reductase enzyme (on brush border of enterocytes)
2) Once in Fe2+ form, iron moves into enterocytes via DMT1. Transported into blood stream through BL membrane via ferroportin.
3) Fe2+ oxidised back to Fe3+ via hephaestin which allows it to be transported around the body by transferrin.
4) Hepcidin produced by the liver inhibits ferroportin which limits the amount of iron we can absorb from the diet.
List some factors that have a positive and negative influence on non-haem iron absorption from food?
Negative = Tannins (in tea), Phytates (e.g.: chapattis), Fibre + Antacids - can bind non-haem iron in intestine + reduce absorption.
Positive = Vitamin C + Citrate, vit c also helps reduce Fe3+ to Fe2+.
What are the 2 pools of iron that exist in the body and how much of the total 3350mg iron do they contain?
1) Functional (available) Iron - includes iron in Hb, myoglobin, enzymes and transported ion (2350mg)
2) Stored Iron - in the soluble ferritin form, a globular protein with hollow core, pores allow iron to enter + exit. As well as insoluble haemosiderin form, which are aggregates of clumped ferritin particles, which accumulates in macrophages, particularly in the liver.
What are the 4 stages of cellular iron uptake?
1) Fe3+ bound transferrin binds to transferrin receptor and enters cytosol via receptor-mediated endocytosis
2) Fe3+ within endosome released by acidic environment and reduced to Fe2+
3) Fe2+ transported to cytosol via DMT1
4) Once in cytosol, Fe2+ stored in ferritin or taken up by mitochondria for use in cytochrome enzymes.
Only a small fraction of total daily iron requirement is obtained via diet, how is most (>80%) of the requirement met?
- By Iron Recycling (from damaged or old RBC’s)
- Old RBC’s engulfed by macrophages, primarily splenic macrophages and liver kupffer cells.
- Macrophages catabolise haem, release from RBC’s
- Iron transported to blood via transferrin or returned to storage pool as ferritin in macrophage.
How is iron absorption regulated?
- Regulation dependent on dietary factors, body iron stores + erythropoiesis.
- Dietary iron levels sensed by enterocytes.
Control mechanisms =
1) Regulation of transporters (e.g.: ferroportin)
2) Regulation of receptors (transferrin receptor)
3) Hepcidin + cytokines
4) Crosstalk - between epithelial cells and other cells like macrophages.
How does hepcidin have a negative impact on iron absorption?
When is hepcidin synthesis increased/decreased?
- Hepcidin induces internalisation and degradation of ferroportin. Therefore reduces amount of iron that can be absorbed from the diet and released from macrophages.
- Synthesises increased in iron overload
- Synthesises reduced by high EPO activity
How do chronic inflammatory disease (e.g.: RA), lead to iron deficiency and ultimately anaemia?
- Condition results in cytokine release from immune cells.
- This causes increased production of hepcidin by liver, inhibiting ferroportin.
- Decreased release of iron by RES and decreased iron absorption in gut, reduces plasma iron concentration
- This inhibits erythropoiesis in bone marrow causing anaemia.
Describe 5 potential causes of iron deficiency.
1) Insufficient dietary iron - e.g.: vegans
2) Malabsorption of iron
3) Bleeding - e.g.: menstruation, gastric bleeding due to chronic NSAID use
4) Increased requirement - e.g.: pregnancy/rapid growth
5) Anaemia of chronic disease e.g.: RA
Which groups of people are at high risk of iron deficiency + why?
- Infants, children, women of child bearing age.
- Iron requirements are higher, particularly in females of child bearing age + pregnant women.
What are the signs and symptoms associated with iron deficiency?
1) Those associated w/anaemia - e.g.: tiredness, pallor, reduced exercise tolerance etc.
2) Pica (usual cravings for non-nutritive substances, e.g.: dirt)
3) Cold hands + feet
4) Epithelial changes - e.g.: angular chelitis, glossy tongue + koilonychia (spoon nails)
