Recent research has implicated abnormal copper homeostasis in the underlying pathophysiology of several clinically important disorders, some of which may be encountered by the anesthetist in daily clinical practice. The purpose of this narrative review is to summarize the physiology and pharmacology of copper, the clinical implications of abnormal copper metabolism, and the subsequent influence of altered copper homeostasis on anesthetic management. 1. Introduction Copper is an essential trace element whose absorption, distribution, and elimination are highly regulated. In vivo, copper is required for the catalytic activity of several critical enzyme systems. Copper zinc superoxide dismutase (Cu/Zn SOD) acts as a free radical scavenger, cytochrome c oxidase functions in energy production, dopamine β-hydroxylase catalyzes the conversion of dopamine into noradrenaline, tyrosinase is required for pigment formation, ceruloplasmin is a copper transport protein and anti-oxidant, and lysyl oxidase (LOX) is important for tissue integrity [1]. Copper dependent transcriptions factors may also play an important role in the regulation of cellular proliferation [2]. Clinically defined copper deficiency is rare in western societies; however, altered copper metabolism may influence the conduct and outcome of anesthesia secondary to abnormalities in hemopoietic, cardiovascular, connective tissue, immune and nervous systems. Clinically relevant circumstances predisposing to copper deficiency can include prolonged unsupplemented total parental nutrition (TPN) or enteral nutrition, infants fed with unmodified cow milk based diets, prematurity, gastric bypass and laparoscopic adjustable gastric banding surgery, burns, malabsorption syndromes, and large doses of over the counter vitamins containing zinc and iron [3]. Loss of ceruloplasmin bound copper can also occur in patients undergoing continuous ambulatory peritoneal dialysis for renal failure [4]. Clinical copper toxicity is also rare but is found in genetic overload disorders, occupational exposure, or through ingestion and may also influence anesthetic management through multiorgan failure [5]. 2. Distribution of Total Body Copper Content Copper is the third most abundant trace element in the body. It is readily absorbed from the diet and is found in foods including legumes, potatoes, grains, shellfish, and beef. Minor sources include tap water, jewellery, intrauterine devices, copper containing pesticides, and cooking utensils. Daily intake is approximately 1.5？mg depending on dietary copper content and regional
References
[1]
C. G. Fraga, “Relevance, essentiality and toxicity of trace elements in human health,” Molecular Aspects of Medicine, vol. 26, no. 4-5, pp. 235–244, 2005.
[2]
S. Itoh, W. K. Ha, O. Nakagawa et al., “Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation,” Journal of Biological Chemistry, vol. 283, no. 14, pp. 9157–9167, 2008.
[3]
A. Boyuk, O. Banli, M. Gumus, et al., “Plasma levels of zinc, copper, and ceruloplasmin in patients after undergoing laparoscopic adjustable gastric banding,” Biological Trace Element Research, vol. 143, no. 3, pp. 1282–1288, 2011.
[4]
D. Beshgetoor and M. Hambidge, “Clinical conditions altering copper metabolism in humans,” American Journal of Clinical Nutrition, vol. 67, no. 5, pp. 1017S–1021S, 1998.
[5]
B. R. Stern, M. Solioz, D. Krewski et al., “Copper and human health: biochemistry, genetics, and strategies for modeling dose-response relationships,” Journal of Toxicology and Environmental Health B, vol. 10, no. 3, pp. 157–222, 2007.
[6]
K. A. Cockell, J. Bertinato, and M. R. L'Abbé, “Regulatory frameworks for copper considering chronic exposures of the population,” American Journal of Clinical Nutrition, vol. 88, no. 3, pp. 863S–866S, 2008.
[7]
D. G. Barceloux, “Copper,” Journal of Toxicology, vol. 37, no. 2, pp. 217–230, 1999.
[8]
R. A. Wapnir, “Copper absorption and bioavailability,” American Journal of Clinical Nutrition, vol. 67, supplement 5, pp. 1054S–1060S, 1998.
[9]
M. Arredondo and M. T. Nunez, “Iron and copper metabolism,” Molecular Aspects of Medicine, vol. 26, no. 4-5, pp. 313–327, 2005.
