Session 4: Iron Metabolism and Microcytic Anaemias Flashcards
What are the features of microcytic anaemias?
Reduced rate of haemoglobin synthesis
Erythrocytes smaller than normal
Cells are often paler than normal
There are two subgroups of microcytic anaemias, which?
Reduced haem synthesis
Reduced global chain synthesis
Which causes of microcytic anaemias are the most common?
TAILS Thalassemia (alpha and beta) Anaemia of chronic disease (hepcidin results in functional iron deficiency, not absolute deficiency) Iron deficiency Lead poisoning Sideroblastic anaemia
What are the causes of microcytic anaemia of reduced haem synthesis?
Anaemia of chronic disease
Iron deficiency
Lead poisoning
Sideroblastic anaemia
What are the causes of microcytic anaemia of reduced globin chain synthesis?
Alpha and beta thalassemia
What are the roles of iron?
Oxygen carriers in haemoglobin in red cells and myoglobin in muscle
Co-factor in many enzymes:
Cytochromes in oxidative phosphorylation
Kreb’s Cycle enzymes
Cytochrome P450 enzymes for detoxification
Catalase in protection against ROS/free radicals
How does the body excrete iron?
The body has no mechanism to regulate excretion of iron. Although there is loss of iron: Desquamation of epithelia Menstrual bleeding Sweat Pregnancy
What are the two most common of states of which iron exists in, in the body?
As ferrous iron and ferric iron.
Ferrous = Fe2+
Ferric = Fe3+
What does dietary iron consist of?
Haem iron which is Fe2+
But also a non-haem iron which is a mixture of Fe2+ and Fe3+.
What aids oxidation of ferrous to ferric iron?
An alkaline pH
What aids reduction of ferric to ferrous iron?
An acidic pH.
Ferric iron cannot be absorbed in the body, how can it then be utilised?
Due to the low pH in the stomach reduction of ferric iron occurs to the make ferrous iron. Then ferrous iron can be absorbed.
What is the daily recommended dietary intake of iron?
10-15 mg
Where is iron absorbed?
Duodenum and jejunum
Explain the dietary absorption of iron.
Cytochrome B reductase converts ferric iron to ferrous with the help of vitamin C.
Fe2+ is then transported into the cell which are enterocytes via DMT1 (Divalent metal transporter) on the apical surface.
Fe2+ is then either stored in the enterocytes as a Fe3+-ferritin complex or transported into the blood via ferroportin on the basolateral surface of the enterocyte.
Once in the blood Fe2+ needs to be converted back into Fe3+ in order to be transported around safely. Hephaestin oxidises Fe2+ into ferric iron and it can now be bound to transferrin in order to be transported around the body.
Explain how lead poisoning can result in anaemia.
Lead inhibits enzymes involved in haem synthesis.
What is sideroblastic anaemia?
Inherited defect in haem synthesis.
Give factors that affect absorption of non-harm iron from food.
Negative:
Tannins in tea
Phytates
Fibres
These 3 can bind non-harm iron in the intestine causing a reduction in absorption.
Antacids also reduce absorption because of a higher pH in the stomach resulting in less reduction of ferric to ferrous.
Positive:
Vitamin C and citrate
- Prevent formation of insoluble iron compounds
- Vitamin C also helps reduce ferric to ferrous iron seen in Cytochrome B reductase.
Iron exists in two other gross forms which are functional, and stored iron.
Give examples of functional iron and where it can be found.
Haemoglobin
Myoglobin
Enzymes such as cytochromes
Transported iron in serum which is mainly in transferrin.
The top three are ferrous iron, bound to transferrin is ferric. All of them are soluble irons.
Give examples of stored iron.
Stored as ferric-ferritin complex. These are globular protein complexes with hollow cores. The pores allow iron to enter and be released.
As haemosiderin:
This is aggregation of clumped ferritin particles, denatured proteins and lipids. They accumulate in macrophages particularly in the liver, spleen and marrow. This is not something we want. Haemosiderin is also insoluble meaning it is not found in blood.
Explain the cellular uptake of iron.
The Fe3+ that is bound to the transferrin binds to a transferrin receptor and enters the cell by receptor-mediated endocytosis.
Well in an endosome (vesicle formed by endocytosis) the Fe3+ is released into the endosome by dissociating from the transferrin receptor. The endosome has an acidic environment and reduction of Fe3+ to Fe2+ will occur.
The Fe2+ can now be transported out of the endosome into the cytosol via DMT-1. The Fe2+ can will now be in an iron pool, it can now either be stored in ferritin as Fe3+ again, be exported by Ferroportin or taken up by mitochondria for use in cytochrome enzymes.
The transferrin receptor will go back and fuse with the plasma membrane again.
Explain how iron is recycled.
Most of our iron requirement comes via recycling and not from dietary intake.
80% of iron comes from recycling damaged or senescent red blood cells.
Also from old red blood cells engulfed by macrophages such as splenic macrophages and kupffer cells in the liver.
Macrophages catabolise haem from red blood cells. Amino acids rested and iron exported to blood or returned to storage pool as ferritin complex in macrophage.
How does regulation of iron absorption occur?
It depends on dietary factors, body’s iron storage and erythropoiesis.
The dietary iron levels are sensed by enterocytes as well.
What are control mechanisms of iron absorption?
Regulation of transporters such as ferroportin.
Regulation of receptors like transferrin receptors and HFE protein that interacts with transferrin receptors.
Hepcidin and cytokines
Crosstalk between the epithelial cells and other cells like macrophages.
