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Copper

Copper is an essential trace element that serves as a cofactor for approximately 25 cuproenzymes involved in oxidative metabolism, antioxidant defense, neurotransmitter synthesis, connective tissue formation, iron metabolism, and immune function.[1][2][3] The average adult has approximately 50–120 mg of copper in the body, with almost two-thirds in skeleton and muscle; the liver helps regulate copper through biliary excretion.[4][29] ATP7A- and ATP7B-related transport defects produce different tissue copper distributions: Menkes disease causes low copper in blood, liver and brain despite accumulation in other tissues, while Wilson disease causes copper overload in the liver and brain.[5][6]

For reconstructive practice, consider copper deficiency in myeloneuropathy or unexplained cytopenias with a relevant risk factor: gastric or bariatric surgery, malabsorption, prolonged nutrition support, or excessive zinc exposure. Urinary symptoms occur in a minority of reported copper-deficiency myelopathy cases; isolated urgency or retention is not a reason for routine copper screening. B12 deficiency and other neurologic causes must also be assessed.[7][9][27]

Biochemistry and Homeostasis​

Dietary copper is absorbed primarily in the duodenum and proximal jejunum via the copper transporter CTR1 (SLC31A1), which imports reduced Cu⁺ into enterocytes.[3][4] From enterocytes, copper is exported into the portal circulation by the copper-transporting ATPase ATP7A and travels to the liver bound to albumin and histidine.[3][4] Within hepatocytes, copper is incorporated into ceruloplasmin (which carries approximately 90% of circulating copper in normal individuals), delivered to cuproenzymes, or excreted into bile via ATP7B, the primary route of elimination.[4]

Key Copper-Dependent Enzymes​

EnzymeFunctionCopper-Related Clinical Relevance
Cytochrome c oxidaseTerminal electron-transport-chain enzyme; mitochondrial respirationMitochondrial dysfunction, lactic acidosis
Cu/Zn superoxide dismutase (SOD1)Antioxidant defense; scavenges superoxide radicalsOxidative stress; SOD1-associated ALS is a separate genetic disease, not a diagnosis of nutritional copper deficiency
Ceruloplasmin (ferroxidase)Iron oxidation (Fe²⁺ → Fe³⁺) for transferrin loadingImpaired iron handling and anemia; aceruloplasminemia is a separate genetic disorder
Lysyl oxidaseCrosslinks collagen and elastin in connective tissueVascular fragility, bone abnormalities, skin laxity
Dopamine-β-hydroxylaseConverts dopamine → norepinephrineDysautonomia, orthostatic hypotension (Menkes)
TyrosinaseMelanin synthesisHypopigmentation of hair and skin
Peptidylglycine α-amidating monooxygenase (PAM)Amidation of neuropeptidesImpaired neuropeptide signaling

Dietary Sources and Requirements​

Copper is found in organ meats, shellfish, nuts, seeds, chocolate, legumes, and whole grains. For nonpregnant, nonlactating adults, the copper RDA is 0.9 mg/day; it is 1.0 mg/day in pregnancy and 1.3 mg/day during lactation.[29] The adult tolerable upper intake level is 10 mg/day from food and supplements; the upper limit does not govern medically supervised deficiency treatment.[29] Routine adult parenteral nutrition generally provides 0.3–0.5 mg/day IV, adjusted for losses and hepatobiliary function.[28][29]

