HEREDITARY HAEMOCHROMATOSIS

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HEREDITARYHAEMOCHROMATOSIS
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What Is It?

• An inherited disease characterised by excess iron
  deposition in various organs
• Leads to eventual fibrosis and functional organ
  failure

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Prevalence and Aetiology

• Transmitted by an autosomal recessive gene
• Caucasian heterozygote 1/10
• Caucasian homozygote 1/400 (ie1/20 x 1/20)
• Most common form has been shown to be due to a
  missense mutation in the HFE gene on the short
  arm of chromosome 6

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Mechanism of Damage

• Still somewhat unclear but
• There is failure of expression of HFE on the
  basolateral surface of the crypt cell ? the
  duodenal crypts are unable to incorporate iron
  from plasma transferrin and are therefore
  rendered iron deficient ? increased expression of
  DMT-1 protein ? increased intestinal iron
  absorption in relation to body iron stores

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Mechanism of Damage

• Inappropriate iron uptake by the mucosal cells
  exceeds the capacity of transferrin excess iron
  is then taken up by the liver and other tissues
• Excessive iron deposition in the tissues can
  cause serious damage to organs, particularly the
  heart, liver and endocrine organs

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Pathogenesis

• In symptomatic people the total iron body content
  is 20-40g compared with 3-4g in a normal person.
  
• Particularly increased in the liver and pancreas
  (50-100x normal)
• In established disease the liver shows extensive
  iron deposition and fibrosis. Early in the
  disease, the iron is deposited in the periportal
  hepatocytes but later it is distributed widely
  throughout all zones. Cirrhosis is a late
  feature.

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Clinical Features

• Depends on a number of factors including sex,
  diet, presence of associated hepatotoxins
  (especially alcohol) and genotype
• Overt clinical manifestations occur more
  frequently in men
• Most affected individuals present in the 5th
  decade
• Symptoms include weakness/fatigue, arthritis,
  palpitations, abdo pain and those of diabetes
• Classical triad bronze skin pigmentation (due to
  excess melanin deposition), hepatomegaly and
  diabetes mellitus

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Clinical Features

• Hypogonadism secondary to pituitary dysfunction
  is the most common endocrine feature
• Cardiac manifestations, particularly heart
  failure and arrythmias are common, particularly
  in young patients
• Calcium pyrophosphate is deposited asymmetrically
  in both large and small joints (chondrocalcinosis)
  ? arthopathy

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Complications

• 30 of people with cirrhosis will go on to
  develop HCC
• Diagnosis in the pre-cirrhotic stage ? normal
  life expectancy
• Diagnosis once cirrhosis has developed ?
  shortened life expectancy and a high risk of
  liver cancer, even when iron depletion has been
  achieved
• Various complications of other manifestations eg
  of diabetes

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Investigations

• Homozygotes
• Serum iron elevated
• TIBC reduced
• Complete or almost complete transferrin
  saturation - serum iron/ TIBC x 100. A value
  greater than 55 (men) or 50 (women) suggests
  iron accumulation
• Serum ferritin elevated (usually gt500µg/L)
• Liver biochemistry is often normal, even with
  established cirrhosis

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Investigations

• Heterozygotes
• May have normal biochemistry or may have
  modest increases in serum iron transferrin
  saturation or serum ferritin (usually gt400µg/L)
• Liver biopsy may define the extent of tissue
  damage, assess tissue iron and the hepatic iron
  concentration can be measured - gt180µmol/g dry
  weight of liver indicates liver haemochromatosis

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Investigations

• MRI shows dramatic reduction in the signal
  intensity of the liver and pancreas (paramagnetic
  effect of ferritin and haemosiderin). In
  secondary iron overload involving the
  reticuloendothelial cells (haemosiderosis) the
  pancreas is spared allows distinction between
  these two conditions. Can do quantitative MRI
  for liver iron.

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Treatment and Management

• Venesection
• prolongs life
• may reverse tissue damage
• may initially need weekly (250-500ml) then only
  3-4 per year to prevent re-accumulation of iron
• each 500 mL of blood taken removes 250 mg of
  iron (Hb). Synthesis of new Hb removes iron from
  the stores, which are then gradually depleted
• monitor serum iron, ferritin and MCV only fall
  when available iron is depleted

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Treatment and Management

• In the rare patient who cannot tolerate
  venesection (because of severe cardiac disease or
  anaemia) iron chelation therapy via
  desferrioxamine infusion has been successful in
  removing iron
• Manifestations usually improve or disappear,
  except for diabetes (insulin requirements may
  diminish), testicular atrophy and
  chondrocalcinosis

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Screening

• In all cases of hereditary haemochromatosis, all
  first-degree family members must be screened to
  detect early and asymptomatic disease
• Serum ferritin is an excellent test for this but
  genetic markers are also available.
• In the general population, the serum iron and
  transferrin are the best and cheapest tests
  available

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Genetic Screening

1. Confirmation of the diagnosis in cases of
   suspected iron overload. The genetic test will
   reduce costs and accelerate the diagnostic
   process so that effective treatment can be
   started earlier
2. Investigation of the families of patients with
   haemochromatosis if the proband is homozygous for
   HFE C282Y or is a compound heterozygote

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Level of Screening?

• Genetic screening at a population level cannot be
  justified at present because it is not yet
  possible to provide those at risk with a reliable
  estimate of the likelihood of developing clinical
  haemochromatosis
• If heterozygotes for both C282Y and H63D are
  included, about 2 of the population would need
  to be offered regular testing to detect iron
  overload as well as counselling and family
  studies.

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