Diagnostic Workup for Wilson's Disease
When to Suspect Wilson's Disease
Wilson's disease should be suspected in any patient aged 3-55 years presenting with unexplained liver abnormalities, neurologic symptoms, or psychiatric manifestations, though cases can occur from age 5 to the eighth decade. 1
Key clinical scenarios requiring evaluation:
- Pediatric patients with apparent autoimmune hepatitis - all children must be carefully evaluated for Wilson's disease before continuing immunosuppression 1, 2
- Adults with autoimmune hepatitis failing to respond rapidly to corticosteroid therapy 3, 1
- Acute liver failure with Coombs-negative hemolytic anemia - this distinctive pattern includes modest aminotransferase elevations (typically <2000 IU/L), markedly low or normal alkaline phosphatase (typically <40 IU/L), alkaline phosphatase to bilirubin ratio <2, coagulopathy unresponsive to vitamin K, and rapid progression to renal failure 4, 3, 2
Diagnostic Algorithm
No single test definitively confirms or excludes Wilson's disease; diagnosis requires multiple complementary tests. 1, 5
Essential Diagnostic Tests
1. Slit-lamp examination for Kayser-Fleischer rings 1
- Must be performed by an experienced ophthalmologist 1
- Present in 50-62% of hepatic presentations and nearly all neurologic cases 1
- Sensitivity 82.1%, specificity 100% 6
- Critical caveat: Absence does not exclude Wilson's disease, especially in hepatic presentations 4, 7
2. Serum ceruloplasmin 1
- Typically low (<20 mg/dL) in Wilson's disease 8
- Sensitivity 98.2%, specificity 92.3% 6
- Important pitfall: Can be falsely elevated by inflammation, pregnancy, estrogen supplementation, or oral contraceptives 3
- Immunologic assays may overestimate levels 3
- 18% of non-fulminant Wilson's disease patients have normal ceruloplasmin 7
3. 24-hour urinary copper excretion 1
- Greatly elevated in Wilson's disease (typically >100 μg/24h) 4
- In acute liver failure: 844-9375 μg/24h 7
- Sensitivity 100%, specificity 63% 6
- Best used as screening test in combination with ceruloplasmin 6
4. Hepatic copper quantification via liver biopsy 1
- Diagnostic if >250 μg/g dry weight 3, 1, 8
- Normal values (<40-50 μg/g) essentially exclude Wilson's disease 1
- Found elevated in all patients except those who had undergone prolonged penicillamine treatment 7
5. ATP7B mutation analysis 1
- Detects mutations in 84.4% of alleles 1
- Should be performed when diagnosis remains uncertain after clinical and biochemical testing 4, 1
- Most reliable approach for asymptomatic siblings of index patients 5
Additional Diagnostic Studies
6. Serum copper and non-ceruloplasmin copper 4
- In acute liver failure: serum copper typically >200 μg/dL (>31.5 μmol/L) 4, 2
- Non-ceruloplasmin copper in acute liver failure: 325-1743 μg/L 7
7. Brain MRI 1
- Shows basal ganglia abnormalities in 77.7% of patients, even before symptom onset 1
- Increased density on CT and hyperintensity on T2 MRI in basal ganglia region 4
- Should be performed prior to treatment in all patients with neurologic symptoms 4
8. Neurologic evaluation 4
- Required for all patients with Wilson's disease 4
- Consultation with neurologist or movement disorder specialist for patients with evident neurologic symptoms 4
Leipzig Scoring System
The Leipzig score combines clinical signs and laboratory features to overcome diagnostic challenges. 5
Features scored 0 (absent) to 2 (present):
- Kayser-Fleischer rings
- Neurologic symptoms
- Serum ceruloplasmin
- Copper in serum, urine, and liver
- Genetic testing results
If score ≥4, diagnosis of Wilson's disease is very likely. 5
Special Diagnostic Considerations
Acute Liver Failure Pattern
The characteristic pattern includes 4, 2:
- Coombs-negative hemolytic anemia with acute intravascular hemolysis
- Modest aminotransferase elevations (typically <2000 IU/L)
- Markedly subnormal alkaline phosphatase (typically <40 IU/L)
- Female:male ratio 2:1
- Rapid progression to renal failure
- Serum copper typically >200 μg/dL
- Greatly elevated 24-hour urinary copper
Critical pitfall: The relatively modest aminotransferase elevations often lead to underestimation of disease severity 4
Diagnostic Challenges
- Wilson's disease can present at any age - five patients in one series were over 40 years old 7
- Diagnosis may be delayed up to 9 years from symptom onset 7
- In non-fulminant disease, 18% have neither Kayser-Fleischer rings nor low ceruloplasmin 7
Family Screening Protocol
All first-degree relatives of Wilson's disease patients must be screened, as presymptomatic treatment prevents disease progression. 1
Screening should include 3:
- History and physical examination
- Serum ceruloplasmin and copper
- Liver function tests
- Slit-lamp examination for Kayser-Fleischer rings
- ATP7B haplotype analysis or mutation testing
Treatment should be initiated for all individuals >3 years old identified through family screening. 3