What tests are used to diagnose Wilson disease?

Diagnostic Tests for Wilson Disease

The diagnosis of Wilson disease requires a combination of tests, as no single test is sufficient for diagnosis, with the Leipzig scoring system being the most validated diagnostic approach.

Key Diagnostic Tests

Initial Testing

• Serum ceruloplasmin is typically decreased in Wilson disease (usually <0.1 g/L), but this finding alone has significant limitations 1, 2
• Low ceruloplasmin (<50 mg/L or <5 mg/dL) should be considered strong evidence for Wilson disease, but modestly subnormal levels require further evaluation 1
• Normal ceruloplasmin does not exclude Wilson disease, as 15-36% of patients (especially those with hepatic manifestations) may have normal levels 1, 3

24-hour Urinary Copper Excretion

• Basal 24-hour urinary copper excretion >1.6 μmol (>100 μg) is typical in symptomatic patients 1
• In children, a lower threshold of >0.64 μmol/24h may be more appropriate 1
• False negatives can occur with incorrect collection or in children without liver disease 1
• False positives can occur with hepatocellular necrosis, cholestasis, or sample contamination 1

Serum Copper and Non-Ceruloplasmin Bound Copper

• Total serum copper is usually decreased proportionally to decreased ceruloplasmin 1
• Non-ceruloplasmin bound copper (calculated as total serum copper minus ceruloplasmin-bound copper) is typically elevated above 200 μg/L in untreated patients 1
• Calculation: Non-ceruloplasmin bound copper = total serum copper (μg/L) - (3.15 × ceruloplasmin in mg/L) 1

Hepatic Copper Content

• Hepatic copper content >4 μmol/g dry weight provides critical diagnostic information 1
• Normal hepatic copper content (<0.64-0.8 μmol/g dry weight) almost always excludes Wilson disease in untreated patients 1
• Liver biopsy with copper quantification is particularly important when the diagnosis is not straightforward 1

Kayser-Fleischer Rings

• Presence of Kayser-Fleischer rings by slit-lamp examination is highly suggestive of Wilson disease 1
• Absence of Kayser-Fleischer rings does not exclude the diagnosis, especially in patients with hepatic manifestations (absent in up to 50%) 1, 4
• Nearly all patients with neurological Wilson disease have Kayser-Fleischer rings 4

Genetic Testing

• Mutation analysis of the ATP7B gene can confirm the diagnosis 1
• Over 100 mutations have been identified, with His1069Gln being the most common 5
• Genetic testing is particularly useful for screening first-degree relatives 1

Leipzig Diagnostic Scoring System

• A score of 4 or more establishes the diagnosis 1, 2
• A score of 3 indicates possible diagnosis requiring more tests 1
• A score of 2 or less makes the diagnosis very unlikely 1

Scoring Components:

1. Kayser-Fleischer rings: Present (2 points), Absent (0 points) 1
2. Neurological symptoms: Severe (2 points), Mild (1 point), Absent (0 points) 1
3. Serum ceruloplasmin: <0.1 g/L (2 points), 0.1-0.2 g/L (1 point), >0.2 g/L (0 points) 1
4. Coombs-negative hemolytic anemia: Present (1 point), Absent (0 points) 1
5. Hepatic copper: >5× ULN (2 points), 0.8-4 μmol/g (1 point), Normal (0 points) 1
6. Urinary copper: >2× ULN (2 points), 1-2× ULN (1 point), Normal (0 points) 1
7. ATP7B mutation: On both chromosomes (4 points), On one chromosome (1 point) 1

Common Pitfalls and Caveats

• Relying solely on serum ceruloplasmin has a poor positive predictive value (only 5.9% in one study) 6
• Immunologic assays may overestimate ceruloplasmin by not distinguishing between apoceruloplasmin and holoceruloplasmin 1, 7
• Enzymatic ceruloplasmin oxidase activity measurement is superior to immunologic assays but is not widely available 8
• Ceruloplasmin can be elevated by acute inflammation, pregnancy, or estrogen therapy 1
• Approximately 20% of heterozygotes for Wilson disease may have decreased ceruloplasmin levels 1
• Non-ceruloplasmin bound copper may be elevated in acute liver failure of any etiology, chronic cholestasis, and copper intoxication 1