Evaluation of Suspected Wilson's Disease with Normal Ceruloplasmin
A normal serum ceruloplasmin level does not exclude Wilson's disease and requires proceeding with additional diagnostic testing including 24-hour urinary copper excretion, calculation of non-ceruloplasmin-bound (free) copper, slit-lamp examination for Kayser-Fleischer rings, and consideration of genetic testing. 1
Why Normal Ceruloplasmin Doesn't Rule Out Wilson's Disease
Normal ceruloplasmin occurs in a significant proportion of Wilson's disease patients, particularly those with hepatic presentations:
- Approximately 15-36% of children with Wilson's disease have ceruloplasmin in the normal range 1
- Up to 50% of patients with hepatic Wilson's disease may have low-normal ceruloplasmin levels 1
- In one series, 12 out of 55 Wilson's disease patients (22%) had normal ceruloplasmin and no Kayser-Fleischer rings 1
- Early studies showed 10 of 28 children with Wilson's disease had normal serum ceruloplasmin 1
The positive predictive value of low ceruloplasmin alone is poor (only 5.9-6%), meaning many patients with low ceruloplasmin don't have Wilson's disease, and conversely, normal levels don't exclude it. 1, 2
Essential Next Steps in Diagnostic Evaluation
1. Calculate Non-Ceruloplasmin-Bound (Free) Copper
- Use the formula: Free copper (μg/L) = Total serum copper (μg/L) - (3.15 × ceruloplasmin in mg/L) 3, 4
- Values >25 μg/dL (250 μg/L) strongly suggest Wilson's disease 1, 3, 4
- This is elevated in most untreated Wilson's disease patients even when total serum copper appears normal or low 1
2. Obtain 24-Hour Urinary Copper Excretion
- Values >100 μg/24 hours (>1.6 μmol/24 hours) indicate Wilson's disease 1, 3, 4
- Must ensure proper collection technique using copper-free containers 4
- This test remains abnormal regardless of ceruloplasmin level 1
3. Perform Slit-Lamp Examination
- Must be done by an experienced ophthalmologist to detect Kayser-Fleischer rings 1, 4
- Present in nearly all patients with neurologic symptoms 4
- Absent in up to 50% of patients with purely hepatic Wilson's disease 1
- Absence does not exclude the diagnosis 1
4. Consider Hepatic Copper Quantification
- Hepatic copper concentration >4 μmol/g dry weight (>250 μg/g) provides the best biochemical evidence for Wilson's disease 1, 3, 4
- Particularly valuable when other tests are equivocal 3
- Important caveat: In cirrhotic patients, hepatic copper distribution becomes inhomogeneous, making sampling unreliable due to regional variation 1, 3
5. Pursue Genetic Testing for ATP7B Mutations
- Recommended when other diagnostic tests are equivocal or inconclusive 3, 4
- Identification of two pathogenic mutations confirms the diagnosis 1
- Particularly useful in patients with atypical presentations 1
Use the Leipzig Scoring System
Apply the validated Leipzig scoring system to integrate all findings: 1
- Score ≥4: Diagnosis established - proceed with treatment
- Score 3: Diagnosis possible - obtain additional testing (genetic testing, liver biopsy)
- Score ≤2: Diagnosis very unlikely - consider alternative diagnoses
The scoring incorporates:
- Kayser-Fleischer rings (2 points if present)
- Neurologic symptoms (0-2 points based on severity)
- Ceruloplasmin level (0-2 points, with normal = 0 points)
- Coombs-negative hemolytic anemia (1 point if present)
- Urinary copper (1-2 points based on level)
- Hepatic copper (1-2 points based on level)
Critical Pitfalls to Avoid
Do not rely solely on ceruloplasmin for diagnosis or exclusion of Wilson's disease: 1
- Ceruloplasmin is an acute phase reactant and can be falsely elevated by inflammation, pregnancy, or estrogen supplementation 1
- Immunologic assays may overestimate ceruloplasmin by measuring both apo- and holoceruloplasmin 1
- Enzymatic assays measuring oxidase activity are superior but not widely available 5
Do not assume normal total serum copper excludes Wilson's disease: 1, 3
- Total serum copper is usually decreased in Wilson's disease despite copper overload 1, 3
- Only in acute fulminant hepatic failure will serum copper be markedly elevated due to sudden tissue release 1
Consider the patient's age in your diagnostic approach: 1
- Wilson's disease should be considered in any individual aged 3-55 years with unexplained liver abnormalities 1
- Testing outside this age range has very low yield 6
When to Initiate Treatment
If the Leipzig score is ≥4 or if multiple diagnostic tests strongly suggest Wilson's disease (elevated urinary copper, elevated free copper, positive genetic testing), initiate copper chelation therapy immediately with D-penicillamine or trientine to prevent irreversible organ damage. 4
- Start D-penicillamine at 250 mg/day orally, gradually increasing to 0.75-1.5 g/day in divided doses 4
- Take on empty stomach, at least 1 hour before or 2 hours after meals 4
- Monitor 24-hour urinary copper (target >2 mg in first week, then 3-8 μmol/24 hours on treatment) and free serum copper (target <10 μg/dL) 3, 4