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Haemochromatosis

1. HAEMOCHROMATOSIS

  • Amount of total body iron is increased (normal = 4g)
  • Excess iron deposits cause damage to several organs, commonly liver
  • Causes – see box

Hereditary Haemochromatosis (HHC)

  • Iron deposited throughout the body ≈20-40g (N=4g)
  • Organs involved – liver, pancreas islets, endocrine glands, heart
  • In the liver – gradual development of fibrous septa causes formation of irregular nodules

Pathophysiology

  • Increased absorption of dietary Fe
  • AR inheritance. Single point mutation, results in cysteine → tyrosine substitution at point 282 in HFE protein
  • HFE normally interacts with the transferrin receptor in the membrane of intestinal epithelial cells
    • When transferrin is ↑ (in IDA), HFE increases the intestinal release of Fe into the blood
  • In HHC, mutation of HFE causes the intestines to interpret a strong transferrin signal (state of iron deficiency)
    • Leads to excessive iron absorption
  • Hepcidin is normally increased iron overload – internalises ferroportin 1 and Fe is trapped inside mucosal cell
    • But HFE mutation also disrupts hepcidin expression – results in ↓hepcidin and facilitates iron overload
    • Excess Fe is then gradually taken up by the liver and other tissues

Clinical features

  • MC in men >40
  • Early symptoms – fatigue, arthropathy
  • Classic triad – bronze skin (melanin deposition), hepatomegaly, DM
  • Impotence, loss of libido, testicular atrophy, arthritis
  • Deposits in heart – cardiac failure or dysrhythmias

Investigations

  • ↑serum iron, ↓TIBC
  • Transferrin saturation >45% suggestive of iron overload
  • ↑↑ferritin – ddx is inflammatory disease/excess ethanol consumption
  • MRI
  • Liver biopsy
  • Hepatic Iron Index (HHI) = μmol of iron per g dry weight of liver / age in years
    • HHI > 1.9 suggestive of HHC
  • Gene testing – identifies mutations C282Y + H63D

Management

  • Weekly venesection of 500ml blood (250mg iron) until serum iron is normal – can take 2y or more
  • Aim to reduce ferritin to <50μg/l
  • Liver and cardiac problems improve after iron removal, but joint pain is less predictable
  • DM doesn’t resolve after venesection – may need insulin
  • Investigate first degree family members

Secondary haemochromatosis

  • Causes
    • Many conditions requiring multiple blood transfusions – chronic haemolytic disorders, siderolastic anemia
    • Dietary iron overload
  • Features are similar to HHC
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