Does a low ceruloplasmin level in a child, adolescent, or young adult with hepatic or neuro‑psychiatric symptoms indicate Wilson disease?

Does Low Ceruloplasmin Indicate Wilson Disease?

Low ceruloplasmin is suggestive but not diagnostic of Wilson disease—it must be interpreted within a comprehensive diagnostic algorithm, as only 5.9% of patients with low ceruloplasmin actually have Wilson disease, and 15-36% of children with confirmed Wilson disease have normal ceruloplasmin levels. 1, 2

Diagnostic Interpretation of Low Ceruloplasmin

When Low Ceruloplasmin Strongly Suggests Wilson Disease

• Extremely low levels (<50 mg/L or <5 mg/dL) should be taken as strong evidence for Wilson disease and warrant immediate comprehensive evaluation 1, 3
• In confirmed Wilson disease, ceruloplasmin is typically <0.1 g/L (10 mg/dL), which contributes 2 points to the Leipzig diagnostic scoring system 1
• The combination of low ceruloplasmin (<0.1 g/L) plus Kayser-Fleischer rings is typically sufficient to establish diagnosis 1

Critical Limitations of Ceruloplasmin as a Standalone Test

Ceruloplasmin alone is insufficient to diagnose or exclude Wilson disease, with a positive predictive value of only 6% when used as a screening test in patients with liver disease 1, 2

False Negatives (Normal Ceruloplasmin Despite Wilson Disease):

• 15-36% of children with Wilson disease have ceruloplasmin in the normal range 1
• Approximately 50% of patients with active Wilson's liver disease have low-normal ceruloplasmin levels 1
• Ceruloplasmin may rise to normal levels due to acute inflammation (it is an acute phase reactant) 1
• Pregnancy and estrogen supplementation elevate ceruloplasmin levels 1, 3
• The predictive value is particularly poor in acute liver failure presentations 1

False Positives (Low Ceruloplasmin Without Wilson Disease):

• Approximately 20% of heterozygous carriers have decreased ceruloplasmin without having Wilson disease 1
• Severe end-stage liver disease of any etiology 1
• Marked renal or enteric protein loss 1
• Malabsorption syndromes (including celiac disease) 1, 2
• Aceruloplasminemia (genetic ceruloplasmin deficiency without copper accumulation) 1
• Autoimmune hepatitis 1

Recommended Diagnostic Algorithm

Use the Leipzig Scoring System rather than relying on ceruloplasmin alone 1, 3:

Leipzig Score Components:

• Kayser-Fleischer rings: Present (2 points), Absent (0 points) 1, 3
• Neurologic symptoms: Severe (2 points), Mild (1 point), Absent (0 points) 1, 3
• Serum ceruloplasmin: <0.1 g/L (2 points), 0.1-0.2 g/L (1 point), >0.2 g/L (0 points) 1, 3
• Coombs-negative hemolytic anemia: Present (1 point), Absent (0 points) 1, 3
• 24-hour urinary copper: >2× ULN or >1.6 μmol/24h (2 points), 1-2× ULN (1 point), Normal (0 points) 1, 3
• Hepatic copper content: >4 μmol/g dry weight (2 points), 0.8-4 μmol/g (1 point), Normal (0 points) 1, 3
• ATP7B mutation analysis: Two mutations (4 points), One mutation (1 point), No mutations (0 points) 1, 3

Score Interpretation:

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

Essential Complementary Testing

When ceruloplasmin is low, immediately proceed with 1, 3:

1. Slit-lamp examination for Kayser-Fleischer rings by an experienced ophthalmologist (absent in up to 50% of hepatic presentations) 1
2. 24-hour urinary copper excretion (>1.6 μmol/24h typical in Wilson disease; in children the cutoff can be lowered to 0.64 μmol/d) 1, 3
3. Non-ceruloplasmin-bound ("free") copper calculation: Total serum copper (μg/L) minus [ceruloplasmin (mg/L) × 3.15]; typically >200 μg/L in untreated Wilson disease 1, 3
4. Hepatic copper quantification via liver biopsy when feasible (>4 μmol/g dry weight diagnostic) 1, 3
5. ATP7B genetic testing, particularly for asymptomatic siblings or when diagnosis remains uncertain 3, 4

Critical Clinical Pitfalls

• Never exclude Wilson disease based solely on normal ceruloplasmin, especially in children with hepatic presentations 1, 5
• Consider Wilson disease in any patient aged 3-45 years with unexplained liver abnormalities, neuropsychiatric symptoms, or hemolytic anemia 1, 6
• Immunologic assays may overestimate ceruloplasmin by measuring both apo- and holoceruloplasmin; enzymatic assays measuring oxidase activity are superior but less widely available 1
• In acute liver failure, both ceruloplasmin and total serum copper may be misleading—serum copper can be markedly elevated due to sudden hepatic copper release 1
• For children under 1 year, molecular diagnosis is the only definitive means as biochemical parameters are unreliable 4