Assessment of Copper Status​

  • Serum copper and ceruloplasmin. Interpret together with clinical risk, the laboratory's reference intervals and CRP and inflammation. Both can rise with inflammation, estrogen exposure and pregnancy; a normal value does not reliably exclude depletion in these settings. Low values also occur in conditions other than nutritional deficiency. Total serum copper alone cannot diagnose Wilson disease.[4][28][30]
  • 24-hour urinary copper. In a 55-case review of copper-deficiency myelopathy, 24-hour urinary copper was low in 13/26 measured cases, normal in 11/26, and elevated in 2/26.[27] For a complete, uncontaminated 24-hour collection (check volume and total creatinine), excretion above 100 μg/day is typical in symptomatic Wilson disease; values above 40 μg/day may warrant further investigation, particularly in children or asymptomatic individuals. Neither threshold establishes the diagnosis alone.[4][10][30]
  • Non-ceruloplasmin-bound copper (NCC). The subtraction estimate is assay dependent and can produce biologically impossible negative values. Do not use a calculated “free copper” result as a stand-alone diagnostic test. EASL–ERN 2025 incorporates the Leipzig score and relative exchangeable copper, where available, into a specialist diagnostic assessment.[30]
  • Functional cuproenzyme assays are research or specialist methods rather than routine first-line clinical tests.[1]

Causes of Deficiency​

CategoryExamples
Zinc-inducedExcessive zinc supplements, zinc-containing denture adhesives, coin ingestion
MalabsorptionBariatric surgery (RYGB, BPD/DS), celiac disease, short bowel syndrome, IBD
Inadequate intakeTPN without copper supplementation, severe malnutrition
Increased lossesProlonged continuous renal-replacement therapy
GeneticMenkes disease (ATP7A mutations)

Excess zinc upregulates metallothionein in enterocytes, which has a higher affinity for copper than zinc. When these enterocytes are sloughed, copper is lost into the GI tract, a functional copper malabsorption state.[12] A 2026 systematic review of 37 cases found zinc-induced hematologic toxicity most commonly resulted from oral supplements, denture-adhesive creams, and coin ingestion, with daily elemental zinc doses ranging from approximately 50 mg to > 1,500 mg.[13] In a Scottish national review, 9 of 16 copper-deficient patients were using zinc-containing dental fixatives at diagnosis.[12] In a retrospective case-note review of 70 patients prescribed zinc, 62% were prescribed doses sufficient to cause copper deficiency; plasma copper was measured in only 2.[14] Unexplained anemia (9%) and compatible neurologic symptoms (7%) were signals in this retrospective audit and not confirmed incidence estimates of zinc-induced copper deficiency.[14]

Clinical Manifestations of Deficiency​

Hematologic — The MDS Mimic​

Copper deficiency can cause anemia (macrocytic, normocytic, or microcytic), neutropenia, and less commonly thrombocytopenia or pancytopenia.[7][12][15] Bone marrow findings include vacuolated myeloid and erythroid precursors, ring sideroblasts, and multilineage dysplasia, potentially mimicking myelodysplastic syndrome (MDS).[12][13] In the 16-patient Scottish review, 14/15 cytopenias (93%) normalized within 8–12 weeks after oral copper replacement and removal of zinc exposure.[12] In the same severe-hypocupremia series, neurologic symptoms partly improved in 3/12 (25%), were unchanged in 5/12 (42%) and deteriorated in 4/12 (33%).[12] Include copper testing in the evaluation of otherwise unexplained cytopenias when malabsorption or excess zinc is plausible.[12]

Neurologic — Myeloneuropathy Mimicking B12 SCD​

Myeloneuropathy mimicking subacute combined degeneration (vitamin B12 deficiency) is the most important neurologic manifestation, peaking in the 5th–6th decades with a female predominance.[16][9] Patients present with:

  • Posterior column dysfunction (sensory ataxia, loss of vibration and proprioception)
  • Spasticity and hyperreflexia (UMN signs)
  • Peripheral neuropathy (large fiber > small fiber)
  • Urinary dysfunction in some patients, less commonly than gait and sensory abnormalities.[27]

MRI may show dorsal cervical or thoracic cord T2 hyperintensity resembling B12-related subacute combined degeneration; a normal MRI does not exclude the condition. Spinal MRI was abnormal in 22 of the 47 cases with reported MRI results (47%) in an older 55-case review.[27] A 2024 systematic review assembled 198 reported cases, including 55 with prior gastric surgery. It reported neurologic improvement in 24% and return to baseline in 5.1%, but these are selected published cases with variable follow-up and not reliable individual prognostic probabilities.[9] The consistent clinical message is to diagnose and treat promptly because neurologic recovery may be incomplete.[9]