[10]
P. V. E. van den Berghe and L. W. J. Klomp, “New developments in the regulation of intestinal copper absorptionn,” Nutrition Reviews, vol. 67, no. 11, pp. 658–672, 2009.
[11]
J. P. Kehrer, “The Haber-Weiss reaction and mechanisms of toxicity,” Toxicology, vol. 149, no. 1, pp. 43–50, 2000.
[12]
J. R. Prohaska, “Biochemical changes in copper deficiency,” Journal of Nutritional Biochemistry, vol. 1, no. 9, pp. 452–461, 1990.
[13]
C. T. Dameron and M. D. Harrison, “Mechanisms for protection against copper toxicity,” American Journal of Clinical Nutrition, vol. 67, no. 5, pp. 1091S–1097S, 1998.
[14]
H. J. McArdle, H. S. Andersen, H. Jones, and L. Gambling, “Copper and iron transport across the placenta: regulation and interactions,” Journal of Neuroendocrinology, vol. 20, no. 4, pp. 427–431, 2008.
[15]
S. G. Kaler, “Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency,” American Journal of Clinical Nutrition, vol. 67, no. 5, pp. 1029S–1034S, 1998.
[16]
B. C. Kirodian, N. J. Gogtay, V. P. Udani, and N. A. Kshirsagar, “Treatment of menkes disease with parenteral copper histidine,” Indian Pediatrics, vol. 39, no. 2, pp. 183–185, 2002.
[17]
E. A. Roberts and B. Sarkar, “Liver as a key organ in the supply, storage, and excretion of copper,” American Journal of Clinical Nutrition, vol. 88, no. 3, pp. 851S–584S, 2008.
[18]
A. Ala, A. P. Walker, K. Ashkan, J. S. Dooley, and M. L. Schilsky, “Wilson's disease,” The Lancet, vol. 369, no. 9559, pp. 397–408, 2007.
[19]
G. J. Brewer, “Recognition, diagnosis, and management of Wilson's disease,” Proceedings of the Society for Experimental Biology and Medicine, vol. 223, no. 1, pp. 39–46, 2000.
[20]
D. B. Milne, “Copper intake and assessment of copper status,” American Journal of Clinical Nutrition, vol. 67, no. 5, pp. 1041S–1045S, 1998.
[21]
I. Iakovidis, I. Delimaris, and S. M. Piperakis, “Copper and its complexes in medicine: a biochemical approach,” Molecular Biology International, vol. 2011, Article ID 594529, 13 pages, 2011.
[22]
M. Olivares, M. A. Mendez, P. A. Astudillo, et al., “Present situation of biomarkers for copper status,” American Journal of Clinical Nutrition, vol. 88, no. 3, pp. 859S–862S, 2008.
[23]
S. G. Kaler, C. S. Holmes, D. S. Goldstein et al., “Neonatal diagnosis and treatment of Menkes disease,” New England Journal of Medicine, vol. 358, no. 6, pp. 605–614, 2008.
[24]
R. Arnon, J. F. Calderon, M. Schilsky, S. Emre, and B. L. Shneider, “Wilson disease in children: serum aminotransferases and urinary copper on triethylene tetramine dihydrochloride (trientine) treatment,” Journal of Pediatric Gastroenterology and Nutrition, vol. 44, no. 5, pp. 596–602, 2007.
[25]
E. S？zeri, D. Feist, H. Ruder, and K. Sch？rer, “Proteinuria and other renal functions in Wilson's disease,” Pediatric Nephrology, vol. 11, no. 3, pp. 307–311, 1997.
[26]
E. A. Roberts and M. L. Schilsky, “Diagnosis and treatment of Wilson disease: an update,” Hepatology, vol. 47, no. 6, pp. 2089–2111, 2008.
[27]
E. Madsen and J. D. Gitlin, “Copper and iron disorders of the brain,” Annual Review of Neuroscience, vol. 30, pp. 317–337, 2007.
