What laboratory tests are used to diagnose Wilson disease?

Laboratory Tests for Wilson Disease Diagnosis

The diagnosis of Wilson disease requires a combination of laboratory tests including serum ceruloplasmin, 24-hour urinary copper excretion, serum copper levels, and hepatic copper quantification, as no single test is sufficient for definitive diagnosis. 1

Primary Diagnostic Tests

Serum Ceruloplasmin

• Low levels (<0.1 g/L or <10 mg/dL) strongly suggest Wilson disease 1
• Sensitivity: 98.2%, Specificity: 92.3% 2
• Limitations:
  • May be normal in 15-36% of children with Wilson disease 1
  • Can be falsely low in:
    • Malabsorption syndromes
    • Aceruloplasminemia
    • Heterozygous carriers
    • Severe hepatic insufficiency 1
  • May be falsely normal/elevated during:
    • Acute inflammation (acute phase reactant)
    • Pregnancy
    • Estrogen therapy 1

24-Hour Urinary Copper Excretion

• Values >1.6 μmol/24h (>100 μg/24h) typically diagnostic in symptomatic patients 1
• Sensitivity: 100%, Specificity: 63% 2
• Considerations:
  • Lower threshold of >0.64 μmol/24h (>40 μg/24h) may be useful for detecting asymptomatic patients 1
  • 16-23% of patients may have values <1.6 μmol/24h at presentation 1
  • Ensure proper collection technique to avoid contamination 1
  • May be elevated in other liver diseases (autoimmune hepatitis, cholestasis) 1

Serum Copper

• Total serum copper is usually decreased proportional to decreased ceruloplasmin 1
• Non-ceruloplasmin bound copper (free copper):
  • Calculated as: Total serum copper (μg/L) - [3.15 × ceruloplasmin (mg/L)]
  • Values >250 μg/L suggest Wilson disease 1
  • More valuable for monitoring treatment than initial diagnosis 1
  • May be elevated in acute liver failure from any cause 1

Hepatic Copper Content

• >4 μmol/g dry weight is diagnostic 1
• Normal levels (<0.64-0.8 μmol/g) almost always exclude Wilson disease 1
• Critical diagnostic information when diagnosis is not straightforward 1
• Regional variation in copper distribution may affect results 1

Additional Diagnostic Elements

Kayser-Fleischer Rings

• Present in cornea on slit-lamp examination
• Sensitivity: 82.1%, Specificity: 100% 2
• Absent in up to 50% of patients with hepatic Wilson disease 1
• Almost always present in patients with neurological manifestations 3

Genetic Testing

• Mutation analysis of ATP7B gene
• Most useful for screening first-degree relatives 1
• Challenging due to >600 different mutations 4

Diagnostic Algorithm

1. Initial screening:

   • Serum ceruloplasmin
   • 24-hour urinary copper
   • Slit-lamp examination for Kayser-Fleischer rings

2. If results are equivocal:

   • Calculate non-ceruloplasmin bound copper
   • Perform liver biopsy for hepatic copper quantification
   • Consider genetic testing

3. Apply Leipzig scoring system 1:

   • Score ≥4: Diagnosis established
   • Score 3: Diagnosis possible, more tests needed
   • Score ≤2: Diagnosis very unlikely

Special Considerations

• Acute liver failure presentation:

  • Serum copper may be markedly elevated due to sudden release from liver tissue 1
  • Look for Coombs-negative hemolysis
  • Low alkaline phosphatase and ratio of alkaline phosphatase to bilirubin <2 1

• Family screening:

  • First-degree relatives should undergo complete evaluation 1
  • Genetic testing is preferred if mutations are known in the index case 1

• Combined testing approach:

  • Using KF rings, serum ceruloplasmin, and 24-hour urinary copper together:
    • Sensitivity: 70.4%, Specificity: 100% 2

The diagnosis of Wilson disease remains challenging and requires careful interpretation of multiple test results in the clinical context, as no single test is sufficient for definitive diagnosis.