Wilson's Disease

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Wilson's Disease, also known as Hepatolenticular Degeneration, is an autosomal recessive rare inborn error of copper metabolism resulting in copper deposition in, and damage to, the liver, basal ganglia and cornea.

  • Potentially treatable, Wilson's Disease must be screened for in all children with liver disease.


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Incidence

  • Incidence = 1:30 000 - 1:100 000
    • Heterozygote carrier rate: 1:100
  • Age: variable age at presentation, including during infancy.
    • Liver disease: peak at 10-13 years
    • Neuropsychiatric disease: peak at 19-20 years
  • Sex: females:males 4:1
  • Geography: occurs worldwide. Increased risk in areas where consanguinuity is more common.


Aetiology

Dietary copper is absorbed in the stomach and small intestine. It travels to the liver loosely bound to albumin, where it is joined with caeruloplasmin (a liver synthesised glycoprotein) and secreted into the blood. Copper is normally removed by excretion into bile.


Wilson's Disease is caused by a mutation in the ATP7B gene on chromosome 13q. This gene encodes a copper-transporting ATPase.

  • over 60 mutations have been identified, although 50% of patients in europe and the USA have the His1070 Gly mutation.
  • autosomal recessive inheritance


The fundamental problem in Wilson's Disease is impaired biliary excretion of copper.

  • 80% of patients will have a low caeruloplasmin due to poor synthesis.
  • The mechanism for failure of copper excretion is not known.


Copper deposition in organ tissues results in damage (see below).


Clinical features

Presentation is variable and may be with liver disease (usually children) or primarily with neurological disorders (usually young adults) including tremor, dysarthria, involuntary movements and later dementia.

  • Liver disease: spectrum from acute hepatitis to fulminant hepatic failure or chronic hepatitis and cirrhosis.


Liver Histology

  • not diagnostic
  • Spectrum from chronic hepatitis to macronodular cirrhosis
  • Stains for copper: periportal distribution (unreliable)


Basal Ganglia: copper deposition damages the basal ganglia and may cause cavitation with associated movement disorders.

  • Parkinsonism: 45%
  • Tremor: 24% ("pseudosclerotic" - resemblance to multiple sclerosis)
  • Dystonia: 15%
  • Chorea: 11%
  • Psychiatric features: 10-20%
    • emotional lability, impulsiveness, disinhibition, self-injury.


Kidneys: tubular damage / degeneration occurs


Bones: osteopenia / erosions may be seen >50%


Eyes: Kaiser-Fleischer Rings may be seen within the cornea on slit-lamp examination. This is caused by copper deposition in Descemet's membrane in the cornea. It looks like a green-brown ring within the cornea close to the junction with the sclera. It may be absent in younger children.

  • K-F rings are pathognomic if accompanied by neurological features.
    • Present in 90% with symptomatic disease


Haemolytic anaemia: 10-15%


Morbidity and Mortality

Early diagnosis and treatment improves outlook.


Neurological damage is permanent.


Fulminant hepatic failure or decompensated cirrhosis requires liver transplantation.


Investigations

  • Serum copper and Serum caeruloplasmin: usually reduced but may be normal
    • NB: caeruloplasmin is an acute phase reactant and may rise following inflammation.
  • 24hr Urinary copper excretion: increased >100 micrograms (normally <40 mcg)
  • Liver biopsy: diagnosis depends on measurement of the amount of copper in the liver (may also be high in chronic cholestasis)
    • Radiolabelled Cu(64) allows direct assay of hepatic copper metabolism.
    • See above for histological features (non-diagnostic)
  • Haemolysis / anaemia may be present.
  • d-Penicillamine challenge test: a non-invasive test which aids diagnosis in children with active liver disease.
  • Genetic testing
  • Brain imaging, if indicated.


Management

Penicillamine is an effective copper chelator aiding urinary excretion.

  • Lifetime treatment with 1 - 1.5g daily is required.
  • Urine copper levels should be monitored and the dose reduced after 2-3 years.
  • Side effects occur in ~10%: rashes, leucopenia and renal damage.


Zinc - an important co-factor for many enzymes.


Diet

  • Avoid foods with a high copper content: liver, chocolate, nuts, mushrooms, legumes, and shellfish (especially lobster).
  • Water: atypical sources (eg, wells) should be analyzed for copper content and replaced with purified water if the copper content is greater than 0.2 parts per million.


Siblings / children should be screened.

  • treatment should be given even if asymptomatic on diagnosis if there is evidence of copper accumulation.



References


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