The Alterations of Copper and Zinc Homeostasis in Acute Appendicitis and the Clinical Significance

Abstract

Copper (Cu) and zinc (Zn) are involved in inflammatory process. This study was to investigate the clinical significance of Cu and Zn homeostasis alterations in acute appendicitis (AA). One hundred twenty-two AA patients and 102 healthy controls were enrolled in this study. Of which, 85 patients’ appendixes were collected after appendectomy. Another six appendixes from colon cancer patients were collected as tissue controls. The contents of Cu and Zn in serum or appendix were detected, and the Cu to Zn ratio (CZr) was calculated. The concentrations of serum ceruloplasmin (CP), Cu/Zn superoxide dismutase (SOD1), interleukin-6 (IL-6), and interleukin-22 in serum were measured, as well as the activity of CP and SOD1. The serum Zn concentration and SOD1 activity, appendix contents of Cu and Zn significantly decreased in AA patients, compared with those of controls, while serum CZr, concentrations of CP, SOD1, and IL-6, as well as CP activity increased significantly in AA patients. Additionally, serum concentrations of Zn, CP, CZr, or SOD1 activity varied in different pathological types of AA. Indicators such as serum SOD1 activity might serve as predictors for pathological classification before surgery. The serum Zn and CZr may be helpful for diagnosis of pure AA. The Cu and Zn homeostasis was altered in AA patients, which might contribute to inflammatory process of AA.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Harris ED (2003) Basic and clinical aspects of copper. Crit Rev Clin Lab Sci 40:547–586

    CAS  PubMed  Google Scholar 

  2. 2.

    Fedoseienko A, Bartuzi P, Sluis BVD (2014) Functional understanding of the versatile protein copper metabolism MURR1 domain 1 (COMMD1) in copper homeostasis. Ann N Y Acad Sci 1314:6–14

    CAS  PubMed  Google Scholar 

  3. 3.

    Rink L, Kirchner H (2000) Zinc-altered immune function and cytokine production. J Nutr 130:1407S–1411S

    CAS  PubMed  Google Scholar 

  4. 4.

    Mulder TP, Verspaget HW, Janssens AR, de Bruin PAD et al (1991) Decrease in two intestinal copper/zinc containing proteins with antioxidant function in inflammatory bowel disease. Gut 32:1146–1150

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Song M, Li X, Zhang X, Shi H et al (2017) Dietary copper-fructose interactions alter gut microbial activity in male rats. Am J Physiol Gastrointest Liver Physiol Am Physiological Soc 314:G119–G130

    Google Scholar 

  6. 6.

    Rainsford KD, Whitehouse MW (1976) Gastric mucus effusion elicited by oral copper compounds: potential anti-ulcer activity. Experientia 32:1172–1173

    CAS  PubMed  Google Scholar 

  7. 7.

    Stewart B, Khanduri P, McCord C, Ohene-Yeboah M, Uranues S, Vega Rivera F et al (2013) Global disease burden of conditions requiring emergency surgery. Br J Surg 101:e9–e22

    PubMed  Google Scholar 

  8. 8.

    Ramdass M, Young Q, Milne D, Mooteeram J, Barrow S (2015) Association between the appendix and the fecalith in adults. Can J Surg 58:10–14

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Swidsinski A, Dorffel Y, Loening-Baucke V, Theissig F et al (2010) Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/necrophorum. Gut 60:34–40

    Google Scholar 

  10. 10.

    Bhangu A, Søreide K, Di Saverio S, Assarsson JH, Drake FT (2015) Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management. Lancet 386:1278–1287

    PubMed  Google Scholar 

  11. 11.

    Saverio SD, Birindelli A, Kelly MD, Catena F, Weber DG, Sartelli M et al (2016) WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis. World J Emerg Surg 11:34

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Leeuwenburgh MM, Stockmann HB, Bouma WH, Houdijk AP, Verhagen MF, Vrouenraets B, Cobben LP, Bossuyt PM, Stoker J, Boermeester MA, OPTIMAP Study Group (2014) A simple clinical decision rule to rule out appendicitis in patients with nondiagnostic ultrasound results. Acad Emerg Med 21:488–496

    PubMed  Google Scholar 

  13. 13.

