Medical Molecular Morphology

, Volume 39, Issue 3, pp 121–126 | Cite as

Compound overload of copper and iron in patients with Wilson's disease

  • Hisao Hayashi
  • Motoyoshi Yano
  • Yoshikazu Fujita
  • Shinya Wakusawa


This review of the copper–iron interaction in Wilson's disease was mainly based on ten patients (three females and seven males) studied in our institutes because the genetic tests of ATP7B for Wilson's disease of primary copper toxicosis and HFE for hemochromatosis, the biochemical parameters of copper and iron, and morphological studies on biopsied liver specimens were complete. All patients had hypoceruloplasminemia and hepatic lesions compatible with Wilson's disease. One patient was homozygous and nine patients were compound heterozygous for the mutations in ATP7B, and all patients were free from the major mutation, C282Y, of HFE. The biochemical parameters of iron metabolism were not specific, except for serum ferritin concentration. Judging from the traditional criteria, seven patients had hyperferritinemia. Histochemical iron was stained in the livers of seven patients and histochemical copper was found in nine patients. Microanalysis was more sensitive than histochemistry, detecting copper and iron accumulation in the hepatocellular lipofuscin particles of all patients. Using an improved fixative, intralipofuscin distribution was found to be different between cuprothionein and iron complexes. Iron overload in Wilson's disease might be worsened after treatment because of the close relation to hypoceruloplasminemia, in which the iron efflux from the liver to the circulation is disturbed.