Other​

Hypopigmentation of hair, impaired wound healing, osteoporosis, increased susceptibility to infections (neutropenia and impaired phagocytic function).[1][8][17]

Immune Function​

Copper is needed for both innate and adaptive immunity. Neutropenia is a recognized manifestation of copper deficiency. Human reports describe altered phagocytosis in copper deficiency, while evidence for oxidative-burst and microbial-killing defects comes mainly from animal studies; the effects of marginal deficiency in humans remain uncertain.[17] Macrophages actively accumulate copper in phagosomes via ATP7A translocation to kill intracellular pathogens, a mechanism particularly important in defense against mycobacteria.[18][19]

Treatment of Copper Deficiency​

Replacement depends on severity, absorption and ongoing losses. ASMBS post-bariatric guidance (Grade C/BEL 3) recommends oral elemental copper 3–8 mg/day for mild-to-moderate deficiency until indices normalize, and initial IV copper 2–4 mg/day for severe deficiency for 6 days or until serum levels normalize and neurologic symptoms resolve, with reassessment and subsequent oral treatment as appropriate.[31] These are low-certainty recommendations for that population. ESPEN 2024 general clinical-nutrition guidance gives a different severe-deficiency regimen (4–8 mg/day IV by slow infusion); select the regimen with the nutrition and pharmacy team rather than combining them.[20][28][31]

Remove an excessive zinc source and investigate the underlying cause. Monitor copper indices, blood counts and neurologic response; hematologic recovery generally occurs over weeks, while neurologic improvement may be partial. After normalization, ASMBS recommends copper monitoring every 3 months in patients treated for copper deficiency after weight-loss surgery (Grade C, BEL 3).[7][12][15][31]

Post-Bariatric Surgery Monitoring​

  • RYGB or BPD/DS: ASMBS 2016 recommends 2 mg/day copper supplementation and copper-status screening every 3–6 months in the first year, then at least annually, using serum copper and ceruloplasmin (Grade C, BEL 4 for screening).[31]
  • Sleeve gastrectomy or adjustable gastric band: ASMBS 2016 recommends 1 mg/day copper for both; OMA 2025 lists 2 mg/day as the minimum for sleeve gastrectomy.[31][34]
  • Assess sooner for unexplained anemia, neutropenia, myeloneuropathy, poor healing or excess zinc exposure.
  • The preventive ratio of 8–15 mg elemental zinc per 1 mg copper belongs to bariatric supplementation guidance.[31] It is not an instruction to add copper to Wilson disease treatment.[20][31]

Genetic Disorders of Copper Metabolism​

Menkes Disease​

X-linked recessive disorder caused by mutations in ATP7A, resulting in impaired intestinal copper absorption and defective copper delivery to cuproenzymes.[11][21] Clinical features reflect decreased activity of copper-dependent enzymes:

  • Presents at 2–3 months of age with hypotonia, seizures, failure to thrive, progressive neurodegeneration.
  • Characteristic sparse, kinky ("steely") hair, hypopigmentation, and connective-tissue abnormalities, including bladder diverticula. A Korean retrospective series documented diverticula in 8/11 children who underwent urologic imaging.[36]
  • Low serum copper and ceruloplasmin (though unreliable in neonates).
  • Without treatment, death typically by age 3 years.

The FDA approved Zycubo (copper histidinate) on January 12, 2026 for pediatric Menkes disease, the first US-approved treatment.[32] Among children born after 1999 with severe pathogenic ATP7A variants in the FDA's external-control comparison, Zycubo started within four weeks of birth (corrected for prematurity where applicable) was associated with lower mortality (31 treated versus 17 untreated; overall-survival HR 0.22, 95% CI 0.10–0.49).[32] No child in the external-control cohort survived beyond six years.[32] Neurologic outcome depends on timing and genotype; prevention of neurodegeneration is not guaranteed. The approval does not include occipital horn syndrome. Zycubo labeling calls for serum copper and ceruloplasmin, electrolytes, kidney and liver function, and blood counts every 6 weeks for the first 6 months, every 3 months for the next 18 months, then every 6 months; copper accumulation can cause renal tubular injury, hepatic dysfunction and hematologic abnormalities.[21][22][32][35]

