Diagnosing Copper Deficiency
Diagnose copper deficiency by measuring serum copper (<70 μg/dL), serum ceruloplasmin (<20 mg/dL), and 24-hour urinary copper excretion (<20 μg/24 hours), while carefully excluding Wilson disease through clinical context and additional testing. 1, 2, 3
Key Diagnostic Tests
Serum Copper and Ceruloplasmin
- Measure serum copper levels: Values <70 μg/dL suggest copper deficiency, though interpretation requires clinical correlation 1, 3
- Measure serum ceruloplasmin: Low levels (<20 mg/dL) support copper deficiency, but extremely low levels (<5 mg/dL) raise concern for Wilson disease 4
- Critical distinction: In copper deficiency, both serum copper and ceruloplasmin are low; in Wilson disease, ceruloplasmin is low but non-ceruloplasmin-bound copper may be elevated 4
24-Hour Urinary Copper Excretion
- In copper deficiency: Urinary copper is typically very low (<20 μg/24 hours) 5, 1
- In Wilson disease: Urinary copper is elevated (>40 μg/24 hours, often >100 μg/24 hours in symptomatic patients) 4, 5
- Collection requirements: Use copper-free containers with complete 24-hour collection; measure volume and creatinine to confirm completeness 5
Clinical Context Is Essential
Identify Risk Factors for Acquired Copper Deficiency
- Gastrointestinal surgery: Bariatric bypass surgery is now the most common cause of severe copper deficiency 2, 6
- Malabsorption disorders: Celiac disease, inflammatory bowel disease, chronic diarrhea 1, 2
- Excessive zinc intake: Zinc competes with copper absorption and is a frequent iatrogenic cause 2, 3
- Prolonged parenteral nutrition: Without adequate copper supplementation (requires 0.3 mg/day IV) 2
- Prolonged renal replacement therapy: Continuous renal replacement therapy can deplete copper 2
Recognize Clinical Manifestations
- Hematologic: Anemia (often refractory to iron), neutropenia, thrombocytopenia 2, 3, 6
- Neurologic: Myeloneuropathy with sensory ataxia, posterior column dysfunction, spasticity—these may be irreversible if not treated early 2, 6, 7
- Other systems: Cardiovascular abnormalities, skin changes, immune dysfunction 2
Critical Differential: Excluding Wilson Disease
Wilson disease must be excluded in any patient with low serum copper and ceruloplasmin, as it represents copper toxicity despite low serum levels. 4, 6
Features Distinguishing Wilson Disease from Copper Deficiency
- Age: Wilson disease typically presents before age 40; copper deficiency can occur at any age with risk factors 8
- Urinary copper: Elevated in Wilson disease (>40 μg/24 hours), very low in copper deficiency 4, 5
- Non-ceruloplasmin-bound copper: Calculate as [serum copper (μg/dL) - (3 × ceruloplasmin mg/dL)]; elevated (>25 μg/dL) in Wilson disease, low or negative in copper deficiency 4
- Kayser-Fleischer rings: Present in Wilson disease (though may be absent in 50% of acute presentations), absent in copper deficiency 8
- Hepatic copper content: If liver biopsy performed, >250 μg/g dry weight confirms Wilson disease 4, 8
Common Pitfalls and Caveats
Interpretation Challenges
- Normal ceruloplasmin does not exclude Wilson disease: 10-20% of Wilson disease patients have ceruloplasmin in the normal range 4
- Heterozygotes for Wilson disease: Approximately 20% have decreased ceruloplasmin but do not have disease 4
- Acute phase reactant: Ceruloplasmin increases with inflammation, pregnancy, or estrogen use, potentially masking low levels 1
- Coexisting deficiencies: Copper deficiency often coexists with other nutritional deficiencies (B12, zinc, iron), which may confuse the clinical picture 6
MRI Findings
- Posterior column hyperintensities on T2-weighted MRI: Seen in both copper deficiency myelopathy and B12 deficiency (subacute combined degeneration)—indistinguishable radiologically 7
- Always measure both copper and B12 levels in patients with myelopathy and posterior column signs 7
Treatment Considerations
Copper Repletion
- Oral supplementation: Copper gluconate or copper sulfate 2-8 mg/day for mild-moderate deficiency 3
- Intravenous repletion: Required for severe deficiency with neurologic manifestations; doses 4-8 times usual recommendations (1.2-2.4 mg/day IV) 2
- Duration: Hematologic manifestations reverse within 4-12 weeks; neurologic manifestations may only partially reverse 3, 7