What are the symptoms and diagnostic criteria for Wilson's disease?

Wilson's Disease: Clinical Presentation and Diagnostic Approach

Clinical Manifestations

Wilson's disease presents with highly variable clinical features, most commonly affecting the liver (especially in younger patients), brain (neurological symptoms), or both, with age at diagnosis ranging from 5 to 58 years. 1, 2

Hepatic Presentations

The spectrum of liver disease is broad and includes: 1

• Asymptomatic hepatomegaly with incidentally discovered elevated aminotransferases 1
• Acute hepatitis-like illness that may be indistinguishable from viral hepatitis 1
• Autoimmune hepatitis mimicry with similar clinical and histological features 1
• Chronic liver disease with compensated or decompensated cirrhosis 1
• Isolated splenomegaly from clinically silent cirrhosis with portal hypertension 1
• Acute liver failure with Coombs-negative hemolytic anemia and acute renal failure (carries 95% mortality without emergency liver transplantation) 1, 3

Neurological Presentations

Neurological disease manifests as: 1

• Motor abnormalities including Parkinsonian features (dystonia, hypertonia, rigidity) 1
• Choreic or pseudosclerotic movements with tremors and dysarthria 1
• Disabling muscle spasms leading to contractures 1
• Dysarthria, dysphonia, and dysphagia 1
• Rarely, polyneuropathy or dysautonomia 1

Other Manifestations

• Hemolytic anemia (Coombs-negative) occurring as single acute episodes, recurrent episodes, or chronic low-grade hemolysis (presenting feature in 11% of cases) 1, 3
• Psychiatric disturbances 1
• Kayser-Fleischer rings (golden-brown corneal deposits visible on slit-lamp examination) 1, 4

Diagnostic Criteria and Algorithm

The diagnosis of Wilson's disease requires a combination of clinical findings and biochemical testing, with the Leipzig Scoring System (score ≥4) being the most validated diagnostic approach. 5

Leipzig Diagnostic Scoring System 5

The following parameters are scored:

1. Kayser-Fleischer rings: Present (2 points), Absent (0 points)
2. Neurological symptoms: Severe (2 points), Mild (1 point), Absent (0 points)
3. Serum ceruloplasmin: <0.1 g/L (2 points), 0.1-0.2 g/L (1 point), >0.2 g/L (0 points)
4. Coombs-negative hemolytic anemia: Present (1 point), Absent (0 points)
5. Hepatic copper content: >5× ULN or >4 μmol/g dry weight (2 points), 0.8-4 μmol/g (1 point), Normal (0 points)
6. 24-hour urinary copper: >2× ULN or >1.6 μmol/day (2 points), 1-2× ULN (1 point), Normal (0 points)
7. ATP7B mutation analysis: On both chromosomes (4 points), On one chromosome (1 point)

A score of 4 or more establishes the diagnosis of Wilson's disease. 5

Key Biochemical Tests

Low serum ceruloplasmin (<50 mg/dL or <0.2 g/L) is strong evidence for Wilson's disease, but normal levels do NOT exclude the diagnosis, as 15-36% of patients (especially those with hepatic manifestations) have normal ceruloplasmin. 1, 5

• 24-hour urinary copper excretion >1.6 μmol (>100 μg) per day is typical in symptomatic patients 5
• Non-ceruloplasmin bound copper (calculated as total serum copper minus ceruloplasmin-bound copper) is typically elevated above 200 μg/L in untreated patients 5
• Hepatic copper content >250 μg/g dry weight (or >4 μmol/g) provides critical diagnostic information and should be obtained when diagnosis is not straightforward 1, 5

Diagnostic Approach for Acute Liver Failure

In acute liver failure with suspected Wilson's disease, the combination of alkaline phosphatase (AP) to total bilirubin ratio <4 AND AST:ALT ratio >2.2 has been reported to have 100% sensitivity and specificity, though this has been challenged and should be used with other diagnostic parameters. 1

Additional features in acute liver failure include: 1, 3

• Evidence of Coombs-negative hemolytic anemia 3
• Markedly elevated urinary copper (844-9375 μg/24h) 2
• Very high non-ceruloplasmin copper (325-1743 μg/L) 2
• Serum copper typically ≥200 μg/dL (31.5 μmol/L) 3
• Kayser-Fleischer rings may be absent in 50% of acute liver failure cases 3

Genetic Testing

Comprehensive ATP7B gene sequencing should be performed when diagnosis is difficult to establish by clinical and biochemical testing. 1, 5

• Direct molecular diagnosis is challenging due to >500 possible mutations, with most patients being compound heterozygotes 1
• Population-specific mutations can be rapidly identified: H1069Q in Central Europe, R778L in Far East, -441/-427 deletion in Sardinia 1
• Identification of two mutations confirms the diagnosis 1, 5
• Genetic testing is essential for family screening of first-degree relatives (25% risk for siblings, 0.5% for offspring) 1

Neurological and Radiological Evaluation

MRI or CT imaging of the brain should be performed in all patients with neurological symptoms or as part of initial evaluation, typically showing hyperintensity on T2-weighted MRI in the basal ganglia. 1

• Significant brain imaging abnormalities may be present even before symptom onset 1
• Neurologic evaluation by a movement disorder specialist should be obtained for patients with evident neurological symptoms 1

Critical Diagnostic Pitfalls

Ceruloplasmin Interpretation Caveats 6, 5

• Ceruloplasmin is an acute phase reactant and can be elevated by inflammation, infection, malignancy, pregnancy, or estrogen therapy 6, 5
• Approximately 20% of heterozygous carriers may have decreased ceruloplasmin levels 6, 5
• Immunologic assays may overestimate ceruloplasmin by not distinguishing apoceruloplasmin from holoceruloplasmin 6

Other Important Considerations

• Non-ceruloplasmin bound copper may be elevated in acute liver failure of any etiology, chronic cholestasis, and copper intoxication 5
• Normal hepatic copper content (<40-50 μg/g dry weight) almost always excludes Wilson's disease in untreated patients 1
• All children with apparent autoimmune hepatitis should be screened for Wilson's disease 1
• Wilson's disease should be considered in any patient with unexplained liver disease between ages 5-40 years, though diagnosis has been made in patients up to 58 years old 1, 2
• Diagnosis can be delayed up to 9 years from symptom onset, emphasizing the need for high clinical suspicion 2