Iron Metabolism Flashcards
What are microcytic anaemias?
- Reduced rate of haemoglobin synthesis
- Erythrocytes smaller than normal (microcytic)
- Cells often paler than normal (hypochromic)
Reduced haem synthesis:
Iron deficiency - insufficient iron for haem synthesis
Anaemia of chronic disease - hepcidin results in functional iron deficiency
Lead poisoning - acquired defect. Lead inhibits enzymes involved in haem synthesis
Sideroblastic anaemia - inherited defect in haem synthesis
Reduced globin chain synthesis:
alpha thalassaemia - Deletion or loss of function of one or more of the four a globin genes
Beta thalassaemia - mutataion in beta globin genes leading to reduction or absence of the beta globin
What is the role of iron in the body?
• Essential element in all living cells
• Required for:
• Oxygen carriers:
Haemoglobin in red cells Myoglobin in myocytes
• Co-factor in many enzymes:
Cytochromes (oxidative phosphorylation)
Krebs cycle enzymes
Cytochrome P450 enzymes (detoxification)
Catalase
• Free iron potentially very toxic to cells - Participates in Fenton reaction which can produce free radicals
• Complex regulatory systems to ensure the safe absorption, transportation & utilisation
• Body has no mechanism for excreting iron
What is the difference between ferrous and ferric iron?
- Iron can exists in a range of oxidation states
- Ferrous iron (Fe2+) and Ferric iron (Fe3+) most common
- Fe2+ is the reduced form Fe3+ is the oxidised form
- Dietary iron consists of haem iron (Fe2+) and non-haem (mixture of Fe2+ and Fe3+). Ferric iron must be reduced to ferrous iron (Fe2+) before it can be absorbed from diet
How much iron is needed in diet and where is it absorbed?
10-15mg/day
Absorbed in duodenum and upper jejunum
What are good sources of dietary iron
Haem iron best source: liver, kidney, beef steak, chicken, duck, pork, salmon, tuna
Non-haem iron - fortified cereals, raisins, beans, figs, barley, oats, rice, potatoes
Describe the absorption of iron
Haven’t yet identified specific transporters for haem transporters into celll
Non haem iron is ferrous and ferric - only absorb ferrous form
Need to convert ferric to ferrous first by REDUCTASE enzyme on brush border of enterocytes
Fe2+ pass through co transporter (DMT1) - can store some iron in enterocyes
Some transported to blood by FERROPORTIN - pass across cell memb into blood
TRANSFERRIN = transport molecule transports iron around body - only takes fe3+
Fe2+ need sto be converted to Fe3+ first by HEPHAESTIN
HEPCIDIN takes iron from liver
What factors affect absorption of nonhaem iron from food?
Negative influence • Tannins (in tea) - can bind non haem iron - reduces absorption - tea inhibits absorption of iron • Phytates (e.g. Chapattis, pulses) • Fibre • Antacids (e.g. Gaviscon)
Positive influence
Vitamin C & Citrate
• Prevent formation of insoluble iron compounds
• Vit C also helps reduce ferric to ferrous iron
What is functional vs stored iron?
Functional (available) iron • Haemoglobin (~2000 mg) • Myoglobin (~300 mg) • Enzymes e.g. cytochromes (~50 mg) • Transported iron (in serum mainly in transferrin) (~3 mg)
Stored iron (~1000 mg)
Ferritin - soluble
• Globular protein complex with hollow core
• Pores allow iron to enter and be released.
Haemosiderin - insoluble
• Aggregates of clumped ferritin particles,
denatured protein & lipid.
• Accumulates in macrophages,
particularly in liver, spleen and marrow.
Describe cellular iron uptake
1) Fe3+ bound transferrin binds transferrin receptor and enters the cytosol receptor-mediated endocytosis.
2) Fe3+ within endosome released by acidic microenvironment and reduced to Fe2+. Proton pump lowers pH in vesicle - facilitate release of iron
3) The Fe2+ transported to the cytosol via DMT1.
4) Once in the cytosol, Fe2+ can be stored in ferritin, exported by ferroportin (FPN1), or taken up by mitochondria for use in cytochrome enzymes
What is iron recycling?
- Only small fraction of total daily iron requirement gained from the diet.
- Most (>80%) of iron requirement met from recycling damaged or senescent red blood cells
- Old RBCs engulfed by macrophages (phagocytosis)
- Mainly by splenic macrophages and Kupffer cells of liver
- Macrophages catabolise haem released from red blood cells
- Amino acids reused and Iron exported to blood (transferrin) or returned to storage pool as ferritin in macrophage.
How is iron absorption regulated?
• Depends on dietary factors, body iron stores and
erythropoiesis
• Dietary iron levels sensed by enterocytes
• Control mechanisms
• Regulation of transporters e.g. ferroportin
• Regulation of receptors e.g. transferrin receptor & HFE protein (interacts with transferrin receptor)
• Hepcidin and cytokines
• Crosstalk between the epithelial cells and other cells blike macrophages
What is hepcidin?
Negative regulator of iron utilisation and absorption
Made by liver and released into blood stream
Synthesis increased in iron overload / decreas by high erythropoietin activity
Has effect on ferroportin protein - inhibits this - hepcidn causes it to be internalised and degraded
Ferroportin needed in enterocytes
Also needed in RE system when macrophages have recycled it - need it for iron to leave macophage
Give an overview o anaemia of chronic disease
Il6 can inhibited erythropoietin production my kidney - lowering rbc protection
Can also inhibit erythropoesisat bronze marrow directly
Main mechanism mainly il6 stimulate liver to produce more hepcidin - inhibition ferroportin - decreases iron release from RE system and decreased iron absorption in gut - plasma iron reduced - inhibition of erythropoiesis in bone marrow
Give an overview of iron homeostasis
See side
What is iron deficiency
Most common nutritional disorder worldwide.
1/3rd of world population (2 billion people) are anaemic with at least half of these due to iron deficiency
Iron deficiency is a sign not a diagnosis! Clinician must always seek to determine underlying reason why patient is iron deficient.
Could be due to: • Insufficient intake/poor absorption • Physiological reasons e.g. pregnancy • Pathological reasons e.g. bleeding
