Causes of Low Ceruloplasmin Without Wilson's Disease
Low ceruloplasmin with elevated RBC copper can occur in several conditions beyond Wilson's disease, including heterozygous carrier status for ATP7B mutations, severe protein-losing conditions (nephrotic syndrome, protein-losing enteropathy, malabsorption), end-stage liver disease of any etiology, and aceruloplasminemia. 1
Primary Non-Wilson Causes of Low Ceruloplasmin
Heterozygous Carrier Status
- Approximately 20% of heterozygous carriers of ATP7B mutations (Wilson's disease gene carriers) have decreased ceruloplasmin levels without having the disease itself 1
- These individuals may show mildly elevated urinary copper excretion but typically do not develop clinical disease 1
Severe Protein Loss Conditions
- Marked renal protein loss (nephrotic syndrome) can cause low ceruloplasmin 1
- Enteric protein loss from protein-losing enteropathy reduces ceruloplasmin levels 1
- Malabsorption syndromes of various etiologies decrease ceruloplasmin 1, 2
End-Stage Liver Disease
- Severe end-stage liver disease of any etiology can result in low ceruloplasmin due to impaired hepatic synthetic function 1
- This occurs regardless of the underlying cause of cirrhosis 1
Aceruloplasminemia
- Patients with aceruloplasminemia have mutations in the ceruloplasmin gene on chromosome 3, causing complete absence of the protein 1
- Critical distinction: These patients exhibit hemosiderosis (iron accumulation) but do NOT have copper accumulation 1
- This is a completely different disease from Wilson's disease despite the low ceruloplasmin 1
Conditions with Elevated Ceruloplasmin (Opposite Pattern)
While your question focuses on low ceruloplasmin, it's important to recognize when ceruloplasmin is elevated, as this essentially excludes Wilson's disease:
- Acute inflammation (ceruloplasmin is an acute phase reactant) 1, 3
- Pregnancy and estrogen supplementation (hyperestrogenemic states) 1, 3
- Infectious diseases 3
- Malignancies 3
Diagnostic Approach When Wilson's Disease is Excluded
Confirm Wilson's Disease is Truly Excluded
Before attributing low ceruloplasmin to other causes, ensure Wilson's disease is definitively ruled out using the Leipzig scoring system 1:
- Check for Kayser-Fleischer rings by slit lamp examination 1
- Measure 24-hour urinary copper excretion (>1.6 μmol/24h suggests Wilson's) 1
- Calculate free (non-ceruloplasmin-bound) copper: most untreated Wilson's patients have levels >200 μg/L 1
- Consider genetic testing for ATP7B mutations if suspicion remains 3
- Liver biopsy with hepatic copper quantification (>4 μmol/g dry weight suggests Wilson's) 1
Evaluate for Alternative Causes
Once Wilson's disease is excluded:
- Assess protein status: Check for proteinuria (24-hour urine protein), albumin levels, and signs of malabsorption 1
- Evaluate liver synthetic function: If end-stage liver disease is present, low ceruloplasmin may simply reflect poor hepatic synthesis 1
- Family screening: If heterozygous carrier status is suspected, consider genetic testing and family member screening 4
- Consider aceruloplasminemia: Look for iron overload (elevated ferritin, transferrin saturation) rather than copper accumulation 1
Critical Pitfalls to Avoid
Assay Method Matters
- Immunologic assays (radioimmunoassay, radial immunodiffusion, nephelometry) may overestimate ceruloplasmin concentrations because they measure both apoceruloplasmin (without copper) and holoceruloplasmin (with copper) 1, 3
- Enzymatic assays measuring copper-dependent oxidase activity are more accurate but less widely available 1
Normal Ceruloplasmin Doesn't Exclude Wilson's Disease
- 15-36% of children with Wilson's disease have ceruloplasmin in the normal range 1, 5
- About half of patients with active Wilson's liver disease have low-normal ceruloplasmin 1
- In one series, 12 out of 55 Wilson's disease patients had normal ceruloplasmin and no Kayser-Fleischer rings 1
- The positive predictive value of low ceruloplasmin as a screening test is only 6% 5, 2