Wilson disease

Wilson disease (hepatolenticular degeneration) is an autosomal recessive metabolic disorder in which impaired copper excretion causes copper to accumulate in the body. In its initial stages, Wilson disease leads to copper deposits in the liver. As the disease progresses, copper also accumulates in other organs, most importantly in the brain and cornea. The disease often goes undiagnosed until the typical combination of hepatitis (or even cirrhosis), dementia, and parkinsonism raises clinical suspicion. Kayser-Fleischer rings, brownish copper deposits visible around the iris, are a further indication of Wilson disease. Low serum ceruloplasmin (copper transport protein) concentrations and increased urinary copper excretion confirm the diagnosis. Genetic testing or liver biopsies with quantitative copper assays can provide further information if the diagnosis is indeterminate. Primary management consists of maintaining a low-copper diet and administration of a chelating agent such as penicillamine. Patients with Wilson disease have a good prognosis if the condition is diagnosed and treated early.

• Age of onset: : 5–35 years ; (mean age 12–23 years) ^[1][2]
• Prevalence: ∼ 1/30,000 ^[3]

Epidemiological data refers to the US, unless otherwise specified.

• Autosomal recessive mutations in the ATP7B gene (Wilson gene) on chromosome 13, which encodes for a membrane-bound, copper-transporting ATPase → defective ATP7B protein ^[4]
  • Reduced incorporation of copper into apoceruloplasmin; → ↓ serum ceruloplasmin
  • Reduced biliary copper excretion
• Results in ↑ free serum copper → accumulation in the liver, cornea, CNS (basal ganglia, brain stem, cerebellum), kidneys, and enterocytes ^[5]

• Liver: different degrees of liver disease possible, including acute liver failure, acute or chronic hepatitis, and cirrhosis
  • Hepatosplenomegaly
  • Portal hypertension
  • Abdominal pain
  • Jaundice
  • Ascites
  • Hepatic encephalopathy
• Kayser-Fleischer rings
  • Copper accumulation in Descemet membrane of the cornea; that results in 1–2 mm wide, green-brown rings in the periphery of the iris
  • While the rings are characteristic for Wilson disease and occur in ∼ 98% of patients who also have neurological symptoms, their absence does not rule out the condition. ^[6]
• Neurological symptoms: extrapyramidal motor disturbances, but no sensory changes ^[7]
  • Dysarthria
  • Dystonia
  • Parkinsonism
  • Drooling
  • 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 with the arms outstretched anteriorly or laterally
  • Behavioral changes (e.g., depression, irritability, psychosis)
  • Cognitive impairment
• Renal: Fanconi syndrome

Wilson disease should be suspected in cases of nonspecific, noninfectious liver disease and nonspecific extrapyramidal movement disorders appearing before the age of 35.

• Slit lamp examination: Kayser-Fleischer rings (best initial test)
• Blood tests ^[2]
  • ↑ Transaminases
  • CBC: Coombs-negative hemolytic anemia, thrombocytopenia
  • ↓ Serum ceruloplasmin (normal value > 20 mg/dL)
  • ↑ Free serum copper, but ↓ total serum copper
• Urine tests: ↑ Urine copper excretion (over 24 hours)
• Liver biopsy: if other tests are inconclusive
  • Hepatic copper concentration (> 250 μg/g dry weight) ^[8]
  • Histology: copper staining
• Genetic testing: can be performed for confirmation; consider also testing family members ^[2]
• Cranial MRI
  • Hyperintensities in the putamen, thalamus, and brain stem due to copper accumulation
  • In some cases, a specific pattern of midbrain copper accumulation occurs, known as the “face of the giant panda” sign.

• Hepatic: autoimmune and viral hepatitis, cirrhosis, hemochromatosis
• Neuropsychologic: Parkinson disease, Huntington disease, multiple sclerosis, schizophrenia, personality disorders

The differential diagnoses listed here are not exhaustive.

General management

• Low-copper diet: avoid foods such as organ meats, shellfish, nuts, and chocolate
• Regular check-ups: liver biochemical tests every 6 months if disease is stable ^[9]
• Liver transplantation in cases of fulminant liver failure

Medical therapy ^[2][6]

• Initial therapy: chelating agents
  • Penicillamine ^[10]
    • Other indications: cystinuria, rheumatoid arthritis
    • Adverse effects
      • Allergic: rash, pruritus, pemphigus, exfoliative dermatitis
      • Gastrointestinal: anorexia, diarrhea, loss of taste, hepatic failure)
      • Hematological: bone marrow suppression, agranulocytosis, thrombocytopenia
      • Renal: proteinuria, immune complex membranous glomerulopathy, Goodpasture syndrome
      • Neuropsychiatric: tinnitus, peripheral sensory and motor neuropathies, agitation, anxiety, behavioral changes
      • Neuromuscular: myasthenia gravis, dystonia
      • Other: vasculitis, polymyositis, dermatomyositis
  • Alternatives: trientine; or zinc salts
• Maintenance therapy: zinc salts or low dose chelating agents

Treatment with a chelating agent should be titrated gradually, as mobilizing the copper stored in tissues too rapidly may exacerbate neurological symptoms.