[28]
F. Aedo, R. Delgado, D. Wolff, and C. Vergara, “Copper and zinc as modulators of neuronal excitability in a physiologically significant concentration range,” Neurochemistry International, vol. 50, no. 4, pp. 591–600, 2007.
[29]
R. Delgado, C. Vergara, and D. Wolff, “Divalent cations as modulators of neuronal excitability: emphasis on copper and zinc,” Biological Research, vol. 39, no. 1, pp. 173–182, 2006.
[30]
H. T. Liu, M. W. Hollmann, W. H. Liu, C. W. Hoenemann, and M. E. Durieux, “Modulation of NMDA receptor function by ketamine and magnesium: part I,” Anesthesia and Analgesia, vol. 92, no. 5, pp. 1173–1181, 2001.
[31]
M. L. Schlief and J. D. Gitlin, “Copper homeostasis in the CNS: a novel link between the NMDA receptor and copper homeostasis in the hippocampus,” Molecular Neurobiology, vol. 33, no. 2, pp. 81–90, 2006.
[32]
S. Lutsenko, A. Bhattacharjee, and A. L. Hubbard, “Copper handling machinery of the brain,” Metallomics, vol. 2, no. 9, pp. 596–608, 2010.
[33]
V. Desai and S. G. Kaler, “Role of copper in human neurological disorders,” American Journal of Clinical Nutrition, vol. 88, no. 3, pp. 855S–888S, 2008.
[34]
J. C. Tan, D. L. Burns, and H. R. Jones, “Severe ataxia, myelopathy, and peripheral neuropathy due to acquired copper deficiency in a patient with history of gastrectomy,” Journal of Parenteral and Enteral Nutrition, vol. 30, no. 5, pp. 446–450, 2006.
[35]
N. Kumar, “Copper deficiency myelopathy (human swayback),” Mayo Clinic Proceedings, vol. 81, no. 10, pp. 1371–1384, 2006.
[36]
J. T. Saari and D. A. Schuschke, “Cardiovascular effects of dietary copper deficiency,” BioFactors, vol. 10, no. 4, pp. 359–375, 1999.
[37]
J. D. Hicks, A. Donsante, T. M. Pierson, et al., “Increased frequency of congenital heart defects in Menkes disease,” Clinical Dysmorphology, vol. 21, no. 2, pp. 59–63, 2012.
[38]
Z. Hlubocka, Z. Marecek, A. Linhart, et al., “Cardiac involvement in Wilson disease,” Journal of Inherited Metabolic Disease, vol. 25, no. 4, pp. 269–277, 2002.
[39]
S. T. Zhang, X. G. Li, and C. H. Liu, “Effects of copper chloride on electromechanical activities of myocardial cells,” Zhongguo Yao Li Xue Bao, vol. 11, pp. 166–168, 1990.
[40]
Y. F. Qi and X. P. Che, “Effects of Cu2+ on the neuromuscular junction transmission,” Acta Pharmaceutica Sinica, vol. 27, no. 2, pp. 81–85, 1992.
[41]
N. Prasun, M. Bagchi, A. Joseph et al., “Recurrent bleeding and bulbar myasthenia-like symptoms as the initial presentation of Wilson's disease: a case report,” Neurology Asia, vol. 16, no. 2, pp. 167–169, 2011.
[42]
F. Agertt, A. C. S. Crippa, P. J. Lorenzoni et al., “Menkes' disease: case report,” Arquivos de Neuro-Psiquiatria, vol. 65, no. 1, pp. 157–160, 2007.
[43]
L. Zhang, J. Lv, and S. Sun, “Elements in lung tissues of patients from a high lung cancer incidence area of China,” Biological Trace Element Research, vol. 148, no. 1, pp. 7–10, 2012.
[44]
A. C. Tanrikulu, A. Abakay, O. Evliyaoglu, et al., “Coenzyme Q10, copper, zinc, and lipid peroxidation levels in serum of patients with chronic obstructive pulmonary disease,” Biological Trace Element Research, vol. 143, no. 2, pp. 659–667, 2011.
[45]
V. L. Kinnula and J. D. Crapo, “Superoxide dismutases in the lung and human lung diseases,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 12, pp. 1600–1619, 2003.
