What is the appropriate initial work‑up for a patient with suspected Wilson disease?

Work-up for Wilson Disease

Initial Diagnostic Approach

For any patient aged 3-55 years with unexplained liver abnormalities, or any patient with unexplained liver disease combined with neurological or psychiatric symptoms, initiate a systematic work-up for Wilson disease. 1, 2

The diagnostic evaluation should proceed algorithmically, recognizing that no single test is definitive and diagnosis relies on a constellation of findings 3.

Essential Initial Tests

First-Line Laboratory Studies

• Serum ceruloplasmin: Low levels (<20 mg/dL or 0.2 g/L) are typical in symptomatic patients, though this can be falsely elevated by inflammation, pregnancy, estrogen supplementation, or oral contraceptives 1, 2
• 24-hour urinary copper excretion: Values >100 μg/day (>1.6 μmol/day) support the diagnosis 4, 1
• Serum aminotransferases and liver function tests: Including albumin, bilirubin (conjugated and unconjugated), and INR 3
• Complete blood count: To assess for hemolytic anemia 3
• Serum copper: May be low in chronic presentations but elevated in acute liver failure 1

Critical Physical Examination

• Slit-lamp examination by an experienced ophthalmologist: Mandatory to detect Kayser-Fleischer rings, which appear as golden-brownish pigment deposits in Descemet's membrane near the limbus 2
  • Present in 50-62% of patients with predominantly hepatic presentations 2
  • Nearly always present in neurological presentations 3
  • Not visible by direct inspection alone—slit-lamp examination is required 2

Advanced Diagnostic Testing

When Initial Tests Are Inconclusive

• Hepatic copper concentration on liver biopsy: Values >250 μg/g dry weight are confirmatory of Wilson disease 1
• ATP7B mutation analysis: Should be performed when diagnosis remains uncertain after clinical and biochemical testing 1, 2
• Calculated non-ceruloplasmin-bound copper: Can be estimated from serum copper and ceruloplasmin levels 3, 1

Special Clinical Scenarios Requiring High Suspicion

Fulminant Hepatic Failure Presentation

Wilson disease should be strongly suspected when the following constellation is present 3:

• Coombs-negative hemolytic anemia with acute intravascular hemolysis
• Modest aminotransferase elevations (typically <2,000 IU/L)
• Normal or markedly low serum alkaline phosphatase (typically <40 IU/L)
• Ratio of alkaline phosphatase to total bilirubin <2
• Coagulopathy unresponsive to parenteral vitamin K
• Rapid progression to renal failure
• Female predominance (2:1 ratio)

In this setting, serum copper is typically elevated and urinary copper excretion is markedly increased 1, 5.

Autoimmune Hepatitis-Like Presentation

• All pediatric patients presenting with autoimmune hepatitis should be investigated for Wilson disease 3
• Adults with atypical autoimmune hepatitis or poor response to corticosteroid therapy must be evaluated for Wilson disease before continuing immunosuppression 3, 1

Other Hepatic Presentations

• Consider Wilson disease in patients with nonalcoholic fatty liver disease or NASH on pathology 3
• Evaluate patients presenting with isolated splenomegaly or unexplained hepatomegaly 3

Diagnostic Pitfalls and Caveats

Common Diagnostic Challenges

• Age range is broader than traditionally recognized: Cases have been diagnosed from age 3 to the eighth decade of life, with documented cases in patients aged 55-62 years 3, 2
• 18% of patients with non-fulminant disease have neither Kayser-Fleischer rings nor low ceruloplasmin 5
• Serum aminotransferase elevations may be mild and do not reflect disease severity 1
• Immunologic assays for ceruloplasmin may overestimate levels; enzymatic activity measurement is more reliable 1

Overlapping Features with Common Conditions

Wilson disease shares histological features with more common liver diseases, including hepatic steatosis, glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies 6. This overlap makes liver biopsy findings supportive but not pathognomonic.

Family Screening Protocol

All first-degree relatives of any patient newly diagnosed with Wilson disease must be screened 3, 2. The screening protocol includes:

• History focusing on jaundice, liver disease, and neurological symptoms 3
• Physical examination 3
• Serum ceruloplasmin and copper 3, 2
• Liver function tests including aminotransferases, albumin, and bilirubin 3
• Complete blood count 3
• Slit-lamp examination for Kayser-Fleischer rings 3, 2
• 24-hour urinary copper excretion 3
• ATP7B genotype or haplotype studies based on findings in the proband (if available) 3, 2

Individuals without Kayser-Fleischer rings who have subnormal ceruloplasmin and abnormal liver function tests should undergo liver biopsy to confirm diagnosis 3.

Timing Considerations

• 70% of patients are diagnosed within 6 months of symptom onset, but delays up to 9 years have been documented 5
• Early diagnosis is crucial: Presymptomatic patients identified through screening who receive treatment have excellent long-term prognosis and rarely develop symptoms 3
• Treatment should be initiated immediately upon diagnosis for all individuals over 3-4 years old 3, 1