Laboratory Tests for Diagnosis and Management of Wilson's Disease
The diagnosis of Wilson's 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
Initial Diagnostic Tests
Serum Ceruloplasmin
- Low levels (<0.1 g/L or <10 mg/dL) strongly suggest Wilson's disease 1
- Limitations:
24-Hour Urinary Copper Excretion
- Values >1.6 μmol/24h (>100 μg/24h) typically diagnostic in symptomatic patients 1
- Recent studies suggest 40 μg/24h (0.6 μmol/24h) as a better diagnostic threshold 3
- Collection must be done in copper-free glassware to avoid contamination 4
- Most valuable during the first week of therapy for monitoring treatment response 4
Serum Copper
- Total serum copper is usually decreased proportional to decreased ceruloplasmin
- Non-ceruloplasmin bound copper (free copper) >250 μg/L suggests Wilson's disease 1
- Calculation: Non-ceruloplasmin bound copper = serum copper (μg/dL) - 3 × ceruloplasmin (mg/dL) 3
- More valuable for monitoring treatment than initial diagnosis 1
Hepatic Copper Quantification
4 μmol/g dry weight is diagnostic for Wilson's disease
- Normal levels (<0.64-0.8 μmol/g) almost always exclude Wilson's disease 1
- Gold standard when diagnosis is not straightforward
Additional Diagnostic Evaluations
Clinical Examination
- Slit-lamp examination for Kayser-Fleischer rings
- Present in cornea, but absent in up to 50% of patients with hepatic Wilson's disease
- Almost always present in patients with neurological manifestations 1
Genetic Testing
- Mutation analysis of ATP7B gene
- Most useful for screening first-degree relatives
- Challenging due to >600 different mutations identified 1
Diagnostic Algorithm
Initial screening:
- Serum ceruloplasmin
- 24-hour urinary copper
- Slit-lamp examination for Kayser-Fleischer rings
- Liver function tests
If results are equivocal:
- Calculate non-ceruloplasmin bound copper
- Perform liver biopsy for hepatic copper quantification
- Consider genetic testing
Apply Leipzig scoring system:
- Score ≥4: Diagnosis established
- Score 3: Possible diagnosis, requires further evaluation
- Score ≤2: Diagnosis unlikely 1
Monitoring During Treatment
- 24-hour urinary copper excretion is the most valuable test for monitoring treatment response initially 4
- Free serum copper (non-ceruloplasmin bound copper) is the most reliable method for monitoring maintenance treatment 4
- Adequately treated patients typically have <10 μg/dL of free copper in serum 4
- Non-ceruloplasmin bound copper <5 μg/dL (50 μg/L) may signal systemic copper depletion from prolonged treatment 3
Special Considerations
Acute Liver Failure Presentation
- Markedly elevated serum copper (usually 200 μg/dL or 31.5 μmol/L)
- Coombs-negative hemolysis
- Low alkaline phosphatase
- Ratio of alkaline phosphatase to bilirubin <2
- Modest elevations in serum aminotransferases compared to other causes of acute liver failure 3
Family Screening
- All first-degree relatives of newly diagnosed patients must be screened
- Assessment should include:
Pitfalls and Caveats
- No single test is sufficient for diagnosis - a combination approach is necessary
- Serum ceruloplasmin alone has poor positive predictive value (5.9%) 2
- Urinary copper excretion may overlap with other liver diseases, particularly autoimmune hepatitis 3
- Genetic testing is complicated by the large number of possible mutations
- Kayser-Fleischer rings may be absent in up to 50% of hepatic cases 3
- In some patients, neither Kayser-Fleischer rings nor low ceruloplasmin may be present (18% of non-fulminant cases) 5
By following this comprehensive diagnostic approach and monitoring protocol, clinicians can effectively diagnose Wilson's disease and manage treatment to prevent the serious complications of copper accumulation.