What are the diagnostic criteria and when to suspect Wilson disease?

Diagnosis of Wilson Disease

Wilson disease should be considered in any individual between the ages of 3 and 55 years with liver abnormalities of uncertain cause, and must be excluded in any patient with unexplained liver disease along with neurological or neuropsychiatric disorders. 1

When to Suspect Wilson Disease

Wilson disease should be suspected in the following clinical scenarios:

• Age: Typically between 3-55 years, though cases have been reported in patients as young as 3 and as old as 70s 1
• Liver manifestations:
  • Unexplained elevated liver enzymes
  • Chronic hepatitis or cirrhosis of unknown etiology
  • Acute liver failure with Coombs-negative hemolytic anemia
  • Isolated splenomegaly due to clinically inapparent cirrhosis
  • Patients with apparent autoimmune hepatitis not responding to corticosteroids 1
• Neurological manifestations:
  • Movement disorders (tremor, dystonia)
  • Dysarthria, dysphagia, drooling
  • Deterioration in handwriting (micrographia)
  • Pseudobulbar palsy 1
• Psychiatric manifestations:
  • Behavioral changes, personality disorders
  • Depression, anxiety, psychosis
  • Deterioration in school performance in children 1
• Other presentations:
  • Hemolytic anemia (Coombs-negative)
  • Renal abnormalities (aminoaciduria, nephrolithiasis)
  • Skeletal abnormalities (premature osteoporosis, arthritis)
  • Cardiomyopathy 1

Diagnostic Algorithm

Step 1: Initial Screening Tests

• Serum ceruloplasmin (enzymatic assay preferred)
• 24-hour urinary copper excretion
• Slit-lamp examination for Kayser-Fleischer rings
• Liver function tests

Step 2: Interpretation of Initial Tests

• Highly suggestive of Wilson disease:

  • Ceruloplasmin <0.1 g/L (<10 mg/dL)
  • 24-hour urinary copper >1.6 μmol/24h (>100 μg/24h)
  • Presence of Kayser-Fleischer rings
  • Ratio of alkaline phosphatase to bilirubin <2 (in acute liver failure) 1

• Equivocal results requiring further testing:

  • Ceruloplasmin 0.1-0.2 g/L
  • Borderline urinary copper excretion
  • Absence of Kayser-Fleischer rings (present in only 50-62% of hepatic cases) 1

Step 3: Confirmatory Tests

• Liver biopsy with hepatic copper quantification (>4 μmol/g dry weight is diagnostic)
• Calculation of non-ceruloplasmin bound copper (>1.6 μmol/L or >250 μg/L suggests Wilson disease)
• Genetic testing for ATP7B mutations (especially useful for family screening) 1, 2

Step 4: Apply Leipzig Scoring System

The Leipzig scoring system provides a structured approach to diagnosis 1:

Parameter	Points
Kayser-Fleischer rings
Present	2
Absent	0
Neurological symptoms
Severe	2
Mild	1
Absent	0
Serum ceruloplasmin
Normal (>0.2 g/L)	0
0.1-0.2 g/L	1
<0.1 g/L	2
Hemolytic anemia
Present	1
Absent	0
Liver copper
>5× ULN (>4 μmol/g)	2
0.8-4 μmol/g	1
Normal (<0.8 μmol/g)	-1
Urinary copper
>2× ULN	2
1-2× ULN	1
Normal	0
ATP7B mutation
On both chromosomes	4
On one chromosome	1
No mutations detected	0

Score interpretation:

• ≥4: Diagnosis established
• 3: Diagnosis possible, more tests needed
• ≤2: Diagnosis very unlikely 1

Special Diagnostic Considerations

Acute Liver Failure Presentation

In patients presenting with acute liver failure, suspect Wilson disease if:

• Coombs-negative hemolytic anemia
• Relatively modest elevations in serum aminotransferases (typically <2,000 IU/L)
• Low serum alkaline phosphatase (typically <40 IU/L)
• Ratio of alkaline phosphatase to bilirubin <2
• Rapid progression to renal failure
• Female predominance (2:1 ratio) 1

Pediatric Patients

• Kayser-Fleischer rings are often absent in children with hepatic presentation
• Behavioral changes or declining school performance may be early neurological signs
• Consider Wilson disease in all children with apparent autoimmune hepatitis 1

Family Screening

• First-degree relatives of patients with Wilson disease must be screened
• Assessment should include:
  • History and physical examination
  • Serum aminotransferases and liver function tests
  • Ceruloplasmin level
  • 24-hour urinary copper
  • Slit-lamp examination for Kayser-Fleischer rings
  • Genetic testing if mutations are known in the index case 1, 2

Common Pitfalls in Diagnosis

• False-negative ceruloplasmin: Normal levels may be seen in 15-36% of patients with Wilson disease, especially in those with active inflammation (ceruloplasmin is an acute phase reactant) 2
• False-positive ceruloplasmin: Low levels can occur in malabsorption, aceruloplasminemia, heterozygous carriers, and severe hepatic insufficiency 1
• Absence of Kayser-Fleischer rings: Does not exclude Wilson disease, especially in hepatic presentations where they may be absent in up to 50% of cases 1
• Delayed diagnosis: The average time from symptom onset to diagnosis remains long (often years), leading to irreversible damage 3
• Age-related misconceptions: Wilson disease can present at any age, not just in children and young adults 4

By systematically applying this diagnostic approach, Wilson disease can be identified early, allowing for timely treatment and prevention of irreversible organ damage.