RBC Copper as a Diagnostic Tool in Wilson's Disease
RBC copper measurement is not recommended as a diagnostic tool for Wilson's disease, as it is not included in any established diagnostic guidelines or scoring systems and lacks validation in the literature. 1, 2, 3
Why RBC Copper Is Not Used
The established diagnostic approach for Wilson's disease relies on a combination of validated tests, none of which include RBC copper measurement. 1, 3 The European Association for the Study of the Liver emphasizes that no single test is sufficient for diagnosis, and the Leipzig scoring system—the most validated diagnostic approach—does not incorporate RBC copper. 3, 4
Recommended Diagnostic Tests Instead
The following tests are evidence-based and should be used for Wilson's disease diagnosis:
Serum Ceruloplasmin
- Extremely low levels (<0.1 g/L or <5 mg/dL) strongly suggest Wilson's disease, contributing 2 points in the Leipzig scoring system. 1, 2, 3
- Sensitivity ranges from 65-99% and specificity from 96.6-100% at the 0.1 g/L cutoff. 5
- Critical caveat: 15-36% of children with Wilson's disease have normal ceruloplasmin levels, particularly those with hepatic manifestations. 1, 2, 3
24-Hour Urinary Copper Excretion
- Baseline excretion >1.6 μmol/24 hours (>100 μg/24 hours) is diagnostic in symptomatic patients. 1, 3
- Sensitivity of 50-100% with specificity of 63-98.3% depending on cutoff used. 5, 4
- Important limitation: 16-23% of patients with Wilson's disease present with levels <100 μg/24 hours, especially children and asymptomatic siblings. 1
Non-Ceruloplasmin-Bound (Free) Copper
- Calculated as: total serum copper (μg/L) minus [3.15 × ceruloplasmin (mg/L)]. 1
- Typically elevated above 200 μg/L (or 25 μg/dL) in untreated Wilson's disease patients. 1, 3, 6
- More valuable for monitoring treatment than initial diagnosis, as it depends on accurate measurement of both serum copper and ceruloplasmin. 1
Hepatic Copper Content
- Liver biopsy showing copper >4 μmol/g dry weight provides critical diagnostic information. 3
- Sensitivity of 65.7-94.4% with specificity of 52.2-98.6%. 4
Kayser-Fleischer Rings
- Detected by slit-lamp examination. 3, 5
- Sensitivity of 82.1% with 100% specificity. 5
- Absent in 12 of 55 Wilson's disease patients in one series who also had normal ceruloplasmin. 1
The Leipzig Scoring System Approach
A score of ≥4 establishes the diagnosis; 3 indicates possible diagnosis requiring more tests; ≤2 makes diagnosis very unlikely. 2, 3
Points are assigned as follows:
- Kayser-Fleischer rings present: 2 points 3
- Neurological symptoms (severe/mild): 2/1 points 3
- Serum ceruloplasmin <0.1 g/L: 2 points; 0.1-0.2 g/L: 1 point 3
- Coombs-negative hemolytic anemia: 1 point 3
- Hepatic copper >5× ULN: 2 points; 0.8-4 μmol/g: 1 point 3
- Urinary copper >2× ULN: 2 points; 1-2× ULN: 1 point 3
- ATP7B mutation on both chromosomes: 4 points; one chromosome: 1 point 3
Common Pitfalls to Avoid
- Never rely on ceruloplasmin alone—it can be falsely elevated by inflammation, pregnancy, or estrogen therapy. 3
- Total serum copper is usually decreased in Wilson's disease, not elevated (except in acute liver failure when copper is suddenly released from tissue stores). 1, 6
- Non-ceruloplasmin-bound copper can be elevated in acute liver failure of any etiology, chronic cholestasis, and copper intoxication—not specific to Wilson's disease. 1, 3, 6
- Approximately 20% of heterozygotes may have decreased ceruloplasmin levels, creating diagnostic confusion. 3