Haemochromatosis

Excess total body iron leading to deposition in specific organs, particularly the liver.

• Can be
  • Primary
    • Most commonly Hereditary Haemochromatosis (see below)
    • Other causes include congenital acaeruloplasminaemia and congenital atransferrinaemia
  • Secondary
    • Parenteral iron-overload (e.g. repeated blood transfusions)
    • Iron-loading anaemia (e.g. thalassaemia, sideroblastic anaemia, pyruvate kinase deficiency)
    • Liver disease
    • NB In secondary disease, the history/examination will usually point towards the diagnosis.  The patient, however, can present similarly to HHC.
      • They can be managed by iron chelating drugs e.g. Desferrioxamine, deferiprone and deferasirox
  • Complex
    • Juvenile haemochromatosis
    • Neonatal haemochromatosis
    • Alcoholic liver disease
    • Porphyria cutanea tarda

Hereditary Haemochromatosis

• In HHC, iron is deposited throughout the body and total iron stores can reach 20-60g (normally 4g).
  • Due to increased intestinal absorption
    • Homozygous (autosomal recessive) condition, most commonly due to a point mutation (C282Y) in the HFE protein, which is normally though to interact with the transferrin receptor in the basolateral membrane of intestinal enterocytes
      • Other mutations can also cause HHC e.g. H63D
    • Note that this mutation is present in around 0.4% of the population but <50% of these people have HHC
      • Other factors are inevitable
• Most commonly/seriously affects the liver, first periportally and then further out.
  • Leads to the development of fibrous tissue and formation of a nodular cirrhosis

Presentation

• Patients usually present in middle age (30-50)
• Initial symptoms are often vague (and may not be present)
  • e.g. fatigue, weakness, varus joint arthropathy, non-specific abdominal pain; impotence, loss of libido
  • features of liver disease may be present, as can features of diabetes (deposition in pancreatic cells) and heart failure.
  • Lead-grey skin pigmentation due to excess melanin in exposed areas, axillae, groins and genitalia.
  • Other features may include testicular atrophy
  • Pseudogout

Investigation

• Assess iron stores
  • Ferritin >1000μg/l is suggestive of haemochromatosis
    • If <1000, consider inflammatory disease or excess alcohol
  • Transferrin saturation >45% suggests overload
• LFTs (as well as FBC, U&Es and maybe serum antibodies/serology)
  • U
• MRI may show iron deposition in the liver (but has poor sensitivity)
• Liver Biopsy
  • Hepatic iron index (μmol iron/g liver/age) >1.9 suggests hereditary haemochromatosis (or other primary disease)
• Genetic testing
  • C282Y and H63D are both testable

Management

• Weekly venesection of 500ml of blood (250mg iron) until serum iron normalises (ferritin <50μg/l)
  • Can take 2 years or more
  • Although liver and cardiac function usually improves, symptoms of diabetes and joint pain can persist (diabetes is often permanent)
• Transplant is an option for patients with fulminant liver failure
• First degree relatives should be genetically tested and have LFTs/serum ferritin
  • If LFTs are abnormal, liver biopsy is indicated as cirrhosis may be present
  • If serum ferritin is high, venesection should be considered
• Hepatocellular carcinoma screening should be offered routinely

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