Iron Metabolism

Question 1

Importance of iron

Answer 1

• binds and stabilises oxygen for metabolism: haemoglobin, myoglobin, cytochrome c oxidase, catalase (in RBC removes H2O2 and stops damage)
• handles electrons in ETC in complexes I- IV
• important for aerobic existence

Question 2

Uptake and recycling mechanisms of Fe homeostasis

Answer 2

• only contain 2-4g in blood
• transported in blood via transferrin
• moves to bones for erythropoiesis
• after ~3 months, RBC broken down by spleen macrophages and Fe exits via ferroportin channels
• Fe stored in liver via ferritin

Question 3

Uptake of non-haem iron in duodenum

Answer 3

• proteases in gut release Fe from food
• ferric (Fe3+) is oxidised by DcytB
• ferrous (Fe2+) enters enterocytes via transporter channel
• stored in ferritin in labile Fe pools
• Ferrous then leaves via ferroportin 1
• ferrous oxidised (so doesnt undergo Fenton reaction) by hephaestin or ceruloplasmin

Question 4

Uptake of haem iron in duodenum

Answer 4

• proteases in gut release Fe from food
• can enter enterocytes via putative haem receptor (endocytosed)
• haem oxidase (HO-2 is constitutive form, HO-1 is inducible form) then removes haem from Fe2+ (ferrous) and produces biliverdin, which is reduced to bilirubin by biliverdin reductase
• ferrous leaves vesicle via DMT-1
• can be stored in ferritin
• ferrous can exist the enterocyte via ferroportin-1 and can be oxidised by hephestin to ferric

Question 5

Role of the liver in iron storage and mobilisation

Answer 5

• synthesizes iron transport proteins: transferrin (Fe3), haptoglobins (haemoglobin), haemopexin (haem)
• synthesizes ceruloplasmin
• produces Fe regulatory hormone (Hepcidin) which inhibits Fe recycling

Question 6

Complications of iron overload

Answer 6

• non-transferrin bound Fe circulates in plasma, increases risk of the Fenton reaction (promoting ROS)
• insoluble Fe can be deposited into organs causing toxicity
• complications: cardiac, liver cirrhosis, diabetes, infertility, growth failure
• aceruloplasminemia: mutation leading to Fe and Cu overload in brain and liver
• hypotransferrinemia: genetic disorder limits transferrin
• DMT-1 mutation means cannot transport Fe out properly
• malaria, sickle cell crisis, thalassemia

Question 7

Anaemia/ iron deficiency

Answer 7

• anaemia: RBC count lower than normal
• anaemia of chronic disease is caused by upregulation of hepcidin (such as that seen in cancer and ageing)
• genetic form (rare): IRIDA, mutation in lover protease which inhibits hepcidin transcription
• onset can be slow

Question 8

Treatments for iron deficiency and iron overload

Answer 8

• iron deficiency: supplements (iron citrate> iron sulfate) maybe with vitamin B12. IV infusion better GI symptoms. Transfusions (riskier)
• iron accumulation: chelation therapies (not very specific, desferrioxamine). Novel approaches include chelators targeting the hepcidin/ferroportin axis with an antibody, is which improves iron metabolism and availability