Haemoglobin Flashcards
where does haemoglobin synthesis occur?
in the cytoplasm
how is Haem synthesised?
iron brought into mitochondria and is used the the Krebs cycle
leaves mitochondria to join with porphyrin ring
how much O2 will bind to 1g Hb?
1.34ml
what is the structure of haemglobin?
tetramer made up of 2 alpha globin and 2 (B, D, Y) globin chains
one haem group attached to each globin chain
each haem group contains a Fe ion
what are the major forms of Haemoglobin?
HbA
HbA2
HbF
what is the structure of HbA?
2 alpha chains and 2 beta chains; α2β2
what is the structure of HbA2?
2 alpha and 2 delta; α2δ2
what is the structure of HbF?
2 alpha and 2 gamma; α2γ2
HbF is also known as
foetal haemoglobin
which haemoglobin is the main form in adults?
HbA
alpha globin synthesis is controlled by which gene?
chromosome 16 (2 alpha genes per chromosome (4 per cell))
beta globin synthesis is controlled by which gene?
chromosome 11 (One beta gene per chromosome (2 per cell))
what is haemoglobin cooperativity?
binding affinity for oxygen is increased by the oxygen saturation of the molecule, with the first molecules of oxygen bound allowing for positive conformational changes for the binding sites for the next ones
what shape is the oxygen binding curve of haemoglobin?
S shaped
what is the role of iron?
Oxygen transport - Reversible oxygen binding by haemoglobin Electron transport (e.g. mitochondrial production of ATP) - Ferric (Fe3+ ) and ferrous forms ( Fe2+ )
iron is present in which body compounds?
- Haemoglobin
- Myoglobin
- Enzymes eg cytochromes
where is iron absorbed?
duodenum
iron absorption is enhanced by…
Haem vs non-haem iron
dedicated haem iron transporter
Ascorbic acid
Alcohol
iron absorption is inhibited by…
Tannins eg tea
Phytates eg cereals, bran, nuts and seeds
Calcium eg dairy produce
how is iron absorbed?
o Duodenal cytochrome B
o DMT (divalent metal transporter) -1
o Ferroportin
how is iron absorption regulated?
o Hepcidin
what is the mechanism of hepicidin?
Produced in liver in response to iron load and inflammation
Binds to ferroportin and causes its degradation
Iron ‘trapped’ in duodenal cells and macrophages
how is functional iron status assessed?
Haemoglobin concentration
how is transport iron status assessed?
% saturation of transferrin with iron
how is storage iron status assessed?
serum ferritin, tissue biopsy
what is the role of transferrin?
Transports iron from donor tissues (macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors (especially erythroid marrow)
what is the structure of transferrin?
Protein with two binding sites for iron atoms
how does transferrin saturation measure iron supply?
serum iron/total iron binding capacity(to transferrin) x 100 %
what are the different types of transferrin?
holotransferrin (iron bound), apotransferrin (unbound)
when is transferrin reduced?
iron deficiency
anaemia of chronic disease
when is transferrin increased?
genetic haemachromatosis and iron overload
what is the role of ferritin?
iron storage
what is the structure of ferritin?
Large spherical intracellular protein (450kDa)
what does serum ferritin measure?
indirect measure of storage iron
when is ferritin low?
iron deficiency
when is ferritin raised?
iron overload
inflammation
what are the disorders of iron metabolism?
iron deficiency
Iron malutilisation
Iron overload
what is primary iron overload?
long term excess iron absorption with parenchymal rather than macrophage iron loading
what is the cause of primary iron overload?
Hereditary haemochromatosis
what is the cause of hereditary haemochromatosis?
Mutations of HFE gene
Mutations of other iron regulatory proteins e.g. transferrin receptor, hepcidin, ferroportin very rare
what is the pathophysiology of hereditary haemocromatosis?
o Decreases synthesis of hepcidin
o Increased iron absorption
o Results in gradual iron accumulation with risk of end organ damage
what are the clinical features of hereditary haemocromatosis?
Weakness/fatigue, Joint pains, Impotence, Arthritis, Cirrhosis, Diabetes, Cardiomyopathy, Presentation middle age and later, Iron overload > 5g
how is hereditary hemochromatosis diagnosed?
Genetics
transferrin saturation >50%
serum ferritin >300 g/l in men or >200 g/l in pre-menopausal women
Liver biopsy
what is the management of hereditary haemochromatosis?
Weekly venesection = - 450-500ml, - 200-250mg iron
Initial aim to exhaust iron stores (ferritin <20 µg/l)
Thereafter keep ferritin below 50 µg/l
Family Screening
what are the complications of hereditary haemochromatosis?
Diabetes (BRONZE DIABETICS) Infection Cardiac failure Hepatic failure/bleeding varices hepatoma
what are the causes of secondary iron overload?
o Transfusional
o Iron loading anaemias
what are the sources of iron loading anaemias?
- Repeated red cell transfusions
* Excessive iron absorption related to over-active erythropoiesis
what are the disorders of iron loading anaemia?
Massive ineffective erythropoiesis
o Thalassaemia syndromes
o Sideroblastic anaemias
what are the refractory hypoplastic anaemias that can cause iron loading anaemia?
- Red cell aplasia
* Myelodysplasia (MDS)
what is the management of secondary iron overload?
No venesection
Iron chelating agents: Desferrioxamine, Deferiprone and Deferasirox
