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

Diagnostic Criteria and Treatment Options for Wilson Disease

Wilson disease requires prompt diagnosis and lifelong treatment to prevent mortality and morbidity from copper accumulation in vital organs, particularly the liver and brain. 1

Diagnostic Criteria

Clinical Presentations

• Hepatic manifestations: Ranges from asymptomatic liver enzyme elevations to chronic hepatitis, cirrhosis, or fulminant hepatic failure
• Neurological manifestations: Dystonia, tremor, dysarthria, ataxia
• Psychiatric manifestations: Personality changes, cognitive impairments
• Other presentations: Hemolytic anemia, renal involvement, musculoskeletal issues 2

Key Diagnostic Tests

1. Serum ceruloplasmin: Typically <20 mg/dL or <0.2 g/L (decreased in 98.3% of patients) 2
2. 24-hour urinary copper excretion: >100 μg/24h (>1.6 μmol/24h) diagnostic; elevated in 73% of patients 3, 2
3. Slit-lamp examination: Kayser-Fleischer rings present in 78.3% of patients (virtually all with neurological manifestations, but may be absent in up to 50% of hepatic cases) 3, 2
4. Liver biopsy with copper quantification: >250 μg/g dry weight (>4 μmol/g) is diagnostic 3
5. Non-ceruloplasmin bound copper: >250 μg/L is diagnostic 3
6. Genetic testing: ATP7B gene mutation analysis (identifies disease alleles in up to 92% of cases) 4

Special Diagnostic Scenarios

• Fulminant hepatic failure: Look for:

  • Coombs-negative hemolytic anemia
  • Modest elevations in serum aminotransferases (typically 2,000 IU/L)
  • Low serum alkaline phosphatase (typically 40 IU/L)
  • Alkaline phosphatase to bilirubin ratio <2
  • Rapid progression to renal failure
  • Female:male ratio of 2:1 1

• Neurological presentation: Brain MRI showing hyperintensity on T2 in basal ganglia, "face of the giant panda" sign, and hyperintensities in tectal-plate and central pons 3

Treatment Options

Initial Treatment for Symptomatic Patients

1. D-Penicillamine:

   • First-line therapy in 93.6% of patients 2
   • Initial dose: 250-500 mg/day, gradually increased to 1000-1500 mg/day in 2-4 divided doses
   • Side effects occur in approximately 21.1% of patients, including hypersensitivity reactions, nephrotoxicity, bone marrow suppression 5, 2

2. Trientine:

   • Alternative for patients intolerant to D-penicillamine
   • Fewer side effects than D-penicillamine
   • Typical dose: 750-1500 mg/day in 2-3 divided doses 1, 5

3. Zinc Acetate/Sulfate:

   • Mechanism: Blocks intestinal absorption of copper
   • Dosage: 50 mg three times daily (elemental zinc)
   • Better tolerated but may be less effective for initial treatment of symptomatic disease 6

Maintenance Treatment

• Zinc therapy: 50 mg three times daily or 25 mg three times daily
• Reduced doses of chelators: D-penicillamine (750-1000 mg/day) or trientine 1, 6

Treatment Monitoring

• Free serum copper (non-ceruloplasmin bound copper): Target <10 μg/dL
• 24-hour urinary copper excretion
• Liver function tests: Every 3 months during first year, then every 6 months
• Complete blood count: Regular monitoring for chelator toxicity 3, 5

Special Situations

• Pregnancy:

  • For Wilson disease patients, continue treatment throughout pregnancy
  • Limit D-penicillamine to 750 mg/day during pregnancy
  • Reduce to 250 mg/day for last 6 weeks before cesarean section 5
  • Zinc therapy appears safe during pregnancy 6

• Fulminant hepatic failure:

  • Urgent liver transplantation is required for survival 1

Family Screening

• All first-degree relatives must be screened with:
  • History and physical examination
  • Serum copper and ceruloplasmin
  • Liver function tests
  • Slit-lamp examination for Kayser-Fleischer rings
  • 24-hour urinary copper
  • Genetic testing if mutations are known in the index case 1, 3

Common Pitfalls and Caveats

1. Delayed diagnosis: Average age at diagnosis is 17.4 years, with delays up to 9 years reported 2, 7
2. Misdiagnosis as autoimmune hepatitis: All children with apparent autoimmune hepatitis and adults with atypical or steroid-resistant disease should be evaluated for Wilson disease 1
3. Absence of Kayser-Fleischer rings: Does not exclude the diagnosis, especially in hepatic presentations 3, 7
4. Normal ceruloplasmin: Up to 18% of non-fulminant cases may have normal ceruloplasmin and no Kayser-Fleischer rings 7
5. Neurological worsening: May occur during initial chelation therapy but is not a reason to discontinue treatment 5
6. Treatment compliance: Interruption of therapy even for a few days can lead to sensitivity reactions upon restarting treatment 5

Wilson disease is a treatable disorder if diagnosed early, but requires lifelong therapy and monitoring to prevent progressive organ damage and death.