Biological Trace Element Research

, Volume 168, Issue 1, pp 1–10 | Cite as

Serum Levels of Copper and Zinc in Patients with Rheumatoid Arthritis: a Meta-analysis

  • Lihong Xin
  • Xiao Yang
  • Guoqi Cai
  • Dazhi Fan
  • Qing Xia
  • Li Liu
  • Yanting Hu
  • Ning Ding
  • Shengqian Xu
  • Li Wang
  • Xiaona Li
  • Yanfeng Zou
  • Faming Pan
Article
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Abstract

Many publications with conflicting results have evaluated serum levels of copper (Cu) and zinc (Zn) in patients with rheumatoid arthritis (RA). To derive a more precise estimation of the relationship, a meta-analysis was conducted. Relevant published data were retrieved through PubMed, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Database (CBM) before September 20, 2014. Weighted mean difference (WMD) with a 95 % confidence interval (95 % CI) was calculated using STATA 11.0. A total of 26 studies, including 1444 RA cases and 1241 healthy controls, were collected in this meta-analysis. Pooled analysis found that patients with RA had a higher serum level of Cu and a lower serum Zn level than the healthy controls (Cu (μg/dl), WMD = 31.824, 95 % CI = 20.334, 43.314; Zn (μg/dl), WMD = −12.683, 95 % CI = −19.783, −5.584). Subgroup analysis showed that ethnicity had influence on the serum level of Cu (μg/dl) (Caucasian, WMD = 43.907, 95 % CI = 35.090, 52.723, P < 0.001; Asian, WMD = 14.545, 95 % CI = −12.365, 41.455, P = 0.289) and Zn (μg/dl) (Caucasian, WMD = −11.038, 95 % CI = −23.420, 1.344, P = 0.081; Asian, WMD = −14.179, 95 % CI = −18.963, −9.394, P < 0.001) in RA and healthy controls. No evidence of publication bias was observed. This meta-analysis suggests that increased serum level of Cu and decreased serum level of Zn are generally present in RA patients.

Keywords

Zinc Copper Rheumatoid arthritis Meta-analysis 
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Notes

Acknowledgments

The study was supported by grants from the National Natural Science Foundation of China (30771849, 30972530, 81273169).

Conflicts of interest

None of the authors has any conflicts of interest to declare.