    Chong CF, Thien A, Mackie AJ, Tin AS, Tripathi S, Ahmad MA, Tan LT, Ang SH, Telisinghe PU (2011) Comparison of RIPASA and Alvarado scores for the diagnosis of acute appendicitis. Singap Med J 52:340–345

    CAS  Google Scholar 

  14. 14.

    Kollar D, McCartan DP, Bourke M, Cross KS, Dowdall J (2015) Predicting acute appendicitis? A comparison of the Alvarado score, the appendicitis inflammatory response score and clinical assessment. World J Surg 39:104–109

    CAS  PubMed  Google Scholar 

  15. 15.

    Escribá A, Gamell AM, Fernaández Y, Quintillá JM, Cubells CL (2011) Prospective validation of two systems of classification for the diagnosis of acute appendicitis. Pediatr Emerg Care 27:165–169

    PubMed  Google Scholar 

  16. 16.

    Linder MC (2016) Ceruloplasmin and other copper binding components of blood plasma and their functions: an update. Metallomics 8:887–905

    CAS  PubMed  Google Scholar 

  17. 17.

    Fetherolf MM, Boyd SD, Taylor AB, Kim HJ, Wohlschlegel JA, Blackburn NJ, Hart PJ, Winge DR, Winkler DD (2017) Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site. J Biol Chem 292:12025–12040

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Mc Cord JM, Fridovich I (1969) Superoxide dismutase, an enzymatic function for erythrocuperin. J Biol Chem 244:6049–6055

    CAS  Google Scholar 

  19. 19.

    Bonaventura P, Benedetti G, Albarède F, Miossec P (2015) Zinc and its role in immunity and inflammation. Autoimmun Rev 14:277–285

    CAS  PubMed  Google Scholar 

  20. 20.

    Klimczak M, Dziki A, Kilanowicz A, Sapota A, Duda-Szymańska J, Daragó A (2016) Concentrations of cadmium and selected essential elements in maligant large intestine tissue. Prz Gastroenterol 11:24–29

    CAS  PubMed  Google Scholar 

  21. 21.

    Krzciuk K (2015) Intelligent analysis of samples by semiquantitative inductively coupled plasma-mass spectrometry (ICP-MS) technique: a review. Crit Rev Anal Chem 46:284–290

    PubMed  Google Scholar 

  22. 22.

    Margalioth EJ, Udassin R, Cohen C, Maor J, Anteby SO, Schenker JG (1987) Serum copper level in gynecologic malignancies. Am J Obstet Gynecol 157:93–96

    CAS  PubMed  Google Scholar 

  23. 23.

    Livingstone C (2015) Zinc: physiology, deficiency, and parenteral nutrition. Nutr Clin Pract 30:371–382

    CAS  PubMed  Google Scholar 

  24. 24.

    Yuan WA, Yu XJ, Liu FQ, Wang HP, Wang D, Lai X-P (2010) Effects of trace element supplementation on the inflammatory response in a rabbit model of major trauma. J Trace Elem Med Biol 24:36–41

    CAS  PubMed  Google Scholar 

  25. 25.

    Ojuawo A, Keith L (2002) The serum concentrations of zinc, copper and selenium in children with inflammatory bowel disease. Cent Afr J Med 48:116–119

    CAS  PubMed  Google Scholar 

  26. 26.

    Altamura C, Squitti R, Pasqualetti P, Gaudino C, Palazzo P, Tibuzzi F, Lupoi D, Cortesi M, Rossini PM, Vernieri F (2009) Ceruloplasmin/transferrin system is related to clinical status in acute stroke. Stroke 40:1282–1288

    CAS  PubMed  Google Scholar 

  27. 27.

    Di Bella LM, Alampi R, Biundo F, Toscano G, Felice MR (2017) Copper chelation and interleukin-6 proinflammatory cytokine effects on expression of different proteins involved in iron metabolism in HepG2 cell line. BMC Biochem 18(1):1

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Samokyszyn VM, Miller DM, Reif DW, Aust SD (1989) Inhibition of superoxide and ferritin-dependent lipid peroxidation by ceruloplasmin. J Biol Chem 264:21–26

    CAS  PubMed  Google Scholar 

  29. 29.

    Bakhautdin B, Febbraio M, Goksoy E et al (2013) Protective role of macrophage-derived ceruloplasmin in inflammatory bowel disease. Gut BMJ Publishing Group 62:209–219

    CAS  Google Scholar 

  30. 30.