Persistent dopamine-β-hydroxylase dysfunction can contribute to dysautonomia. A 2026 droxidopa crossover study enrolled only three men (two with Menkes disease and one with occipital horn syndrome), primarily to assess safety.[23]

Wilson Disease​

Autosomal recessive disorder caused by mutations in ATP7B, resulting in impaired biliary copper excretion and toxic copper accumulation in liver, brain, cornea, kidneys.[4][6][10] Features:

  • Progressive liver disease (hepatitis, cirrhosis, acute liver failure).
  • Neuropsychiatric manifestations (dystonia, tremor, dysarthria, psychiatric symptoms).
  • Renal tubular dysfunction (Fanconi syndrome, including defective urinary acidification) and nephrolithiasis can occur.[4]
  • Kayser-Fleischer rings (corneal copper deposition in Descemet's membrane).
  • Ceruloplasmin may be low (< 20 mg/dL), but this is nonspecific; basal 24-hour urine copper is typically > 100 μg/day in symptomatic untreated patients, while lower values can occur in asymptomatic patients and children.[4] Hepatic copper may be elevated on biopsy.[10][4]

Treatment requires specialist selection of chelators (D-penicillamine or trientine) or zinc and lifelong monitoring for under- and overtreatment. EASL–ERN 2025 recommends chelators for significant liver disease; absence of symptoms does not automatically make zinc the appropriate initial treatment. Zinc reduces intestinal copper absorption through metallothionein induction.[4][30]

Cuproptosis — An Emerging Concept​

Cuproptosis (2022) is a recently described form of copper-dependent regulated cell death distinct from apoptosis, necrosis, and ferroptosis.[24][25] Excess intracellular copper directly binds to lipoylated proteins in the TCA cycle (particularly DLAT), causing aggregation and destabilizing iron-sulfur cluster proteins, which leads to mitochondrial proteotoxic stress and cell death.[24][26] Particularly active in cells relying on oxidative phosphorylation, a potential therapeutic vulnerability in certain cancers, currently preclinical.[25]

Reconstructive Relevance​

Reconstructive scenarioPractical action
Myeloneuropathy with relevant nutritional risk, with or without bladder dysfunctionCheck copper, ceruloplasmin, zinc and B12 status as part of a neurologic evaluation; consider coexisting deficiencies. Do not assume B12/MMA must be normal or MRI must be abnormal. Address excessive zinc and arrange prompt replacement when deficient.[7][27]
Previous bariatric surgeryVerify the procedure-specific supplement plan and that scheduled surveillance is current; obtain additional testing when symptoms, poor intake, malabsorption or prior deficiency warrant it.[20][31]
Anemia with neutropenia or marrow dysplasiaConsider copper deficiency alongside the hematologic differential, particularly after gastric surgery or with excessive zinc. Do not postpone other indicated evaluation on the assumption that copper explains all cytopenias.[12][15]
Long-term parenteral nutrition or prolonged CRRTReview copper provision and monitoring with nutrition support; adjust for high losses or cholestasis. ESPEN recommends copper measurement when CRRT exceeds 2 weeks and every 6–12 months during long-term parenteral nutrition, with CRP measured concurrently for interpretation. CRRT losses occur in the effluent, not necessarily through urinary excretion.[7][28]
Wilson disease undergoing reconstructionAgree on a perioperative plan with hepatology and avoid unplanned treatment cessation. D-penicillamine or trientine may need temporary perioperative dose reduction to support wound healing; do not prescribe an automatic switch to trientine or a generic combined zinc/chelator schedule.[4][33]

See Also​

References​

1. Olivares M, Uauy R. "Copper as an Essential Nutrient." The American Journal of Clinical Nutrition. 1996;63(5):791S–796S. doi:10.1093/ajcn/63.5.791