References

  1. 1.
    Salgado E, Maneiro JR (2014) New therapies for rheumatoid arthritis. Med Clin. doi: 10.1016/j.medcli.2013.11.011 Google Scholar
  2. 2.
    Huizinga TW, Pincus T (2010) In the clinic. Rheumatoid arthritis. Ann Intern Med 153(1):ITC1-1–ITC1-15. doi: 10.7326/0003-4819-153-1-201007060-01001, quiz ITC11-16Google Scholar
  3. 3.
    Uhlig T, Moe RH, Kvien TK (2014) The burden of disease in rheumatoid arthritis. PharmacoEconomics 32(9):841–851. doi: 10.1007/s40273-014-0174-6 CrossRefPubMedGoogle Scholar
  4. 4.
    Onal S, Naziroglu M, Colak M, Bulut V, Flores-Arce MF (2011) Effects of different medical treatments on serum copper, selenium and zinc levels in patients with rheumatoid arthritis. Biol Trace Elem Res 142(3):447–455. doi: 10.1007/s12011-010-8826-7 CrossRefPubMedGoogle Scholar
  5. 5.
    Afridi HI, Kazi TG, Kazi N, Shah F (2012) Evaluation of status of zinc, copper, and iron levels in biological samples of normal and arthritis patients in age groups 46-60 and 61-75 years. Clin Lab 58(7–8):705–717PubMedGoogle Scholar
  6. 6.
    Chan S, Gerson B, Subramaniam S (1998) The role of copper, molybdenum, selenium, and zinc in nutrition and health. Clin Lab Med 18(4):673–685PubMedGoogle Scholar
  7. 7.
    Strecker D, Mierzecki A, Radomska K (2013) Copper levels in patients with rheumatoid arthritis. Ann Agric Environ Med 20(2):312–316PubMedGoogle Scholar
  8. 8.
    Tuncer S, Kamanli A, Akcil E, Kavas GO, Seckin B, Atay MB (1999) Trace element and magnesium levels and superoxide dismutase activity in rheumatoid arthritis. Biol Trace Elem Res 68(2):137–142. doi: 10.1007/bf02784402 CrossRefPubMedGoogle Scholar
  9. 9.
    Ala S, Shokrzadeh M, Pur Shoja AM, Saeedi Saravi SS (2009) Zinc and copper plasma concentrations in rheumatoid arthritis patients from a selected population in Iran. Pak J Biol Sci 12(14):1041–1044CrossRefPubMedGoogle Scholar
  10. 10.
    Morgenstern H, Machtey I (1983) Serum zinc and copper levels in rheumatoid arthritis. Arthritis Rheum 26(7):933–934CrossRefPubMedGoogle Scholar
  11. 11.
    Li J, Liang Y, Mao H, Deng W, Zhang J (2014) Effects of B-lymphocyte dysfunction on the serum copper, selenium and zinc levels of rheumatoid arthritis patients. Pak J Med Sci 30(5):1064–1067. doi: 10.12669/pjms.305.5214 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Mierzecki A, Strecker D, Radomska K (2011) A pilot study on zinc levels in patients with rheumatoid arthritis. Biol Trace Elem Res 143(2):854–862. doi: 10.1007/s12011-010-8952-2 PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Yazar M, Sarban S, Kocyigit A, Isikan UE (2005) Synovial fluid and plasma selenium, copper, zinc, and iron concentrations in patients with rheumatoid arthritis and osteoarthritis. Biol Trace Elem Res 106(2):123–132. doi: 10.1385/bter:106:2:123 CrossRefPubMedGoogle Scholar
  14. 14.
    Wang D, Chen C, Wang Y, Liu J, Lin R (2014) Effect of black tea consumption on blood cholesterol: a meta-analysis of 15 randomized controlled trials. PLoS One 9(9):e107711. doi: 10.1371/journal.pone.0107711 PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Jin X, Beguerie JR, Zhang W, Blizzard L, Otahal P, Jones G, Ding C (2013) Circulating C reactive protein in osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-204494 Google Scholar
  16. 16.
    Qian LQ, Chen JB MW, Dong GQ (2004) serum copper, zinc, iron and SOD content in patients with rheumatic diseases. Chin J Publ Health 20(6):750Google Scholar
  17. 17.
    Silverio Amancio OM, Alves Chaud DM, Yanaguibashi G, Esteves Hilario MO (2003) Copper and zinc intake and serum levels in patients with juvenile rheumatoid arthritis. Eur J Clin Nutr 57(5):706–712. doi: 10.1038/sj.ejcn.1601601 CrossRefPubMedGoogle Scholar
  18. 18.
    Wanchu A, Sud A, Bambery P, Prasad R, Kumar V (2002) Plasma and peripheral blood mononuclear cells levels of Zn and Cu among Indian patients with RA. Ann Rheum Dis 61(1):88PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Louro MO, Cocho JA, Mera A, Tutor JC (2000) Immunochemical and enzymatic study of ceruloplasmin in rheumatoid arthritis. J Trace Elem Med Biol: Organ Soc Miner Trace Elem (GMS) 14(3):174–178. doi: 10.1016/s0946-672x(00)80007-3 CrossRefGoogle Scholar
