Is copper supplementation an appropriate treatment for iron‑deficiency anemia?

Copper Supplementation for Iron Deficiency Anemia

Copper supplementation is NOT an appropriate primary treatment for iron-deficiency anemia; however, copper deficiency should be evaluated and corrected in patients with persistent anemia despite adequate iron replacement. 1

Primary Treatment Remains Iron Replacement

Iron deficiency anemia requires iron repletion as the cornerstone of therapy, not copper supplementation. 1 The most recent AGA guidelines (2024) emphasize that oral iron supplementation (typically ferrous sulfate 200 mg once daily) should be initiated first, with intravenous iron reserved for patients with severe deficiency, malabsorption, or intolerance to oral formulations. 1, 2

When to Consider Copper in the Diagnostic Algorithm

Copper deficiency should be investigated only when anemia persists after 4 weeks of adequate iron and erythropoietin therapy. 1 This represents a secondary evaluation, not a primary treatment approach.

Specific Clinical Scenarios Requiring Copper Assessment:

• Refractory anemia: Patients who fail to respond to iron supplementation (oral or intravenous) after 4 weeks should undergo evaluation for copper, ceruloplasmin, or vitamin B12 deficiency. 1
• Unexplained cytopenias: Copper deficiency can present with microcytic anemia, neutropenia, and leukopenia that mimics iron deficiency but does not respond to iron therapy. 3, 4, 5
• Long-term enteral/parenteral nutrition: Patients receiving prolonged nutritional support without adequate copper supplementation (typically requiring 0.5-1.2 mg/day in parenteral nutrition) are at risk. 1, 6
• Post-bariatric surgery: These patients have increased risk of copper depletion alongside iron deficiency. 1

Pathophysiological Relationship Between Copper and Iron

Copper plays a critical role in iron metabolism through ceruloplasmin and hephaestin, which are copper-dependent ferroxidases necessary for iron oxidation and export from enterocytes. 4, 7 Copper deficiency impairs iron absorption and utilization, leading to anemia that appears iron-refractory. 7 However, this does not make copper a treatment for typical iron deficiency anemia—it makes copper deficiency a separate diagnosis that must be excluded in non-responders.

Diagnostic Approach for Copper Status

When evaluating for copper deficiency in refractory anemia:

• Serum copper <12 μmol/L with CRP >20 mg/L: Deficiency is likely; consider copper administration. 1
• Serum copper <8 μmol/L (with or without elevated CRP): Repletion is indicated. 1
• Serum ceruloplasmin: Should be measured concurrently, as it reflects copper status (though elevated in inflammatory states). 1, 4
• 24-hour urine copper: Provides additional diagnostic information. 4

Treatment of Confirmed Copper Deficiency

If copper deficiency is confirmed as a contributing factor to anemia:

• Oral copper supplementation: Copper gluconate or copper sulfate at 4-8 mg/day for deficiency treatment (maintenance needs are 1.1-2 mg/day). 1, 4
• Intravenous copper: Reserved for severe deficiency or when oral absorption is blocked (e.g., by excess zinc); typically 10 mg total dose over 5 days. 3
• Expected response: Hematological manifestations are fully reversible over 4-12 weeks with adequate copper replacement. 4
• Monitoring: Reticulocytosis should occur within 10 days, with normalization of neutrophil counts within 2 weeks and complete anemia resolution over 3 months. 6

Critical Pitfalls to Avoid

• Do not substitute copper for iron: Copper supplementation will not correct true iron deficiency anemia. The primary deficiency must be addressed first. 1
• Zinc-induced copper deficiency: Excessive zinc supplementation (common in over-the-counter supplements) can block intestinal copper absorption and cause refractory anemia. 3 Obtain a medication and supplement history in non-responders.
• Premature copper testing: Evaluate copper only after confirming adequate iron replacement has been attempted and failed. 1
• Inflammatory states: Ceruloplasmin and serum copper may be falsely elevated in inflammation, masking true copper deficiency. 1 Use serum copper <8 μmol/L as a more reliable threshold in these cases.