When is a ceruloplasmin test recommended, particularly in patients with a family history of Wilson's disease and unexplained liver disease, neurological symptoms, or psychiatric issues?

Ceruloplasmin Testing in Suspected Wilson's Disease

When to Order Ceruloplasmin

Serum ceruloplasmin should be routinely measured in any patient aged 3-55 years with unexplained liver disease, neurological symptoms, or psychiatric abnormalities, as well as in first-degree relatives of confirmed Wilson's disease patients. 1

Specific Clinical Scenarios Requiring Testing

• Unexplained liver disease at any age between 3-55 years, including isolated hepatomegaly, elevated aminotransferases, fatty liver, cirrhosis, or fulminant hepatic failure 1
• Neurological presentations including tremor, dystonia, dysarthria, drooling, movement disorders, deteriorating handwriting, or coordination problems 1
• Psychiatric manifestations such as depression, anxiety, personality changes, behavioral deterioration, or psychosis, particularly when accompanied by any liver abnormality 1
• Family history of Wilson's disease—all first-degree relatives (siblings, children) should be screened regardless of symptoms 2
• Autoimmune hepatitis that fails to respond to standard therapy, as Wilson's disease can mimic autoimmune hepatitis with elevated immunoglobulins and autoantibodies 1
• Unexplained hemolytic anemia, especially Coombs-negative hemolysis with liver dysfunction 1

Critical Interpretation Pitfalls

Normal Ceruloplasmin Does NOT Exclude Wilson's Disease

• 15-36% of children with Wilson's disease have ceruloplasmin in the normal range 2
• Up to 50% of patients with hepatic Wilson's disease may have low-normal ceruloplasmin levels 2
• In one series, 22% of Wilson's disease patients (12 of 55) had normal ceruloplasmin AND no Kayser-Fleischer rings 2, 3
• Normal ceruloplasmin requires proceeding with additional diagnostic tests rather than stopping the evaluation 1, 2

Low Ceruloplasmin Has Poor Positive Predictive Value

• The positive predictive value of low ceruloplasmin alone is only 5.9-6%, meaning most patients with low ceruloplasmin do not have Wilson's disease 1, 4
• In a screening study of 2,867 patients with liver disease, only 1 of 17 patients with low ceruloplasmin actually had Wilson's disease 1, 4
• Approximately 20% of heterozygous carriers have decreased ceruloplasmin but do not have the disease 1

False Elevations of Ceruloplasmin

• Ceruloplasmin is an acute phase reactant and can be falsely elevated during inflammation, infection, pregnancy, or estrogen supplementation (including oral contraceptives), potentially masking Wilson's disease 1, 2
• Immunologic assays (radioimmunoassay, nephelometry) may overestimate ceruloplasmin because they measure both functional holoceruloplasmin and non-functional apoceruloplasmin 1, 2
• Enzymatic assays measuring oxidase activity are superior to immunologic methods, with sensitivity of 93.6% and specificity of 100% at a cut-off of 55 U/L 5

Diagnostic Algorithm When Ceruloplasmin is Abnormal

Extremely Low Ceruloplasmin (<50 mg/L or <5 mg/dL)

• This provides strong evidence for Wilson's disease and should trigger immediate comprehensive evaluation 1, 2, 6
• Proceed directly to:
  • Slit-lamp examination for Kayser-Fleischer rings by experienced ophthalmologist 1
  • 24-hour urinary copper excretion (>100 μg/24 hours indicates Wilson's disease) 2
  • Serum copper to calculate non-ceruloplasmin-bound (free) copper (>25 μg/dL strongly suggests Wilson's disease) 2
  • Consider genetic testing for ATP7B mutations 2

Modestly Low Ceruloplasmin (50-200 mg/L or 5-20 mg/dL)

• Further evaluation is mandatory as this range is consistent with but not diagnostic of Wilson's disease 1, 2
• Order the same battery of tests as above 2, 7
• Consider hepatic copper quantification if liver biopsy is performed (>250 μg/g dry weight provides best biochemical evidence) 2

Normal Ceruloplasmin (>200 mg/L or >20 mg/dL)

• Do NOT stop the diagnostic workup if clinical suspicion remains high 1, 2
• Proceed with 24-hour urinary copper excretion 2, 7
• Calculate non-ceruloplasmin-bound copper using serum copper and ceruloplasmin measurements 2, 7
• Perform slit-lamp examination 1
• Consider genetic testing, particularly in patients with strong family history 2

Age-Specific Considerations

• Ceruloplasmin is physiologically very low in infancy (up to 6 months of age), peaks above adult levels in early childhood, then normalizes 1
• Wilson's disease should be considered from age 3 to 55 years, though cases have been diagnosed as young as 3 years and as old as 62 years 1
• Age alone should never be the basis for eliminating Wilson's disease from the differential 1

Presentation-Specific Testing Patterns

Hepatic Presentation

• Only 65% of patients presenting with liver disease have the typical findings of low ceruloplasmin and Kayser-Fleischer rings 3
• Kayser-Fleischer rings are usually absent in children presenting with liver disease 1
• Ceruloplasmin was normal in 27% of all Wilson's disease patients at diagnosis 3

Neurological/Psychiatric Presentation

• 90% have Kayser-Fleischer rings and 85% have low ceruloplasmin 3
• Even with neurological disease, 5% may lack Kayser-Fleischer rings 1
• Ceruloplasmin levels are typically lower in patients with neurological symptoms than those with purely hepatic disease 3

Complementary Diagnostic Tests

When ceruloplasmin testing is performed, the following should be obtained simultaneously or sequentially based on results:

• 24-hour urinary copper (normal <40 μg/24 hours; Wilson's disease typically >100 μg/24 hours) with sensitivity of 100% and specificity of 63% 2, 7, 8
• Serum copper to calculate free copper (total serum copper is paradoxically LOW in Wilson's disease despite copper overload) 2, 7
• Slit-lamp examination for Kayser-Fleischer rings (sensitivity 82.1%, specificity 100%) 8
• Combined testing of ceruloplasmin, 24-hour urinary copper, and Kayser-Fleischer rings together yields sensitivity of 70.4% and specificity of 100% 8