haemochromatosis

see also:

• liver diseases
• iron poisoning
• haemosiderosis

• the excessive accumulation of iron in the body due to a homozygous recessive inherited disorder that causes excessive iron absorption from the gut
  • NB. “secondary haemochromatosis” due to acquired causes is called haemosiderosis
• 1st described by von Recklinghausen in 1889
• it is one of the most common hereditary disorders, with HZ C282Y mutation occurring in 0.45% of white Europeans but phenotype is low due to low penetrance

• adult form:
  • mutation of genes encoding either:
    • HFE
      • accounts for the far majority of cases
      • gene is on chromosome 6 close to the HLA gene locus and HFE is a HLA-1 class like protein
      • > 70% have the homozygous C282Y mutation which is mainly confined to whites of European origin (0.45% of this population - 11% of white Europeans are heterozygous!)
        • however, penetrance of the disorder is low in homozygous C282Y mutation and thus not all develop the disease
      • others have a milder form due to either homozygous H63D mutation or C232Y/H63D compound heterozygous mutation
    • transferrin receptor 2 (TfR2)
• more severe juvenile onset haemochromatosis:
  • mutation of genes encoding either:
    • HJV (haemojuvelin) which is expressed in liver, heart and skeletal muscle
    • hepcidin / HAMP
• NB. there is a neonatal form which develops in utero and does not appear to be a hereditary condition

• normal iron physiology:
  • normal adult total body iron pool is 2-6g with 0.5g stored in the hepatocytes
  • regulation of iron absorption from the gut:
    • mainly via the protein hepcidin (aka LEAP1) encoded by the HAMP gene and produced by the liver. It binds to the cellular iron efflux channel ferroportin (FPN) thereby inhibiting its transport action by causing internalisation of the channel.
      • hepcidin is regulated by:
        • haemojuvelin
        • transferrin receptor 2 (TfR2)
        • HFE
  • accumulation of iron in haemochromatosis,
    • there is a net accumulation of total body iron of 0.5-1g/year in men
    • total body iron pool may be greater than 50g with a over a third in the liver resulting in chronic inflammation and cirrhosis
      • symptoms generally commence when > 20g has accumulated
    • in addition it may accumulate in the heart, joints and endocrine organs

• usually develop symptoms by middle age, rarely before age 40yrs.
• men 5-7x women as less physiologic iron losses
• fully developed cases:
  • all have micronodular cirrhosis and 200x risk of hepatocellular carcinoma (Rx does not remove this risk)
  • 75% have diabetes mellitus due to destruction of pancreatic islet cells
  • 75% have skin pigmentation
  • pancreatic fibrosis
  • cardiomegaly with cardiomyopathy and possible cardiac blocks
  • synovitis and pseudo-gout due to calcium pyrophosphate deposits
  • deranged hypothalamic-pituitary axis causing atrophic testes and reduced testosterone levels
  • hepatomegaly
  • abdominal pain

• early detection through screening of family members is important as this allows earlier reduction of iron levels via venesections and a normal life expectancy for adult forms
  • serum iron studies showing high serum iron and ferritin levels
  • need to exclude acquired causes - see haemosiderosis