[46]
S. Mizuno, M. Yasuo, H. J. Bogaard, et al., “Copper deficiency induced emphysema is associated with focal adhesion kinase inactivation,” PLoS One, vol. 7, Article ID e30678, 2012.
[47]
J. D. Tobias, “Anaesthetic considerations in the child with Menkes' syndrome,” Canadian Journal of Anaesthesia, vol. 39, no. 7, pp. 712–715, 1992.
[48]
M. Passariello, N. Almenrader, and P. Pietropaoli, “Anesthesia for a child with Menkes disease,” Paediatric Anaesthesia, vol. 18, no. 12, pp. 1225–1226, 2008.
[49]
A. B. de Souza Hobaika, “Anesthesia for a patient with Wilson's disease—a case report,” Middle East Journal of Anesthesiology, vol. 19, no. 4, pp. 905–908, 2008.
[50]
M. Baykal and S. Karapolat, “Anesthetic management of a pediatric patient with wilsons disease,” Journal of Clinical Medicine Research, vol. 2, no. 2, pp. 99–101, 2010.
[51]
R. Vaja, L. McNicol, and I. Sisley, “Anaesthesia for patients with liver disease,” Continuing Education in Anaesthesia, Critical Care and Pain, vol. 10, no. 1, Article ID mkp040, pp. 15–19, 2009.
[52]
P. Narayanan, G. Chetan, and S. Mahadevan, “Wilson's disease presenting as respiratory failure,” Indian Journal of Pediatrics, vol. 73, no. 1, pp. 99–100, 2006.
[53]
M. S. Mandell, “Hepatopulmonary syndrome and portopulmonary hypertension in the model for end-stage liver disease (MELD) era,” Liver Transplantation, vol. 10, no. 10, pp. S54–S58, 2004.
[54]
S. S. Percival, “Copper and immunity,” American Journal of Clinical Nutrition, vol. 67, supplement 5, pp. 1064S–1068S, 1998.
[55]
M. Bonham, J. M. O'Connor, B. M. Hannigan, and J. J. Strain, “The immune system as a physiological indicator of marginal copper status?” British Journal of Nutrition, vol. 87, no. 5, pp. 393–403, 2002.
[56]
C. White, J. Lee, T. Kambe, K. Fritsche, and M. J. Petris, “A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity,” Journal of Biological Chemistry, vol. 284, no. 49, pp. 33949–33956, 2009.
[57]
J. R. Turnlund, R. A. Jacob, C. L. Keen et al., “Long-term high copper intake: effects on indexes of copper status, antioxidant status, and immune function in young men,” American Journal of Clinical Nutrition, vol. 79, no. 6, pp. 1037–1044, 2004.
[58]
A. Czlonkowska and B. Milewski, “Immunological observations on patients with Wilson's disease,” Journal of the Neurological Sciences, vol. 29, no. 2–4, pp. 411–421, 1976.
[59]
P. Milkiewicz, S. Saksena, S. G. Hubscher, and E. Elias, “Wilson's disease with superimposed autoimmune features: report of two cases and review,” Journal of Gastroenterology and Hepatology, vol. 15, no. 5, pp. 570–574, 2000.
[60]
R. G. Santos, F. Alissa, J. Reyes, L. Teot, and N. A. Ameen, “Fulminant hepatic failure: Wilson's disease or autoimmune hepatitis? Implications for transplantation,” Pediatric Transplantation, vol. 9, no. 1, pp. 112–116, 2005.
[61]
O. Imataki, H. Ohnishi, A. Kitanaka, Y. Kubota, T. Ishida, and T. Tanaka, “Pancytopenia complicated with peripheral neuropathy due to copper deficiency: clinical diagnostic review,” Internal Medicine, vol. 47, no. 23, pp. 2063–2065, 2008.
[62]
S. Sharma, A. Toppo, B. Rath, A. Harbhajanka, and P. Lalita Jyotsna, “Hemolytic anemia as a presenting feature of wilson's disease: a case report,” Indian Journal of Hematology and Blood Transfusion, vol. 26, no. 3, pp. 101–102, 2010.
