Wilson’s Disease

Background

• Rare autosomal recessive disorder of copper metabolism (worldwide prevalence of 1:30,000
  • Most caused by mutations of the ATP7B gene (ch13)
    • Encodes a protein involved in copper-transport (P-type ATP family)- primarily exporting copper out of cells
• Normally, dietary copper is absorbed from the stomach/duodenum and rapidly taken up by the liver where it is stored and added into caeruloplasmin, before being secreted into the blood.  Excess copper is usually excreted in bile.
  • In Wilson’s disease, most patients fail to synthesise caeruloplasmin, although this is not always the case.

Presentation

• Usually presents between 5-45 years old
• Hepatic disease occurs early (childhood/adolescence)
  • Episodes of acute hepatitis which can progress to fulminant liver failure (copper is then released into the bloodstream causing haemolysis and renal tubular necrosis)
  • Alternatively, chronic hepatitis can develop insidiously and may present with cirrhosis/portal hypertension etc.
  • I.e. any patient <40 with acute/chronic hepatitis with no underlying cause should be investigated for Wilson’s
• Neurological damage causes basal ganglion syndromes and dementia (late adolescence)
  • Extrapyramidal symptoms e.g. tremor, chorea, dystonia, parkinsonism, dementia
  • First presentation may be of ‘clumsiness’
  • Can be prevented if treatment started before onset (i.e. identified early by liver investigation)
• Other features include renal tubular damage and osteoporosis (rarely presenting features)
• On Examination, the pathognomonic feature is Kayser-Fleischer rings
  • Seen in 60% of adults with Wilson’s (less common in children)
  • Greenish-brown discolourations of the corneal margin (often first in the superotemporal region)
  • Disappear with treatment

Investigations

• Serum caeruloplasmin (usually low but this is not specific for Wilson’s)
• Measure copper levels
  • Free serum copper
  • Urine copper excretions (often whilst given D-penicillamine- see management below)
  • Hepatic copper content (biopsy)

Management

• Penicillamine is a copper-binding agent which causes cupriuresis (urinary excretion of copper)
  • Initial dose is usually higher (e.g. 2g/day) until disease is in remission, then can be reduced but must be taken for life
  • Can be toxic in up to a third, causing rashes, protein-losing nephropathy, lupus-like syndrome and bone marrow depression
    • Zinc or trientine dihydrochloride are alternatives
• Liver transplant can be considered for patients with fulminant liver failure
• First degree relatives should be investigated and also treated, even if asymptomatic, to avoid complications