• Impaired copper excretion causes copper to accumulate in the body.
• Early-stage Wilson disease is characterized by the presence of copper deposits in the liver.
• As the disease progresses, copper accumulates in other organs as well, most importantly in the brain and cornea.

Epidemiology

Etiology

Pathophysiology

• Autosomal recessive mutations in the ATP7B gene (Wilson gene) on chromosome 13, which encodes for a membrane-bound, copper-transporting ATPase → defective ATP7B protein
  • Reduced incorporation of copper into apoceruloplasmin → ↓ serum ceruloplasmin (The major carrier of copper in the blood and an important enzyme with ferroxidase activity.)
  • Reduced biliary copper excretion
• Results in ↑ free serum copper → accumulation in the liver, cornea, CNS (basal ganglia, brain stem, cerebellum), kidneys, and enterocytes

Clinical features

• Neurological
  • Cerebellar symptoms, e.g.:
    • Dysarthria (most common)
  • Extrapyramidal symptoms, e.g.:
    • Dystonia
    • Parkinsonism
    • Tremor (usually asymmetric, affecting the hands), which may be any combination of:
      • Resting tremor
      • Intention tremor
      • Wing-beating tremor: a low frequency, high amplitude tremor that is most prominent when the arms are outstretched anteriorly or laterally
  • Drooling (caused by oropharyngeal dysphagia)
  • Cognitive impairment

Diagnostics

Treatment

General principles

• Encourage a low-copper diet (e.g., avoidance of organ meats, shellfish, nuts, chocolate, copper-containing dietary supplements).
• Refer patients with refractory decompensated cirrhosis or acute liver failure for liver transplantation.

Pharmacological therapy

• First line: chelating agents, e.g., penicillamine (preferred) or trientine
  • Chelating agents facilitate renal excretion of copper by forming water-soluble compounds.
  • Adverse effect: Membranous nephropathy
• Maintenance therapy: reduced-dose zinc salts or a chelating agent