What are the diagnostic criteria and treatment options for Wilson disease?

Wilson Disease Diagnosis and Treatment

Wilson disease should be considered in any individual with liver abnormalities or neurological movement disorders of uncertain cause, particularly in patients between 5-40 years of age, and diagnosis requires a combination of clinical findings and biochemical testing. 1

Diagnostic Criteria

Clinical Presentations

Wilson disease can present with various clinical manifestations:

• Hepatic manifestations: Range from asymptomatic with only biochemical abnormalities to acute liver failure

  • Chronic liver disease and cirrhosis
  • Acute hepatitis-like presentation
  • Fulminant hepatic failure with characteristic findings:
    • Coombs-negative hemolytic anemia
    • Coagulopathy unresponsive to vitamin K
    • Rapid progression to renal failure
    • Modest rises in serum aminotransferases (typically <2000 IU/L)
    • Low serum alkaline phosphatase (typically <40 IU/L)
    • Female:male ratio of 2:1 1

• Neurological manifestations: Usually present later than liver disease, often in the third decade of life

  • Tremors and dysarthria
  • Dystonia and muscle spasms
  • Psychiatric disturbances 1

• Ophthalmologic findings: Kayser-Fleischer rings in the cornea (may be absent in up to 50% of patients with only hepatic presentation) 1, 2

Diagnostic Algorithm

1. Initial biochemical testing:

   • Serum ceruloplasmin (sensitivity 82%) - levels <20 mg/dL (0.2 g/L) are suggestive 1, 2
   • 24-hour urinary copper excretion (sensitivity 100%) - levels >40 μg/day (0.6 μmol/day) 1, 2
   • Serum copper levels - often decreased but may be elevated in acute liver failure

2. Ophthalmologic examination:

   • Slit-lamp examination for Kayser-Fleischer rings (sensitivity 63% overall, 100% in patients with neurological manifestations) 2

3. Liver assessment:

   • Liver biopsy with hepatic copper quantification (>250 μg/g dry weight is diagnostic) 1
   • Orcein staining of liver tissue (sensitivity 88%) 2

4. Neurological evaluation:

   • MRI of the brain for patients with neurological symptoms (may show structural abnormalities in basal ganglia) 1

5. Genetic testing:

   • ATP7B gene mutation analysis when diagnosis is difficult to establish by clinical and biochemical testing
   • Particularly useful for family screening of first-degree relatives 1

Treatment Options

Once diagnosed, treatment for Wilson disease is lifelong and includes:

1. Chelation therapy:

   • D-penicillamine: First-line treatment for symptomatic patients

     • Dosage: 750-1500 mg/day in 2-3 divided doses (20 mg/kg/day for children)
     • Take 1 hour before meals (food inhibits absorption)
     • Requires pyridoxine supplementation (25-50 mg/day)
     • Monitor 24-hour urinary copper excretion 3

   • Trientine: Alternative for patients who cannot tolerate D-penicillamine

     • Similar mechanism of promoting urinary copper excretion 1

2. Zinc therapy:

   • Acts by inducing intestinal metallothionein, which binds copper and prevents absorption
   • Dosage: 50 mg three times daily is standard regimen
   • Alternative: 25 mg three times daily may also be adequate
   • Take on empty stomach, at least 1 hour before meals 4
   • Particularly useful for presymptomatic patients or maintenance therapy after initial chelation 1

3. Dietary modifications:

   • Low copper diet (avoid chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals)
   • Use distilled or demineralized water if drinking water contains >0.1 mg/L of copper 3

4. Liver transplantation:

   • Reserved for patients with acute liver failure or decompensated cirrhosis not responding to medical therapy 1

Special Considerations

• Pregnancy: For women with Wilson disease who become pregnant, treatment must continue

  • D-penicillamine: Limit to 750 mg/day during pregnancy; reduce to 250 mg/day for last 6 weeks if cesarean section is planned 3
  • Zinc therapy has been used successfully during pregnancy 4

• Monitoring treatment:

  • Clinical improvement may take 1-3 months
  • Neurological symptoms may temporarily worsen during initial therapy
  • Regular monitoring of liver function, urinary copper excretion, and neurological status is essential 1

• Family screening:

  • First-degree relatives have a 25% chance of being affected
  • Screening should include biochemical testing and/or genetic analysis 1

Common Pitfalls

1. Delayed diagnosis due to non-specific symptoms or misdiagnosis as other liver diseases (autoimmune hepatitis, NAFLD)

2. Absence of Kayser-Fleischer rings does not exclude Wilson disease, especially in patients with only hepatic manifestations

3. Normal ceruloplasmin levels can occur in approximately 18% of non-fulminant cases 5

4. Age misconceptions - Wilson disease can present at any age, with cases reported in patients over 40 years 5

5. Interruption of treatment can lead to sensitivity reactions upon resumption of therapy and clinical deterioration 3