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.
What is hepcidin and how does it work?
A hormone which inhibits the ferroportin so iron can’t be taken up into the blood. It induces internalisation and degradation of ferroportin.
What is hepcidin increased by?
It is increased in synthesis during iron overload to not allow free iron to circulate in the blood.
Also increased by IL-6.
It is decreased by high erythropoietic activity.
Briefly explain anaemia of chronic disease.
An inflammatory condition like rheumatoid arthritis, chronic infection or a malignancy causes cytokines to be released by immune cells, especially IL-6 in this case.
IL-6 inhibits the production of EPO by kidneys and inhibits erythropoiesis in bone marrow.
IL-6 also increases the production of hepcidin which causes the inhibition of ferroportin. This leads to decreased iron release from reticuloendothelial system (macrophages) and also decreased iron absorption in gut leading to reduced plasma iron.
Give common causes of iron deficiency.
Insufficient iron in diet Malabsorption of iron Bleeding Increased requirement Anaemia of chronic disease Damage to duodenum or upper jejunum
How is iron haemostasis done?
Most of the iron is recycled. This is by destruction of RBCs and retainment of iron in macrophages which will then release them into blood.
Which are the risk groups of iron deficiency?
Infants
Children
Women of child bearing age
Geriatric age group
Signs and symptoms of iron deficiency.
Tiredness Pallor Reduced exercise tolerance Angina, palpitations, development of heart failure Increased respiratory rate Headache, dizziness and light-headedness Pica Cold hands and feet Epithelial changes like angular cheilitis, glossy tongue and koilonychia (spoon nails)
What are you likely to find on a FBC of iron deficiency.
Low mean corpuscular volume (MCV)
Low mean corpuscular haemoglobin concentration (MCHC)
Often elevated platelet count
Normal or elevated WBC
Low serum ferritin, serum iron and %transferrin saturation.
Low reticulocyte haemoglobin content (CHr)
What would a peripheral blood smear (histology) show in iron deficient anaemia?
Microcytic RBCs and hypo chromic
Anisopoikiolcytosis (change in size and shape)
Sometimes pencil cells and target cells
How can you test for iron deficiency?
Plasma ferritin
CHr (reticulocyte haemoglobin content)
Pros and cons of plasma ferritin to indicate iron deficiency.
A low plasma ferritin will definitely indicate an iron deficiency.
However a normal or increased ferritin will not exclude iron deficiency because ferritin levels can also increase in cancer, infection, inflammation, liver disease and alcoholism.
Pros and cons of CHr to indicate iron deficiency.
It is recommended by NICE to test for functional iron deficiency.
This is because the CHr remains low during inflammatory response.
However CHr is also low in patients with thalassaemia so CHr can’t be used here.
Treatment of iron deficiency.
Dietary advice Oral iron supplements Intramuscular iron injections Intravenous iron Blood transfusion
Side-effects of oral iron supplements.
It is the safest first-line therapy for most patients but many may experience GI-side effects like constipation.
Explain why iron excess can be dangerous.
Excess iron can exceed the binding capacity of transferring. This means that the excess iron will be deposited in organs as haemosiderin.
This promotes free radical formation and organ damage via Fenton reaction.
Fenton reaction produces hydroxyl and hydroperoxyl radical that can cause damage to cells via lipid per oxidation, damage to proteins and damage to DNA.
Explain Fenton reaction.
Fe2+ + H2O2 -> Fe3+ + OH* + OH-
Fe3+ + H2O2 -> Fe2+ + OOH* + H+
Explain transfusion associated haemosiderosis.
Repeated blood transfusions give gradual accumulation of iron. (400 ml of blood consisting of 200mg of iron)
There are iron chelating agents such as desferrioxamine which can delay haemosiderosis but it does not stop inevitable effects of iron overload.
Explain the complications of accumulation of haemosiderin in liver, heart and endocrine organs.
Liver cirrhosis Diabetes mellitus Hypogonadism Cardiomyopathy Arthropathy Increased skin pigmentation
Explain hereditary haemochromatosis.
Autosomal recessive disease caused by mutation in HFE gene. (High iron (Fe) gene)
HFE protein usually interacts with transferrin receptor reducing its affinity for iron-bound transferrin.
Mutated HFE can’t bind to transferrin so the negative influence on iron uptake is lost leading to too much iron entering the cells.
Iron will therefore accumulate in end organs causing damage.
Complications of haemochromatosis.
Liver cirrhosis Diabetes mellitus Hypogonadism Cardiomyopathy Arthropathy Increased skin pigmentation
How do you treat haemochromatosis?
Venesections to draw blood.