[63]
K. F. Adams, G. Johnson Jr., K. E. Hornowski, and T. H. Lineberger, “The effect of copper on erythrocyte deformability. A possible mechanism of hemolysis in acute copper intoxication,” Biochim Biophys Acta, vol. 550, no. 2, pp. 279–287, 1979.
[64]
G. J. S. Cooper, “Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and alzheimers disease,” Drugs, vol. 71, no. 10, pp. 1281–1320, 2011.
[65]
S. Y. Goh and M. E. Cooper, “The role of advanced glycation end products in progression and complications of diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 4, pp. 1143–1152, 2008.
[66]
R. Linz, N. L. Barnes, A. M. Zimnicka, J. H. Kaplan, B. Eipper, and S. Lutsenko, “Intracellular targeting of copper-transporting ATPase ATP7A in a normal and Atp7b-/- kidney,” American Journal of Physiology, vol. 294, no. 1, pp. F53–F61, 2008.
[67]
X. H. Zhuang, Y. Mo, X. Y. Jiang, et al., “Analysis of renal impairment in children with Wilson's disease,” World Journal of Pediatrics, vol. 4, no. 2, pp. 102–105, 2008.
[68]
J. H. Sondheimer, S. K. Mahajan, D. L. Rye et al., “Elevated plasma copper in chronic renal failure,” American Journal of Clinical Nutrition, vol. 47, no. 5, pp. 896–899, 1988.
[69]
K. J. Ashok, M. P. Sajida, and S. Joseph, “Plasma ceruloplasmin in chronic renal failure patients undergoing haemodialysis,” Journal of Clinical and Diagnostic Research, vol. 4, no. 1, pp. 2058–2060, 2010.
[70]
J. E. Kiss, D. Berman, and D. Van Thiel, “Effective removal of copper by plasma exchange in fulminant Wilson's disease,” Transfusion, vol. 38, no. 4, pp. 327–331, 1998.
[71]
J. Vukelic, A. Kapamadzija, D. Petrovic, et al., “Variations of serum copper values in pregnancy,” Srpski Arhiv za Celokupno Lekarstvo, vol. 140, no. 1-2, pp. 42–46, 2012.
[72]
C. V. Iseminger, C. M. Anderson, and W. T. Johnson, “Placenta copper transport proteins in preeclampsia,” Journal of Federation of American Societies for Experimental Biology, vol. 24, p. 609.5, 2010.
[73]
C. L. Keen, J. Y. Uriu-Hare, S. N. Hawk et al., “Effect of copper deficiency on prenatal development and pregnancy outcome,” American Journal of Clinical Nutrition, vol. 67, no. 5, pp. 1003S–1011S, 1998.
[74]
L. R. Walker, M. Rattigan, and J. Canterino, “A case of isolated elevated copper levels during pregnancy,” Journal of Pregnancy, vol. 2011, Article ID 385767, 3 pages, 2011.
[75]
J. W. Crayton and W. J. Walsh, “Elevated serum copper levels in women with a history of post-partum depression,” Journal of Trace Elements in Medicine and Biology, vol. 21, no. 1, pp. 17–21, 2007.
[76]
C. Duncan and A. R. White, “Copper complexes as therapeutic agents,” Metallomics, vol. 4, no. 2, pp. 127–138, 2012.
[77]
C. T. Dillon, T. W. Hambley, B. J. Kennedy, P. A. Lay, J. E. Weder, and Q. Zhou, “Copper and zinc complexes as antiinflammatory drugs,” Metal Ions in Biological Systems, vol. 41, pp. 253–277, 2004.
[78]
N. Jiménez-Garrido, L. Perelló, R. Ortiz et al., “Antibacterial studies, DNA oxidative cleavage, and crystal structures of Cu(II) and Co(II) complexes with two quinolone family members, ciprofloxacin and enoxacin,” Journal of Inorganic Biochemistry, vol. 99, no. 3, pp. 677–689, 2005.
