Wilson's disease

From Ganfyd

Consider whenever[1]: Liver abnormalities of uncertain cause New onset movement disorders

Wilson's disease^[2] (Progressive hepatolenticular degeneration, Wilson disease) is an autosomal recessive condition with copper accumulation due to impairment of biliary excretion.

Aetiology

• Mutations of the ATP7B gene that codes for a copper transporting P-type ATPase. It has dual synthetic and excretory roles.

Clinical Presentation

• Many by familial clinical screening after index case
• Index cases usually present in late teens but can be in their 50's and rarely in younger children. Neurological presentation tends to be older (by 5 years) than hepatic presentation^[3]
• Hepatic disease (about ²/₃rds presenting first clinically)
  • Cirrhosis
  • Elevated aminotransferases
  • Chronic hepatitis
  • Fulminant hepatic failure (+/− Coombs negative haemolytic anaemia), about 5% of presentations
• Movement disorders (in about 40% presenting first clinically)
  • Tremor
  • Chorea
  • Parkinsonism
  • Gait disturbances
  • Dysarthria
• Psychiatric symptoms
  • Depression
  • Neuroses
  • Personality changes
  • Psychosis

It can also cause:

• Epilepsy
• Migraine
• Pseudobulbar palsy
• Insomnia
• Sunflower cataracts
• Aminoaciduria
• Renal stones
• Osteomalacia with spontaneous fractures

Diagnosis

Can be tricky given multisystem disorder and limited sensitivity/specificity of tests. Heterozygotes may also have borderline results.

• In classic presentation in young adult life two of the following are diagnostic
  • Kayser-Fleischer rings
  • Extrapyramidal symptoms and personality changes
  • Low serum caeruloplasmin levels (<0.2g/L)
• May require extensive tests of copper metabolism especially with severe hepatic presentation, where up to 50% can have normal caeruloplasmin (an acute phase reactant) eg
  • Non-caeruloplasmin-bound serum copper
  • 24-h urinary copper excretion - can be abnormal in other chronic liver diseases, however. Excretion of >25micromol/24hr after penicillamine is a diagnostic test in children
  • Liver copper content (>250mcg/g dry weight) - best test when others ambiguous
• In fulminant hepatic failure the following features may suggest diagnosis:^[4]
  • Haemolysis (Coombs negative)
  • Increased urinary copper (range 844-9375 microg/24 h)
  • High non-caeruloplasmin copper (range 325-1743 microg/l)
  • Alkaline phosphatase to Bilirubin ratio of less than 1 has 86% sensitivity and 50% specificity in children ^[5]
• Genetic screening of limited utility due to number of known mutations (more than 300)
• Opalski cells (?degenerating astrocytes) on brain biopsy are distinctive for Wilson's disease^[6]
  • Fairly large (up to 35 μm in diameter), with fine granular cytoplasm and slightly abnormal nuclei

Treatment

• Diet - chocolate, liver, nuts, mushrooms, and shellfish are high in copper
• Zinc - reduces copper absorption from gut. Monotherapy is an option for maintenance therapy.
• Chelation
  • D-penicillamine - but note side effects, and some patients with neurological disease deteriorate on starting treatment
  • Trientine - perhaps less side effects
• Liver transplantation - curative, except for long-standing neurological disease. Indicated for fulminant hepatic failure.

Monitoring

• Neurological function
• Liver function tests
• 24hr urinary copper excretion (aim for less than 2 micromol/d)
• Non-caeruloplasmin bound copper of 50-150mcg/L

References