What is the differential diagnosis for a patient with suspected Wilson disease and a normal serum ceruloplasmin level?

Differential Diagnosis for Suspected Wilson Disease with Normal Ceruloplasmin

When Wilson disease is suspected but ceruloplasmin is normal, the differential diagnosis must include Wilson disease itself (as 15-36% of patients have normal levels), autoimmune hepatitis, nonalcoholic steatohepatitis (NASH), heterozygous ATP7B carrier state, and other causes of chronic liver disease. 1, 2

Primary Diagnostic Considerations

Wilson Disease Despite Normal Ceruloplasmin

• Normal ceruloplasmin does NOT exclude Wilson disease, as 15-36% of patients (particularly those with hepatic manifestations) maintain normal ceruloplasmin levels 2, 3
• Ceruloplasmin is an acute phase reactant and can be falsely elevated to the normal range by inflammation, infection, pregnancy, or estrogen therapy, masking underlying Wilson disease 2, 3
• The positive predictive value of low ceruloplasmin alone is only 5.9-6%, making it insufficient as a standalone diagnostic test 1, 2

Autoimmune Hepatitis

• All children presenting with apparent autoimmune hepatitis must be investigated for Wilson disease 4
• Adult patients with atypical autoimmune hepatitis or poor response to corticosteroid therapy should also be evaluated for Wilson disease 4
• Clinical features and liver biopsy findings can be indistinguishable between these two conditions, particularly in younger patients 4

Nonalcoholic Steatohepatitis (NASH)

• Wilson disease should be considered in patients presenting with nonalcoholic fatty liver disease or NASH pathologic findings 4
• Hepatic steatosis in Wilson disease is rarely as severe as in NASH, but occasional patients resemble NASH convincingly or may have both diseases 4
• Steatosis, hepatocyte ballooning, and Mallory-Denk bodies can occur in both conditions 5

Heterozygous ATP7B Carrier State

• Approximately 20% of heterozygotes (carriers with one mutated ATP7B gene) have decreased ceruloplasmin without copper overload disease 1, 2, 3
• These individuals do not develop Wilson disease and require no treatment, only genetic counseling 1

Additional Differential Diagnoses

Acute Liver Failure Presentations

When presenting with acute liver failure, consider:

• Viral hepatitis with underlying Wilson disease (rare patients have acute liver failure from viral hepatitis and are found to have underlying Wilson disease) 4
• Drug-induced liver injury (can trigger acute presentation in undiagnosed Wilson disease) 4
• Wilson disease presenting as fulminant hepatic failure has characteristic features: Coombs-negative hemolytic anemia, modest aminotransferase elevations (typically <2000 IU/L), low alkaline phosphatase (typically <40 IU/L), and alkaline phosphatase to bilirubin ratio <2 4

Other Hepatic Conditions

• Severe end-stage liver disease from any cause can result in low ceruloplasmin due to impaired hepatic synthetic function 1
• Chronic cholestatic liver disease can elevate non-ceruloplasmin bound copper 2
• Alcohol-associated liver disease shares histological features with Wilson disease including steatosis and Mallory-Denk bodies 5

Rare Genetic Conditions

• Familial aceruloplasminemia (patients completely lack ceruloplasmin protein but exhibit hemosiderosis, not copper accumulation) 1

Critical Diagnostic Algorithm

Mandatory Next Steps for Suspected Wilson Disease

1. Slit-lamp ophthalmologic examination for Kayser-Fleischer rings (present in 82% of Wilson disease patients, 100% specific) 1, 6
2. 24-hour urinary copper excretion (>1.6 μmol/24h or >100 μg/24h suggests Wilson disease; sensitivity 100%, specificity 63%) 1, 2, 6
3. Calculate non-ceruloplasmin-bound ("free") copper (typically elevated above 200 μg/L in untreated Wilson disease) 1, 2, 3
4. Hepatic copper quantification (>250 μg/g or >4 μmol/g dry weight provides critical diagnostic information) 2, 3
5. ATP7B genetic testing (identification of two mutations confirms diagnosis) 2, 3

Leipzig Scoring System Application

Use the validated Leipzig Diagnostic Scoring System rather than relying on any single test 1, 2:

• Score ≥4 establishes the diagnosis 2, 3
• Combines Kayser-Fleischer rings, neurological symptoms, ceruloplasmin level, hemolytic anemia, hepatic copper, urinary copper, and ATP7B mutations 2, 3

Critical Pitfalls to Avoid

• Never dismiss Wilson disease based on normal ceruloplasmin alone, as up to 36% of children with Wilson disease have normal levels 1
• Do not rely on ceruloplasmin as a standalone test in the presence of inflammation, as it can be falsely elevated 2, 3
• Consider Wilson disease in any unexplained liver disease between ages 5-40 years, regardless of ceruloplasmin level 3
• Untreated Wilson disease is fatal, progressing to cirrhosis, neurologic degeneration, and death; early treatment with chelating agents is highly effective 1
• The combination of serum ceruloplasmin, 24-hour urinary copper, and Kayser-Fleischer rings together has sensitivity 70.4%, specificity 100%, and accuracy 79.3% 6