2. Maung MT, Carlson A, Olea-Flores M, et al. "The Molecular and Cellular Basis of Copper Dysregulation and Its Relationship With Human Pathologies." FASEB Journal. 2021;35(9):e21810. doi:10.1096/fj.202100273RR

3. Gale J, Aizenman E. "The Physiological and Pathophysiological Roles of Copper in the Nervous System." European Journal of Neuroscience. 2024;60(1):3505–3543. doi:10.1111/ejn.16370

4. Schilsky ML, Roberts EA, Bronstein JM, et al. "A Multidisciplinary Approach to the Diagnosis and Management of Wilson Disease: 2022 AASLD Practice Guidance." Hepatology. 2025;82(3):E41–E90. doi:10.1002/hep.32801

5. Horn N, Møller LB, Nurchi VM, Aaseth J. "Chelating Principles in Menkes and Wilson Diseases: Choosing the Right Compounds in the Right Combinations at the Right Time." Journal of Inorganic Biochemistry. 2019;190:98–112. doi:10.1016/j.jinorgbio.2018.10.009

6. Członkowska A, Litwin T, Dusek P, et al. "Wilson Disease." Nature Reviews Disease Primers. 2018;4(1):21. doi:10.1038/s41572-018-0018-3

7. Altarelli M, Ben-Hamouda N, Schneider A, Berger MM. "Copper Deficiency: Causes, Manifestations, and Treatment." Nutrition in Clinical Practice. 2019;34(4):504–513. doi:10.1002/ncp.10328

8. Uauy R, Olivares M, Gonzalez M. "Essentiality of Copper in Humans." The American Journal of Clinical Nutrition. 1998;67(5 Suppl):952S–959S. doi:10.1093/ajcn/67.5.952S

9. Chen JW, Zeoli T, Hughes NC, Lane A, Berkman RA. "Copper Deficiency Myelopathy Mimicking Cervical Spondylitic Myelopathy: A Systematic Review of the Literature With Case Report." The Spine Journal. 2024;24(11):2026–2034. doi:10.1016/j.spinee.2024.06.018

10. Roberts EA, Schilsky ML. "Current and Emerging Issues in Wilson's Disease." The New England Journal of Medicine. 2023;389(10):922–938. doi:10.1056/NEJMra1903585

11. Bandmann O, Weiss KH, Kaler SG. "Wilson's Disease and Other Neurological Copper Disorders." The Lancet Neurology. 2015;14(1):103–113. doi:10.1016/S1474-4422(14)70190-5

12. Gabreyes AA, Abbasi HN, Forbes KP, et al. "Hypocupremia associated cytopenia and myelopathy: a national retrospective review." European Journal of Haematology. 2013;90(1):1–9. doi:10.1111/ejh.12020

13. Dutta A, Chaudhary V, Kumari S, et al. "Zinc-Induced Hematologic Toxicities: A Systematic Review of Descriptive Studies." Biological Trace Element Research. 2026. doi:10.1007/s12011-026-05136-z

14. Duncan A, Yacoubian C, Watson N, Morrison I. "The Risk of Copper Deficiency in Patients Prescribed Zinc Supplements." Journal of Clinical Pathology. 2015;68(9):723–725. doi:10.1136/jclinpath-2014-202837

15. Myint ZW, Oo TH, Thein KZ, Tun AM, Saeed H. "Copper Deficiency Anemia: Review Article." Annals of Hematology. 2018;97(9):1527–1534. doi:10.1007/s00277-018-3407-5

16. Gwathmey KG, Grogan J. "Nutritional neuropathies." Muscle & Nerve. 2020;62(1):13–29. doi:10.1002/mus.26783

17. Stefanache A, Lungu II, Butnariu IA, et al. "Understanding How Minerals Contribute to Optimal Immune Function." Journal of Immunology Research. 2023;2023:3355733. doi:10.1155/2023/3355733

18. Neyrolles O, Wolschendorf F, Mitra A, Niederweis M. "Mycobacteria, metals, and the macrophage." Immunological Reviews. 2015;264(1):249–263. doi:10.1111/imr.12265