  20. 20.
    Zhang H, Sun SH, Lin YX, Mao Y (1997) Plasma copper, zinc and iron in rheumatoid arthritis. Chin J Postgraduates Med 20(8):433Google Scholar
  21. 21.
    Wang GC, Wang XD, Wang JB (1990) Analysis of erythrocyte superoxide dismutase and serum copper, zinc content in rheumatoid arthritis. Jiangsu Med J 11:602–603Google Scholar
  22. 22.
    Marrella M, Moretti U, Pasqualicchio M, Velo GP, Frigo A, Trevisani E, Bambara LM, Milanino R (1990) Plasma and total blood cell copper in rheumatoid arthritis. Agents Actions 29(1–2):120–121CrossRefPubMedGoogle Scholar
  23. 23.
    Dijkmans BA, van der Voet GB, Cats A, de Wolff FA (1987) Serum aluminium concentrations in patients with rheumatoid arthritis. Scand J Rheumatol 16(5):361–364CrossRefPubMedGoogle Scholar
  24. 24.
    Cimmino MA, Pane L, Cutolo M, Valente T, Rovida S (1986) Zinc concentrations in rheumatoid and psoriatic arthritis. Are they relevant to the inflammatory process? Scand J Rheumatol 15(4):403–406CrossRefPubMedGoogle Scholar
  25. 25.
    Conforti A, Franco L, Menegale G, Milanino R, Piemonte G, Velo GP (1983) Serum copper and ceruloplasmin levels in rheumatoid arthritis and degenerative joint disease and their pharmacological implications. Pharmacol Res Commun 15(9):859–867CrossRefPubMedGoogle Scholar
  26. 26.
    Banford JC, Brown DH, Hazelton RA, McNeil CJ, Sturrock RD, Smith WE (1982) Serum copper and erythrocyte superoxide dismutase in rheumatoid arthritis. Ann Rheum Dis 41(5):458–462PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Scudder PR, Al-Timimi D, McMurray W, White AG, Zoob BC, Dormandy TL (1978) Serum copper and related variables in rheumatoid arthritis. Ann Rheum Dis 37(1):67–70PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Aiginger P, Kolarz G, Willvonseder R (1978) Copper in ankylosing spondylitis and rheumatoid arthritis. Scand J Rheumatol 7(2):75–78CrossRefPubMedGoogle Scholar
  29. 29.
    Aaseth J, Munthe E, Forre O, Steinnes E (1978) Trace elements in serum and urine of patients with rheumatoid arthritis. Scand J Rheumatol 7(4):237–240CrossRefPubMedGoogle Scholar
  30. 30.
    McMurray W, Martin VM, Scudder P, Stocks J, White AG, Dormandy TL (1975) Urinary copper excretion in rheumatoid arthritis. Ann Rheum Dis 34(4):340–345PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Hansson L, Huunan-Seppala A, Mattila A (1975) The content of calcium, magnesium, copper, zinc, lead and chromium in the blood of patients with rheumatoid arthritis. Scand J Rheumatol 4(1):33–38CrossRefPubMedGoogle Scholar
  32. 32.
    Kennedy AC, Fell GS, Rooney PJ, Stevens WH, Dick WC, Buchanan WW (1975) Zinc: its relationship to osteoporosis in rheumatoid arthritis. Scand J Rheumatol 4(4):243–245CrossRefPubMedGoogle Scholar
  33. 33.
    Niedermeier W, Griggs JH (1971) Trace metal composition of synovial fluid and blood serum of patients with rheumatoid arthritis. J Chronic Dis 23(8):527–536CrossRefPubMedGoogle Scholar
  34. 34.
    Niedermeier W (1965) Concentration and chemical state of copper in synovial fluid and blood serum of patients with rheumatoid arthritis. Ann Rheum Dis 24(6):544–548PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Schweigel-Rontgen M (2014) The families of zinc (SLC30 and SLC39) and copper (SLC31) transporters. Curr Top Membr 73:321–355CrossRefPubMedGoogle Scholar
  36. 36.
    McMillin GA, Travis JJ, Hunt JW (2009) Direct measurement of free copper in serum or plasma ultrafiltrate. Am J Clin Pathol 131(2):160–165CrossRefPubMedGoogle Scholar
  37. 37.
    Schumann K, Classen HG, Dieter HH, Konig J, Multhaup G, Rukgauer M, Summer KH, Bernhardt J, Biesalski HK (2002) Hohenheim consensus workshop: copper. Eur J Clin Nutr 56(6):469–483. doi: 10.1038/sj.ejcn.1601315 CrossRefPubMedGoogle Scholar
  38. 38.
