Main Causes of Low Ceruloplasmin Other Than Wilson's Disease
Low ceruloplasmin levels occur in several conditions beyond Wilson's disease, most commonly including severe end-stage liver disease of any etiology, malabsorption syndromes, marked renal or enteric protein loss, heterozygous carriers of ATP7B mutations, and familial aceruloplasminemia. 1
Hepatic Causes
Severe liver disease from any cause can result in low ceruloplasmin due to impaired hepatic synthetic function:
- Chronic cholestatic liver diseases (including sclerosing cholangitis) can present with low ceruloplasmin and elevated hepatic copper, potentially mimicking Wilson's disease 2
- Autoimmune hepatitis is associated with decreased ceruloplasmin levels 1
- Acute viral hepatitis (both hepatitis B and C) can cause low ceruloplasmin 3, 4
- Alcoholic liver disease and drug-induced liver disease may present with subnormal ceruloplasmin 3
- End-stage liver disease of any etiology with severe hepatic insufficiency results in decreased synthesis 1
A key clinical pearl: In viral hepatitis patients, approximately 4% may have low ceruloplasmin without Wilson's disease, with these patients tending to be younger and more often having viral hepatitis as their underlying condition 4
Protein Loss and Malabsorption
- Marked renal protein loss (nephrotic syndrome) causes urinary ceruloplasmin wasting 1
- Enteric protein loss (protein-losing enteropathy) results in gastrointestinal losses 1
- Malabsorption syndromes including celiac disease lead to decreased ceruloplasmin 1, 3
Genetic Causes (Non-Wilson's)
- Heterozygous carriers of ATP7B mutations: Approximately 20% of heterozygotes have decreased ceruloplasmin levels without copper overload disease 1, 5
- Familial aceruloplasminemia: Patients with mutations in the ceruloplasmin gene on chromosome 3 completely lack the protein, exhibiting hemosiderosis but not copper accumulation 1
Key Distinguishing Features from Wilson's Disease
When evaluating low ceruloplasmin, several features help differentiate Wilson's disease from mimickers:
- Ceruloplasmin levels: True Wilson's disease typically shows significantly lower levels (mean 6 mg/dL) compared to mimickers (mean 16 mg/dL) 2
- 24-hour urinary copper: Wilson's disease demonstrates markedly elevated excretion (mean 322 μg/day) versus mimickers (mean 74.5 μg/day) 2
- Serial measurements: In non-Wilson's causes, initially low ceruloplasmin levels may normalize on follow-up, which can serve as a diagnostic indicator 2
- Hepatic copper content: While Wilson's disease shows >4 μmol/g dry weight, cholestatic syndromes can also have elevated hepatic copper, creating diagnostic confusion 1
Critical Diagnostic Pitfalls
The positive predictive value of low ceruloplasmin alone for Wilson's disease is only 5.9-6%, making it insufficient as a standalone diagnostic test 5, 3:
- 15-36% of children with Wilson's disease have normal ceruloplasmin levels 1, 6, 5
- Ceruloplasmin is an acute phase reactant: Inflammation in the liver or elsewhere can elevate levels to normal range, masking Wilson's disease 1
- Immunologic assays may overestimate ceruloplasmin by detecting apoceruloplasmin (copper-free form), leading to false-normal results 1, 7
- Enzymatic assays measuring ceruloplasmin oxidase activity are superior to immunologic assays, with 93.6% sensitivity and 100% specificity at a cut-off of 55 U/L 8
Recommended Diagnostic Approach
When encountering low ceruloplasmin, use the Leipzig Diagnostic Scoring System rather than relying on ceruloplasmin alone 1, 5:
- Score ≥4 establishes Wilson's disease diagnosis
- Score of 3 requires additional testing
- Score ≤2 makes Wilson's disease very unlikely
Essential additional tests include:
- Slit-lamp examination for Kayser-Fleischer rings 1, 5
- 24-hour urinary copper excretion (>1.6 μmol/24h suggests Wilson's) 1, 5
- Non-ceruloplasmin-bound copper calculation (>200 μg/L in untreated Wilson's) 1, 5
- Hepatic copper quantification if liver biopsy performed 1, 5
- ATP7B genetic testing for confirmation 5
In cholestatic liver diseases specifically, be aware that both low ceruloplasmin and elevated hepatic copper can occur, requiring careful integration of all diagnostic criteria to avoid misdiagnosis 2