Physiology - RBCs and Iron Flashcards
Describe the properties of a red blood cell
Full of Hb to carry oxygen No nucleus No mitochondria High surface area/volume ratio Flexible to squeeze through capillaries
Describe the structure of haemoglobin
A tetrameric (4) globular protein
2 alpha and 2 beta chains (in adult Hb)
Heme group: Fe2+ in a flat porphyrin ring
–> one heme per subgroup (4 total)
Where does oxygen bind to haemoglobin?
Fe2+
–> does not bind to Fe3+
What is red cell production regulated by?
Erythropoietin (Epo)
Describe the role of Epo in RBC production
Hypoxia sensed by the kidney
- -> Epo produced by kidney
- -> Epo stimulates RBC production in the bone marrow
- -> Epo levels drop
Where does red cell destruction occur?
Normally spleen (and liver)
What is the average lifespan of a red blood cell?
120 days
What happens to the broken down RBC?
Contents are recycled:
- globin chains recycled to amino acids
- heme group broken down to iron and bilirubin
- bilirubin taken to liver and conjugated, then excreted in bile
Which molecule prevents oxidative damage to cellular enzymes + Hb from free radicals?
Glutathione
Which enzyme is the rate limiting factor in the protection from glutathione?
Glucose-6-phosphate dehydrogenase (G6PD)
How many oxygen molecules can transported by one Hb molecule?
4
What is ‘co-operative binding’ in regard to Hb?
As one oxygen binds to Hb subunit, it changes the shape making it easier for the next oxygen to bind
–> allosteric effect
How is foetal Hb different to adult Hb?
It has 2 alpha + 2 gamma subunits
Why is it important to have safe iron transport/storage mechanisms and that the absorption of iron is regulated?
It can be dangerous: oxidative stress and free radical production
And no mechanism for excretion of iron
Where is iron absorbed?
Mainly in the duodenum
Which dietary factors enhance iron absorption?
Ascorbic acid (vitamin C) --> reduces iron to Fe2+ form Alcohol
Which dietary factors inhibit iron absorption?
Tannins e.g. tea
Phytates e.g. cereals, bran, nuts + seeds
Calcium e.g. dairy products
Which molecules are involved in iron absorption?
Duodenal cytochrome B
DMT (divalent metal transporter) -1
Ferroportin
What does duodenal cytochrome B do?
Found in luminal surface
Reduces ferric iron (Fe3+) to ferrous form (Fe2+)
What does DMT-1 do?
Transports ferrous iron into the duodenal enterocyte
What does ferroportin do?
Facilitates iron export from the enterocyte
Passes on to transferrin for transport elsewhere
Which molecule regulates absorption of iron from the duodenum?
Hepcidin
How does hepcidin regulate the absorption of iron?
Produced in liver in response to increased iron load and inflammation
Binds to ferroportin and causes its degradation
Iron therefore trapped in duodenal cells and macrophages
Hepcidin levels decrease when iron deficient
Which three components of iron status are assessed with iron studies?
Functional iron
Transport iron/iron supply to tissues
Storage iron
How is functional iron measured?
Hb concentration
How is transport iron/supply to tissues measured?
% saturation of transferrin with iron
How is storage iron measured?
Serum ferritin
tissue biopsy - rarely needed
What is transferrin and what does it do?
Protein with two binding sites for iron atoms
- transports iron from donor tissues (macrophages, enterocytes, hepatocytes) to tissues expressing transferrin receptors
What tissues are especially rich in transferrin receptors?
Erythroid marrow
What is a normal transferrin saturation?
20-50%
What is ferritin?
Spherical intracellular protein
Stores up to 4000 ferric ions (Fe3+)
What does serum ferritin represent and when might it be increased?
Serum ferritin reflects intracellular ferritin synthesis –> indirect measure of storage iron
Serum ferritin also acts as an acute phase protein
–> increased in infection, malignancy, liver injury etc
What are the principles of disorders of iron metabolism?
Iron deficiency Iron malutilisation (anaemia of chronic disease) Iron overload
How is iron deficiency confirmed on a blood test?
Combination of anaemia - decreased Hb iron
AND low ferritin - decreased storage iron
What causes iron deficiency?
Insufficient intake
Losing too much (bleeding)
Not absorbing enough (malabsorption e.g. Coeliac)
What is ‘occult blood loss’ in relation to iron deficiency?
GI blood loss of 8-10ml per day (4-5mg of iron) can occur without any symptoms or signs
Maximum dietary absorption or iron is about 4-5mg per day
Therefore, negative iron balance can occur
What causes iron overload?
Primary: - hereditary haemochromatosis Secondary: - transfusions - iron loading anaemias (increased absorption)
How is haemochromatosis diagnosed?
Genetics: mutation HFE gene
Transferrin saturation >50%
Serum ferritin >300 in men, >200 in pre-menopausal women
Liver biopsy (rarely needed)
How is haemochromatosis treated?
Weekly venesection
- initial aim to exhaust iron stores (ferritin <20)
- thereafter keep ferritin below 50
How is secondary iron overload treated?
Iron chelating agents:
- Desferrioxamine (SC or IV infusion)
- Newer oral agents e.g. deferiprone, deferasirox
Why is venesection not used to treat secondary iron overload?
Patients are already anaemic