    Malavolta M, Piacenza F, Basso A, Giacconi R, Costarelli L, Mocchegiani E (2015) Serum copper to zinc ratio: relationship with aging and health status. Mech Ageing Dev. doi: 10.1016/j.mad.2015.01.004 PubMedGoogle Scholar
  39. 39.
    Tapiero H, Townsend DM, Tew KD (2003) Trace elements in human physiology and pathology. Copper Biomed Pharmacother 57(9):386–398CrossRefPubMedGoogle Scholar
  40. 40.
    Klareskog L, Catrina AI, Paget S (2009) Rheumatoid arthritis. Lancet 373(9664):659–672CrossRefPubMedGoogle Scholar
  41. 41.
    Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME (2012) Zinc and human health: an update. Arch Toxicol 86(4):521–534. doi: 10.1007/s00204-011-0775-1 CrossRefPubMedGoogle Scholar
  42. 42.
    Fukada T, Hojyo S, Furuichi T (2013) Zinc signal: a new player in osteobiology. J Bone Miner Metab 31(2):129–135CrossRefPubMedGoogle Scholar
  43. 43.
    McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7(6):429–442CrossRefPubMedGoogle Scholar
  44. 44.
    Maret W (2013) Zinc and human disease. Met Ions Life Sci 13:389–414CrossRefPubMedGoogle Scholar
  45. 45.
    Milanino R, Marrella M, Gasperini R, Pasqualicchio M, Velo G (1993) Copper and zinc body levels in inflammation: an overview of the data obtained from animal and human studies. Agents Actions 39(3–4):195–209CrossRefPubMedGoogle Scholar
  46. 46.
    Filkova M, Vernerova Z, Hulejova H, Prajzlerova K, Veigl D, Pavelka K, Vencovsky J, Senolt L (2015) Pro-inflammatory effects of interleukin-35 in rheumatoid arthritis. Cytokine 73(1):36–43CrossRefPubMedGoogle Scholar
  47. 47.
    Youssef AA, Wood B, Baron DN (1983) Serum copper: a marker of disease activity in rheumatoid arthritis. J Cliti Pathol 36(1):14–17CrossRefGoogle Scholar
  48. 48.
    Shaw JC (1988) Copper deficiency and non-accidental injury. Arch Dis Child 63(4):448–455PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Rucker RB, Murray J, Riggins RS (1977) Nutritional copper deficiency and penicillamine administration: some effects on bone collagen and arterial elastin crosslinking. Adv Exp Med Biol 86b:619–648CrossRefPubMedGoogle Scholar
  50. 50.
    Maret W, Li Y (2009) Coordination dynamics of zinc in proteins. Chem Rev 109(10):4682–4707CrossRefPubMedGoogle Scholar
  51. 51.
    Bonaventura P, Benedetti G, Albarede F, Miossec P (2014) Zinc and its role in immunity and inflammation. Autoimmun Rev 14(4):277–285CrossRefPubMedGoogle Scholar
  52. 52.
    Summersgill H, England H, Lopez-Castejon G, Lawrence CB, Luheshi NM, Pahle J, Mendes P, Brough D (2014) Zinc depletion regulates the processing and secretion of IL-1β. Cell Death Dis 5:e1040. doi: 10.1038/cddis.2013.547 PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Mariani E, Cattini L, Neri S, Malavolta M, Mocchegiani E, Ravaglia G, Facchini A (2006) Simultaneous evaluation of circulating chemokine and cytokine profiles in elderly subjects by multiplex technology: relationship with zinc status. Biogerontology 7(5–6):449–459CrossRefPubMedGoogle Scholar
  54. 54.
    Siebert S, Tsoukas A, Robertson J, McInnes I (2015) Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol Rev 67(2):280–309CrossRefPubMedGoogle Scholar
  55. 55.
    Pandey SP, Bhattacharya SK, Sundar S (1985) Zinc in rheumatoid arthritis. Ind J Med Res 81:618–620Google Scholar
  56. 56.
    Lee SY, Jung YJ, Oh TH, Choi EH (2011) A case of acrodermatitis enteropathica localized on the hands and feet with a normal serum zinc level. Ann Dermatol 23(Suppl 1):S88–S90. doi: 10.5021/ad.2011.23.S1.S88 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lihong Xin
    • 1
  • Xiao Yang
    • 1
  • Guoqi Cai
    • 1
  • Dazhi Fan
    • 1
  • Qing Xia
    • 1
  • Li Liu
    • 1
  • Yanting Hu
    • 1
  • Ning Ding
    • 1
  • Shengqian Xu
    • 2
  • Li Wang
    • 1
  • Xiaona Li
    • 1
  • Yanfeng Zou
    • 1
  • Faming Pan
    • 1
  1. 1.Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiChina
  2. 2.Department of Rheumatism and ImmunityThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina

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