What are the steps for a Wilson disease workup and initial treatment?

Wilson Disease Workup and Initial Treatment

A comprehensive Wilson disease workup requires serum ceruloplasmin, 24-hour urinary copper excretion, slit-lamp examination for Kayser-Fleischer rings, liver function tests, and liver biopsy in cases with unclear diagnosis, followed by initial treatment with a chelating agent such as D-penicillamine or trientine for symptomatic patients. 1

Diagnostic Workup Algorithm

Step 1: Initial Laboratory Tests

• Complete blood count with platelet count
• Liver biochemistries (AST, ALT, alkaline phosphatase, bilirubin)
• International normalized ratio (INR)
• Serum ceruloplasmin (typically decreased, <20 mg/dL)
• Serum copper (may be elevated, typically ≥200 μg/dL in acute cases)
• 24-hour urinary copper excretion (elevated, >40 μg/day)

Step 2: Ophthalmologic Examination

• Slit-lamp examination for Kayser-Fleischer rings
  • Present in nearly all patients with neurological symptoms
  • May be absent in up to 50% of patients with only hepatic manifestations

Step 3: Additional Testing Based on Initial Results

• If diagnosis remains unclear:
  • Liver biopsy for hepatic copper quantification (>250 μg/g dry weight is diagnostic)
  • Genetic testing for ATP7B mutations (particularly useful for family screening)

Step 4: Specific Clinical Scenarios

• For patients with acute liver failure: Look for characteristic findings 1:

  • Coombs-negative hemolytic anemia
  • Modest elevations in serum aminotransferases (typically <2000 IU/L)
  • Low serum alkaline phosphatase (typically ≤40 IU/L)
  • Alkaline phosphatase to bilirubin ratio <2
  • Female:male ratio of 2:1

• For patients with neuropsychiatric symptoms:

  • Brain MRI (may show abnormalities in basal ganglia)
  • Neurological examination for tremor, dysarthria, dystonia

Initial Treatment Approach

For Symptomatic Patients:

1. Initial Chelation Therapy:

   • D-penicillamine: Starting dose of 250-500 mg/day, gradually increased to 1000-1500 mg/day in 2-4 divided doses
   • Take on empty stomach (food reduces absorption by 50%)
   • Add pyridoxine (vitamin B6) 25 mg daily to prevent deficiency

2. Alternative Initial Therapy (if D-penicillamine not tolerated):

   • Trientine: 750-1500 mg/day in 2-3 divided doses

3. Monitoring During Initial Phase:

   • Complete blood count and urinalysis every 1-2 weeks initially
   • Liver function tests monthly
   • 24-hour urinary copper excretion (target: 200-500 μg/day on chelation therapy)

For Asymptomatic Patients:

• Can start with maintenance doses of chelating agents or zinc therapy
• Zinc acetate: 50 mg elemental zinc three times daily

Family Screening:

• First-degree relatives must be screened for Wilson disease 1
• Assessment should include:
  • History and physical examination
  • Liver function tests
  • Serum ceruloplasmin
  • 24-hour urinary copper excretion
  • Slit-lamp examination for Kayser-Fleischer rings
  • Genetic testing if mutations identified in proband

Treatment Monitoring

• Monitor patients at least twice yearly, more frequently during initial treatment phase
• Laboratory testing should include:
  • Liver biochemistries
  • Complete blood count with differential
  • Urinalysis
  • Serum copper and ceruloplasmin
  • 24-hour urinary copper excretion
  • For patients on zinc: serum zinc or 24-hour urinary zinc excretion

Important Caveats

1. Diagnostic challenges: No single test is sufficient for diagnosis; a combination of tests is required 1

2. Neurological worsening: Some patients may experience temporary worsening of neurological symptoms when starting chelation therapy; this is not a reason to discontinue treatment 2

3. Treatment compliance: Poor compliance is a major problem, especially in adolescents and patients with psychiatric disorders, and can lead to disease progression 3

4. Liver transplantation: Reserved for patients with acute liver failure due to Wilson disease who meet specific criteria 1

5. Genetic testing limitations: Genetic testing alone may not be sufficient for diagnosis in asymptomatic patients, as even those carrying two disease-causing mutations may not show alterations in copper metabolism 4