High RBC Copper with Low Ceruloplasmin: Diagnostic Significance
Elevated RBC copper with low ceruloplasmin most strongly suggests Wilson's disease, where impaired hepatic copper excretion leads to tissue copper accumulation despite paradoxically low serum ceruloplasmin and often low total serum copper. 1
Primary Pathophysiology
The combination of high RBC copper and low ceruloplasmin reflects a critical mismatch in copper distribution:
In Wilson's disease, ceruloplasmin is typically decreased (<200 mg/L or <20 mg/dL), with extremely low levels (<50 mg/L or <5 mg/dL) providing strong diagnostic evidence. 1 This occurs because the ATP7B gene mutation impairs both copper incorporation into ceruloplasmin and biliary copper excretion. 1
Total serum copper is usually decreased in proportion to low ceruloplasmin, but the non-ceruloplasmin bound (free) copper is markedly elevated above 25 μg/dL (normal <15 μg/dL). 1 This free copper redistributes into tissues including RBCs, brain, liver, and kidneys. 2
During acute liver failure from Wilson's disease, sudden release of copper from hepatic stores can cause markedly elevated serum and RBC copper levels despite low ceruloplasmin. 1, 2 This represents a medical emergency requiring urgent evaluation.
Calculating Non-Ceruloplasmin Bound Copper
The free (non-ceruloplasmin bound) copper calculation is essential for diagnosis: 3, 2
- Free copper (μg/dL) = Total serum copper (μg/dL) - [3 × ceruloplasmin (mg/dL)]
- For SI units: Free copper (μg/L) = Total serum copper (μg/L) - [3 × ceruloplasmin (mg/L)] 1
- Elevated free copper >25 μg/dL in untreated patients strongly supports Wilson's disease. 1
Differential Diagnosis Beyond Wilson's Disease
While Wilson's disease is the primary concern, other conditions can produce similar patterns:
Acute liver failure of any etiology can elevate non-ceruloplasmin bound copper and RBC copper due to hepatocellular necrosis releasing stored copper. 1 This makes distinguishing Wilson's disease from other causes of acute liver failure challenging. 4
Chronic cholestatic liver disease may elevate free copper levels. 1
Copper deficiency states paradoxically show low serum copper and low ceruloplasmin, but RBC copper would be low, not high. 5, 6 This helps distinguish deficiency from Wilson's disease.
Aceruloplasminemia (mutations in the ceruloplasmin gene) causes absent ceruloplasmin but leads to iron accumulation (hemosiderosis), not copper accumulation. 1
Critical Diagnostic Workup
When encountering high RBC copper with low ceruloplasmin, immediately pursue:
Slit-lamp examination for Kayser-Fleischer rings, which when present with low ceruloplasmin are diagnostic of Wilson's disease. 1 However, absence does not exclude the diagnosis—12 of 55 Wilson's disease patients in one series had normal ceruloplasmin and no rings. 1, 2
24-hour urinary copper excretion: levels >100 μg/24 hours (1.6 μmol/24 hours) support Wilson's disease, though 16-23% of patients may have lower values at presentation. 1, 3 A threshold of >40 μg/24 hours (0.6 μmol/24 hours) provides better diagnostic sensitivity. 1
Hepatic copper concentration from liver biopsy: >250 μg/g dry weight confirms Wilson's disease. 7 However, be aware that copper distribution can be strikingly variable in acute liver failure, with single biopsies potentially misleading. 4
Assess for hemolytic anemia, which may accompany acute Wilson's disease presentations due to sudden copper release. 8, 4
Important Clinical Pitfalls
Do not assume normal ceruloplasmin excludes Wilson's disease—10-22% of confirmed Wilson's disease patients have ceruloplasmin levels in the normal or near-normal range. 1 This is particularly true in children and patients with concurrent inflammation (ceruloplasmin is an acute phase reactant). 1, 2
Avoid relying solely on total serum copper, as it is paradoxically often decreased in stable Wilson's disease despite tissue copper overload. 1, 3 The calculated free copper provides far more diagnostic accuracy. 2
In women, consider that ceruloplasmin levels are physiologically elevated by estrogen, pregnancy, and oral contraceptives, potentially masking Wilson's disease. 1 Conversely, in celiac disease, increased urinary copper loss in women can mimic Wilson's disease biochemically. 9
Approximately 20% of Wilson's disease heterozygotes have decreased ceruloplasmin levels, creating diagnostic confusion. 1 Genetic testing may be necessary for definitive diagnosis in ambiguous cases.
Monitoring Implications
If Wilson's disease is confirmed and treatment initiated:
- Monitor free serum copper every 6-12 months, targeting levels <10 μg/dL in adequately treated patients. 3, 2, 10
- 24-hour urinary copper should decrease to ≤125 μg/24 hours with adequate zinc therapy or chelation. 10
- A significant upward trend in urinary copper indicates impending loss of copper control. 10