What is the difference between whole‑blood copper, plasma copper, and red blood cell (RBC) copper measurements, and what does each indicate about copper status?

Copper Measurement Compartments: Whole Blood, Plasma, and RBC

Whole blood copper is rarely measured clinically and lacks standardized interpretation; plasma (or serum) copper is the standard measurement that reflects both ceruloplasmin-bound and free copper, while RBC copper is not recommended by major guidelines for diagnosing copper disorders. 1, 2

Plasma/Serum Copper: The Clinical Standard

Plasma or serum copper represents the total circulating copper in blood, which includes:

• Ceruloplasmin-bound copper (90% of total): The majority of copper is safely bound to ceruloplasmin, the primary copper transport protein 2, 3
• Non-ceruloplasmin-bound (free) copper (10% of total): This is the metabolically active and potentially toxic fraction 4
• Albumin-bound copper: A smaller fraction that contributes to the free copper pool 3

Plasma copper should be measured in heparinized plasma or serum using ICP-MS or atomic absorption spectroscopy 4. Plasma values are slightly higher than serum values (approximately 20% higher) because some copper and ceruloplasmin become trapped in the fibrin clot during serum preparation 5. The relationship is: plasma copper (μg/ml) = 1.200 × serum copper - 0.032 5.

Clinical Interpretation of Plasma Copper

• In Wilson disease: Total plasma copper is paradoxically decreased (proportional to low ceruloplasmin), despite being a disease of copper overload 4, 2
• In acute liver failure from Wilson disease: Plasma copper may be markedly elevated due to sudden release from tissue stores 4, 1
• In copper deficiency: Both plasma copper and ceruloplasmin are low 6
• The diagnostic value comes from calculating free copper: Free copper (μg/L) = Total serum copper (μg/L) - (3.15 × ceruloplasmin in mg/L) 4, 1

Free copper >25 μg/dL (250 μg/L) indicates Wilson disease, while free copper <5 μg/dL with low urinary copper signals copper depletion 4, 6.

RBC Copper: Not Clinically Useful

Red blood cell copper measurement is notably absent from all major guidelines for diagnosing Wilson disease or other copper metabolism disorders 1. The European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) comprehensively outline diagnostic tests, and RBC copper is not included 1.

Why RBC Copper Is Not Recommended

• No validated reference ranges exist for clinical decision-making in copper disorders 1
• RBC copper does not reflect the metabolically active copper pool that causes toxicity or deficiency 7
• Copper in RBCs is largely sequestered and not in equilibrium with the plasma compartment that drives clinical manifestations 7

Whole Blood Copper: Rarely Used

Whole blood copper combines plasma and RBC copper but offers no diagnostic advantage over plasma measurements alone. It may be measured in suspected toxicity contexts but lacks the specificity needed for diagnosing Wilson disease or copper deficiency 4.

Key Differences Summary

Measurement	What It Shows	Clinical Use
Plasma/Serum Copper	Total circulating copper (ceruloplasmin-bound + free)	Standard test; calculate free copper for diagnosis [4,2]
Free (Non-ceruloplasmin) Copper	Metabolically active, potentially toxic copper	Elevated in Wilson disease (>25 μg/dL); low in deficiency [4,6]
RBC Copper	Sequestered intracellular copper	Not recommended by guidelines [1]
Whole Blood Copper	Combined plasma + RBC copper	Limited clinical utility [4]

Critical Diagnostic Algorithm

When evaluating copper status, follow this sequence:

1. Measure serum ceruloplasmin first as the primary screening test 2, 6
2. If ceruloplasmin is low (<20 mg/dL), add serum copper to calculate free copper 2
3. Obtain 24-hour urinary copper excretion if ceruloplasmin is abnormal:
   • Normal: <40 μg/24 hours 2
   • Wilson disease: typically >100 μg/24 hours 4, 1
   • Copper deficiency: <20 μg/24 hours 6
4. Never rely on total serum copper alone, as it is often paradoxically low in Wilson disease 1, 2

Common Pitfalls to Avoid

• Do not assume elevated serum copper always indicates Wilson disease—it may reflect acute liver failure of any cause or cholestasis 4, 1
• Normal ceruloplasmin does NOT exclude Wilson disease, as 10-20% of patients have normal levels 2, 6
• Ceruloplasmin is an acute phase reactant and may be falsely elevated during inflammation, potentially masking Wilson disease 2
• Approximately 20% of heterozygotes have low ceruloplasmin but do not have disease 2, 6
• Storage of blood samples on ice decreases copper values by 3.5% over 3 days; use correction formulas if samples are stored 5