19. Focarelli F, Giachino A, Waldron KJ. "Copper Microenvironments in the Human Body Define Patterns of Copper Adaptation in Pathogenic Bacteria." PLoS Pathogens. 2022;18(7):e1010617. doi:10.1371/journal.ppat.1010617

20. Mechanick JI, Apovian C, Brethauer S, et al. "Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures — 2019 Update." Obesity. 2020;28(4):O1–O58. doi:10.1002/oby.22719

21. Kaler SG, Holmes CS, Goldstein DS, et al. "Neonatal Diagnosis and Treatment of Menkes Disease." The New England Journal of Medicine. 2008;358(6):605–614. doi:10.1056/NEJMoa070613

22. Kaler SG. "Neurodevelopment and Brain Growth in Classic Menkes Disease Is Influenced by Age and Symptomatology at Initiation of Copper Treatment." Journal of Trace Elements in Medicine and Biology. 2014;28(4):427–430. doi:10.1016/j.jtemb.2014.08.008

23. Kaler MM, Brock G, Jeanty CJ, et al. "Safety and Efficacy of Droxidopa for Dysautonomia in Adults With Menkes Disease and Occipital Horn Syndrome in the USA: A Randomised Phase 1/2a Crossover Trial." EClinicalMedicine. 2026;94:103898. doi:10.1016/j.eclinm.2026.103898

24. Liu WQ, Lin WR, Yan L, Xu WH, Yang J. "Copper homeostasis and cuproptosis in cancer immunity and therapy." Immunological Reviews. 2024;321(1):211–227. doi:10.1111/imr.13276

25. Qin W, Sheng H, Hu X, et al. "Cuproptosis in Cancer: Emerging Mechanism and Therapeutic Opportunities." Trends in Pharmacological Sciences. 2026;47(4):386–402. doi:10.1016/j.tips.2026.02.004

26. Liu S, Chang Y, Li J, et al. "Copper and Cuproptosis: From Homeostasis to Pathogenesis." Chemico-Biological Interactions. 2026;431:112007. doi:10.1016/j.cbi.2026.112007

27. Jaiser SR, Winston GP. "Copper deficiency myelopathy." Journal of Neurology. 2010;257:869–881. doi:10.1007/s00415-010-5511-x

28. Berger MM, Shenkin A, Dizdar OS, et al. "ESPEN practical short micronutrient guideline." Clinical Nutrition. 2024;43:825–857. doi:10.1016/j.clnu.2024.01.030. Full guideline, section 6.

29. NIH Office of Dietary Supplements. Copper: Health Professional Fact Sheet.

30. European Association for the Study of the Liver. "EASL–ERN Clinical Practice Guidelines on Wilson's disease." Journal of Hepatology. 2025;82:690–728. doi:10.1016/j.jhep.2024.11.007

31. Parrott J, Frank L, Rabena R, et al. "American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients." Surgery for Obesity and Related Diseases. 2017;13:727–741. doi:10.1016/j.soard.2016.12.018. Guideline tables.

32. US FDA. FDA Approves First Treatment for Children With Menkes Disease. January 12, 2026. Zycubo trial snapshot.

33. Schilsky ML, Roberts EA, Bronstein JM, et al. "A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 practice guidance on Wilson disease from the American Association for the Study of Liver Diseases." Hepatology. doi:10.1002/hep.32805.

34. Benson-Davies S, Frederiksen K, Patel R. "Bariatric nutrition and evaluation of the metabolic surgical patient: Update to the 2022 Obesity Medicine Association (OMA) bariatric surgery, gastrointestinal hormones, and the microbiome clinical practice statement (CPS)." Obes Pillars. 2025;13:100154. doi:10.1016/j.obpill.2024.100154

35. US Food and Drug Administration. "ZYCUBO (copper histidinate) for injection: Prescribing information." January 2026. FDA label.

36. Kim MY, Kim JH, Cho MH, et al. "Urological problems in patients with Menkes disease." J Korean Med Sci. 2019;34(1):e4. doi:10.3346/jkms.2019.34.e4