[79]
W. Szczepanik, P. Kaczmarek, and M. Jezowska-Bojczuk, “Oxidative activity of copper(II) complexes with aminoglycoside antibiotics as implication to the toxicity of these drugs,” Bioinorganic Chemistry and Applications, vol. 2, no. 1-2, pp. 55–68, 2004.
[80]
M. M. Correia dos Santos, V. Famila, and M. L. Sim？es Gon？alves, “Copper-psychoactive drug complexes: a voltammetric approach to complexation by 1,4-benzodiazepines,” Analytical Biochemistry, vol. 303, no. 2, pp. 111–119, 2002.
[81]
S. Okuyama, S. Hashimoto, and H. Aihara, “Copper complexes of non-steroidal antiinflammatory agents: analgesic activity and possible opioid receptor activation,” Agents and Actions, vol. 21, no. 1-2, pp. 130–144, 1987.
[82]
N. L. Salazar-Weber and J. P. Smith, “Copper inhibits NMDA receptor-independent LTP and modulates the paired-pulse ratio after LTP in mouse hippocampal slices,” International Journal of Alzheimer's Disease, vol. 2011, Article ID 864753, 10 pages, 2011.
[83]
R. A. Harris, S. John Mihic, J. E. Dildy-Mayfield, and T. K. Machu, “Actions of anesthetics on ligand-gated ion channels: role of receptor subunit composition,” FASEB Journal, vol. 9, no. 14, pp. 1454–1462, 1995.
[84]
D. Bousquet-Moore, X. M. Ma, E. A. Nillni et al., “Reversal of physiological deficits caused by diminished levels of peptidylglycine α-amidating monooxygenase by dietary copper,” Endocrinology, vol. 150, no. 4, pp. 1739–1747, 2009.
[85]
J. Wu, M. Ricker, and J. Muench, “Copper deficiency as cause of unexplained hematologic and neurologic deficits in patient with prior gastrointestinal surgery,” Journal of the American Board of Family Medicine, vol. 19, no. 2, pp. 191–194, 2006.
[86]
A. Shander, M. Javidroozi, S. Ozawa, et al., “What is really dangerous: anaemia or transfusion?” British Journal of Anaesthesia, vol. 107, supplement 1, pp. 41–59, 2011.
[87]
K. E. Littlewood, “The immunocompromised adult patient and surgery,” Best Practice and Research, vol. 22, no. 3, pp. 585–609, 2008.
[88]
J. R. Hebl, S. L. Kopp, D. R. Schroeder, and T. T. Horlocker, “Neurologic complications after neuraxial anesthesia or analgesia in patients with preexisting peripheral sensorimotor neuropathy or diabetic polyneuropathy,” Anesthesia and Analgesia, vol. 103, no. 5, pp. 1294–1299, 2006.
[89]
J. E. Schabel, “Subarachnoid block for a patient with progressive chronic inflammatory demyelinating polyneuropathy,” Anesthesia and Analgesia, vol. 93, no. 5, pp. 1304–1306, 2001.
[90]
M. Hughes, I. S. Grant, B. Biccard, and G. Nimmo, “Suxamethonium and critical illness polyneuropathy,” Anaesthesia and Intensive Care, vol. 27, no. 6, pp. 636–638, 1999.
[91]
C. Scurr, B. Sampson, J. Ball, and C. Gabriel, “Copper deficiency myeloneuropathy in a patient with haemachromatosis: a case report,” Cases Journal, vol. 2, no. 8, p. 6168, 2009.
[92]
J. R. Sneyd, “Propofol and epilepsy,” British Journal of Anaesthesia, vol. 82, no. 2, pp. 168–169, 1999.
[93]
D. S. Ramchandra, V. Anisya, and M. Gourie-Devi, “Ketamine monoanaesthesia for diagnostic muscle biopsy in neuromuscular disorders in infancy and childhood: floppy infant syndrome,” Canadian Journal of Anaesthesia, vol. 37, no. 4, pp. 474–476, 1990.
[94]
B. Plaud, O. Meretoja, R. Hofmockel et al., “Reversal of rocuronium-induced neuromuscular blockade with sugammadex in pediatric and adult surgical patients,” Anesthesiology, vol. 110, no. 2, pp. 284–294, 2009.