Key words

Copper Gene Iron Liver Lysosome Wilson's disease X-ray microanalysis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gitlin, JD 2003Wilson diseaseGastroenterology12518681877PubMedCrossRefGoogle Scholar
  2. 2.
    Roberts, EA, Schilsky, ML 2003A practice guideline on Wilson diseaseHepatology3714751492PubMedCrossRefGoogle Scholar
  3. 3.
    Harada, M 2002Wilson diseaseMed Electron Microsc356166PubMedCrossRefGoogle Scholar
  4. 4.
    Tanzi, RE, Petrukhin, K, Chernov, I, Pellequer, JL, Wasco, W, Ross, B, Romano, DM, Parano, E, Pavone, L, Brzustowicz,  1993The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease geneNat Genet5344350PubMedCrossRefGoogle Scholar
  5. 5.
    Bull, PC, Thomas, GR, Rommens, JM, Forbes, JR, Cox, DW 1993The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes geneNat Genet5327337PubMedCrossRefGoogle Scholar
  6. 6.
    Yamaguchi, Y, Heiny, ME, Gitlin, JD 1993Isolation and characterization of a human liver cDNA as a candidate gene for Wilson diseaseBiochem Biophys Res Commun197271277PubMedCrossRefGoogle Scholar
  7. 7.
    Shiono, Y, Wakusawa, S, Hayashi, H, Takikawa, T, Yano, M, Okada, T, Mabuchi, H, Kono, S, Miyajima, H 2001Iron accumulation in the liver of male patients with Wilson's diseaseAm J Gastroenterol9631473151PubMedCrossRefGoogle Scholar
  8. 8.
    Osaki, S, Johnson, DA, Frieden, E 1971The mobilization of iron from the perfused mammalian liver by a serum copper enzyme, ferroxidaseJ Biol Chem24630183023PubMedGoogle Scholar
  9. 9.
    Attieh, ZK, Mukhopadhyay, CK, Seshadri, V, Trioulas, NA, Fox, PL 1999Ceruloplasmin ferroxidase activity stimulates cellular iron uptake by a trivalent cation-specific transport mechanismJ Biol Chem27411161123PubMedCrossRefGoogle Scholar
  10. 10.
    Miyajima, H, Nishimura, Y, Mizoguchi, K, Sakamoto, M, Shimizu, T, Honda, N 1987Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degenerationNeurology37761767PubMedGoogle Scholar
  11. 11.
    Yoshida, K, Furihata, K, Takeda, S, Nakamura, A, Yamamoto, K, Morita, H, Hiyamuta, S, Ikeda, S, Shimizu, N, Yanagisawa, N 1995A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humansNat Genet9267272PubMedCrossRefGoogle Scholar
  12. 12.
    Feder, JN, Gnirke, A, Thomas, W, Tsuchihashi, Z, Ruddy, DA, Basava, A, Dormishian, F, Domingo, R,Jr, Ellis, MC, Fullan, A, Hinton, LM, Jones, NL, Kimmel, BE, Kronmal, GS, Lauer, P, Lee, VK, Loeb, DB, Mapa, FA, MaClelland, E, Meyer, NC, Mintier, GA, Moeller, N, Moore, T, Morikang, E, Prass, CE, Quintana, L, Starnes, SM, Schatzman, RC, Brunke, KJ, Drayna, DT, Rish, NJ, Bacon, BR, Wolff, RK 1996A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosisNat Genet13399408PubMedCrossRefGoogle Scholar
  13. 13.
    Walshe, JM, Cox, DW 1998Effect of treatment of Wilson's disease on natural history of haemochromatosisLancet352112113PubMedCrossRefGoogle Scholar
  14. 14.
    Erhardt, A, Hoffmann, A, Hefter, H, Haussinger, D 2002HFE gene mutations and iron metabolism in Wilson's diseaseLiver22474478PubMedCrossRefGoogle Scholar
  15. 15.
    Shiono, Y, Hayashi, H, Wakusawa, S, Yano, M 2001Ultrastructural identification of iron and copper accumulation in the liver of a male patient with Wilson diseaseMed Electron Microsc345460PubMedCrossRefGoogle Scholar
  16. 16.
    Harashima, A, Hattori, A, Hyashi, H, Wakusawa, S, Kusakabe, A, Fujita, Y, Tanaka, M, Yano, M, Yoshioka, K 2004Compound load of copper and iron in the livers of pretreatment patients with Wilson's diseaseJ Trace Elem Exp Med176573CrossRefGoogle Scholar
  17. 17.
    Hayashi, H, Ueno, T, Yano, M, Okada, T, Mabuchi, H 2005Two male patients with Wilson's disease treated using trientine and iron reduction therapyJ Gastroenterol Hepatol2016271628PubMedCrossRefGoogle Scholar
  18. 18.
    Ferenci, P, Caca, K, Loudianos, G, Mieli-Vergani, G, Tanner, S, Sternlieb, I, Schilsky, M, Cox, D, Berr, F 2003Diagnosis and phenotypic classification of Wilson diseaseLiver Int23139142PubMedCrossRefGoogle Scholar
  19. 19.
    Scheinberg, IH, Gitlin, D 1952Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease)Science116484485PubMedGoogle Scholar
  20. 20.
    Fox, PL 2003The copper-iron chronicles: the story of an intimate relationshipBiometals16940PubMedCrossRefGoogle Scholar
  21. 21.
    Okada, T, Shiono, Y, Hayashi, H, Satoh, H, Sawada, T, Suzuki, A, Takeda, Y, Yano, M, Michitaka, K, Onji, M, Mabuchi, H 2000Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson's diseaseHum Mutat15454462PubMedCrossRefGoogle Scholar
  22. 22.
    Hattori, A, Wakusawa, S, Hayashi, H, Harashima, A, Sanae, F, Kawanaka, M, Yamada, G, Yano, M, Yoshioka, K 2003AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosisHepatol Res26154156PubMedCrossRefGoogle Scholar
  23. 23.
    Kato, J, Fujikawa, K, Kanda, M, Fukuda, N, Sasaki, K, Takayama, T, Kobune, M, Takada, K, Takimoto, R, Hamada, H, Ikeda, T, Niitsu, Y 2001A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overloadAm J Hum Genet69191197PubMedCrossRefGoogle Scholar
  24. 24.
    Koyama, C, Hayashi, H, Wakusawa, S, Ueno, T, Yano, M, Katano, Y, Goto, H, Kidokoro, R 2005Three patients with middle-age-onset hemochromatosis caused by novel mutations in the hemojuvelin geneJ Hepatol43740742PubMedCrossRefGoogle Scholar
  25. 25.
    Hanaichi, T, Kidokoro, R, Hayashi, H, Sakamoto, N 1984Electron probe X-ray analysis on human hepatocellular lysosomes with copper deposits: copper binding to a thiol-protein in lysosomesLab Invest51592759PubMedGoogle Scholar
  26. 26.
    Yasuzumi, G 1962Electron microscopy and x-ray scanning microanalysis of needle biopsy material from human liverJ Cell Biol14421431PubMedCrossRefGoogle Scholar
  27. 27.
    Terms, A, Brunk, UT 2004LipofuscinInt J Biochem Cell Biol3614001404CrossRefGoogle Scholar
  28. 28.
    Hayashi, H, Takikawa, T, Nishimua, N, Yano, M, Isomura, T, Sakamoto, N 1994Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic ironAm J Gastroenterol89986988PubMedGoogle Scholar
  29. 29.
    Piperno, A, Sampietro, M, D'Alba, R, Roffi, L, Fargion, S, Parma, S, Nicoli, C, Corbetta, N, Pozzi, M, Arosio, V, Boari, G, Fiorelli, G 1996Iron stores, response to α-interferon therapy, and effects of iron depletion in chronic hepatitis CLiver16248254PubMedGoogle Scholar
  30. 30.
    Irving, MG, Halliday, JW, Powell, LW 1988Association between alcoholism and increased hepatic iron storesAlcohol Clin Exp Res12713PubMedCrossRefGoogle Scholar
  31. 31.
    Suzuki, Y, Saito, H, Suzuki, M, Hosoki, Y, Sakurai, S, Fujimoto, Y, Kohgo, Y 2002Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver diseaseAlcohol Clin Exp Res2626S31SPubMedCrossRefGoogle Scholar
  32. 32.
    George, DK, Goldwurm, S, MacDonald, GA, Cowley, LL, Walker, NI, Ward, PJ, Jazwinska, EC, Powell, LW 1998Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosisGastroenterology114311318PubMedCrossRefGoogle Scholar
  33. 33.
    Nakashima, T, Sumida, Y, Furutani, M, Hirohama, A, Okita, M, Mitsuyoshi, H, Itoh, Y, Okanoue, T 2005Elevation of serum thioredoxin levels in patients with nonalcoholic steatohepatitisHepatol Res33135137PubMedGoogle Scholar
  34. 34.
    Rocchi, E, Gibertini, P, Cassanelli, M, Pietrangelo, A, Borghi, A, Ventura, E 1986Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutenea tardaJ Lab Clin Med1073642PubMedGoogle Scholar
  35. 35.
    Sampietro, M, Fiorelli, G, Fargion, S 1999Iron overload in porphyria cutenea tardaHaematologica84248253PubMedGoogle Scholar

Copyright information

© The Japanese Society for Clinical Molecular Morphology 2006

Authors and Affiliations

  • Hisao Hayashi
    • 1
  • Motoyoshi Yano
    • 2
  • Yoshikazu Fujita
    • 3
  • Shinya Wakusawa
    • 4
  1. 1.Department of MedicineAsanogawa General HospitalKanazawaJapan
  2. 2.Division of Gastroenterology of Department of Internal MedicineNagoya University Graduate School of MedicineNagoyaJapan
  3. 3.Division for Medical Research EngineeringNagoya University Graduate School of MedicineNagoyaJapan
  4. 4.Department of Medical TechnologyNagoya University School of Health SciencesNagoyaJapan

Personalised recommendations