    Gitlin JD, Schroeder JJ, Lee-Ambrose LM, Cousins RJ (1992) Mechanisms of caeruloplasmin biosynthesis in normal and copper-deficient rats. Biochem J 282:835–839

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Zhang Y, Chen Y, Lin Z, Li Q, Chen Y, Peng L, Han M (2014) Ultrasonic oscillation dialysis-graphite furnace atomic absorption spectrometer method for determination of “free” copper and exchangeable copper in serum. Clin Lab 60:543–551

    CAS  PubMed  Google Scholar 

  32. 32.

    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 151:93–100

    CAS  PubMed  Google Scholar 

  33. 33.

    Srinivas U, Braconier JH, Jeppsson B, Abdulla M, Akesson B et al (1988) Trace element alterations in infectious diseases. Scand J Clin Lab Inv 48:495–500

    CAS  Google Scholar 

  34. 34.

    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 39:195–209

    CAS  PubMed  Google Scholar 

  35. 35.

    Braunschweig CL, Sowers M, Kovacevich DS, Hill GM, August DA (1997) Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response. J Nutr 127:70–74

    CAS  PubMed  Google Scholar 

  36. 36.

    Jarosz M, Olbert M, Wyszogrodzka G, Młyniec K, Librowski T (2017) Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling. Inflammopharmacology 25:11–24

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Foster M, Samman S (2012) Zinc and regulation of inflammatory cytokines: implications for cardiometabolic disease. Nutrients 4:676–694

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Schroeder JJ, Cousins RJ (1990) Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures. Proc Natl Acad Sci U S A 87:3137–3141

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Papa L, Manfredi G, Germain D (2014) SOD1, an unexpected novel target for cancer therapy. Genes Cancer 5:15–21

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Wright GS, Antonyuk SV, Hasnain SS (2016) A faulty interaction between SOD1 and hCCS in neurodegenerative disease. Sci Rep 6:27691

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Zelko IN, Mariani TJ, Folz RJ (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 33:337–349

    CAS  PubMed  Google Scholar 

  42. 42.

    Milani P, Amadio M, Laforenza U, Dell'Orco M, Diamanti L, Sardone V, Gagliardi S, Govoni S, Ceroni M, Pascale A, Cereda C (2013) Posttranscriptional regulation of SOD1 gene expression under oxidative stress: potential role of ELAV proteins in sporadic ALS. Neurobiol Dis 60:51–60

    CAS  PubMed  Google Scholar 

  43. 43.

    Wang GZ, Song Y, Feng W, Liu L, Zhu Y, Xie X, Pan Y, Ke R, Li S, Li F, Yang L, Li M (2016) Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1α and SOD1. Exp Ther Med 12:1551–1555

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Rincon M (2012) Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol 33:571–577

    CAS  PubMed  Google Scholar 

  45. 45.

    Shao Y, Lei Z, Yuan J, Yang Y, Guo Y, Zhang B (2014) Effect of zinc on growth performance, gut morphometry, and cecal microbial community in broilers challenged with Salmonella enterica serovar typhimurium. J Microbiol 52:1002–1011

    CAS  PubMed  Google Scholar 

  46. 46.

    De Man JG, De Winter BY, Boeckxstaens GE, Herman AG, Pelckmans PA (1996) Effect of thiol modulators and Cu/Zn superoxide dismutase inhibition on nitrergic relaxations in the rat gastric fundus. Br J Pharmacol 119:1022–1028

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Science Foundation of China (No.81172088), the Natural Science Foundation of Guangdong Province (2018A030307005), and Natural Science Foundation of Shenzhen University General Hospital (SUGH2018QD002, SUGH2018QD027).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Zhexuan Lin or Ming Han.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lin, W., Han, W., Wen, K. et al. The Alterations of Copper and Zinc Homeostasis in Acute Appendicitis and the Clinical Significance. Biol Trace Elem Res 192, 116–122 (2019). https://doi.org/10.1007/s12011-019-01661-2

Download citation

Keywords

  • Acute appendicitis
  • Copper
  • Zinc
  • Ceruloplasmin
  • Cu/Zn superoxide dismutase
  • Interleukin-6