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Introduction to Copper Metabolism and Wilson Disease

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Book cover Management of Wilson Disease

Part of the book series: Clinical Gastroenterology ((CG))

Abstract

Copper is an essential trace element that is important for proper growth and development and plays a role in many normal metabolic processes. Copper deficiency leads to failure of many of these processes, while excess copper can lead to oxidative stress and cellular injury by impairing protein and mitochondrial function and modifying expression of genes. Maintaining appropriate homeostasis for copper levels requires a balance between the absorption of this essential element from our diet by the small intestine and elimination of excess copper by excretion from the liver into bile for elimination in stool. ATP7B is an important transport protein in liver cells that assists in transporting copper to bile and also in incorporating copper into the protein ceruloplasmin that is secreted by liver cells into the circulation. Ceruloplasmin is an important protein that is mostly involved in iron metabolism. Wilson disease (WD) is a genetic disorder that results from absence or altered function of the ATP7B protein that causes copper accumulation in the liver and later in other organs. Copper accumulation leads to cell injury, causing a chronic inflammatory state that can ultimately lead to fibrosis and cirrhosis of the liver, and injury to the brain that causes neurologic and psychiatric symptoms. Current therapies for WD aim to block absorption of dietary copper or enhance elimination of copper from the sites in the body to prevent further injury and restore normal cellular function.

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References

  1. Roberts EA, Schilsky ML. American Association for Study of liver D. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089–111.

    Article  CAS  PubMed  Google Scholar 

  2. Scheiber IF, Mercer JF, Dringen R. Metabolism and functions of copper in brain. Prog Neurobiol. 2014;116:33–57.

    Article  CAS  PubMed  Google Scholar 

  3. Lazarchick J. Update on anemia and neutropenia in copper deficiency. Curr Opin Hematol. 2012;19(1):58–60.

    Article  CAS  PubMed  Google Scholar 

  4. Pfeiffer R. Wilson’s disease. Semin Neurol. 2007;27(2):123–32.

    Article  PubMed  Google Scholar 

  5. Pfeiffenberger J, Gotthardt DN, Herrmann T, et al. Iron metabolism and the role of HFE gene polymorphisms in Wilson disease. Liver Int. 2012;32(1):165–70.

    Article  CAS  PubMed  Google Scholar 

  6. Rucker RB, Kosonen T, Clegg MS, et al. Copper, lysyl oxidase, and extracellular matrix protein cross-linking. Am J Clin Nutr. 1998;67(5 Suppl):996S–1002S.

    Article  CAS  PubMed  Google Scholar 

  7. Halliwell B, JMC G. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990;186:1–85.

    Article  CAS  PubMed  Google Scholar 

  8. (US) NAP. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. 2001.

    Google Scholar 

  9. Crampton RF, Matthews DM, Poisner R. Observations on the mechanism of absorption of copper by the small intestine. J Physiol. 1965;178(1):111–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ferenci P. Pathophysiology and clinical features of Wilson disease. Metab Brain Dis. 2004;19(3/4):229–39.

    Article  CAS  PubMed  Google Scholar 

  11. Zakim D, Thomas DB. Hepatology: a textbook of liver disease. 4th ed; 2002.

    Google Scholar 

  12. Hassett R, Kosman DJ. Evidence for Cu(II) reduction as a component of copper uptake by Saccharomyces cerevisiae. J Biol Chem. 1995;270(1):128–34.

    Article  CAS  PubMed  Google Scholar 

  13. Lee J, Pena MM, Nose Y, Thiele DJ. Biochemical characterization of the human copper transporter Ctr1. J Biol Chem. 2002;277(6):4380–7.

    Article  CAS  PubMed  Google Scholar 

  14. Wernimont AK, Huffman DL, Lamb AL, O’Halloran TV, Rosenzweig AC. Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins. Nat Struct Biol. 2000;7(9):766–71.

    Article  CAS  PubMed  Google Scholar 

  15. Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function and regulation of human copper-transporting ATPases. Physiol Rev. 2007;87(3):1011–46.

    Article  CAS  PubMed  Google Scholar 

  16. La Fontaine S, Mercer JF. Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Arch Biochem Biophys. 2007;463(2):149–67.

    Article  CAS  PubMed  Google Scholar 

  17. Nyasae L, Bustos R, Braiterman L, Eipper B, Hubbard A. Dynamics of endogenous ATP7A (Menkes protein) in intestinal epithelial cells: copper-dependent redistribution between two intracellular sites. Am J Physiol Gastrointest Liver Physiol. 2007;292(4):G1181–94.

    Article  CAS  PubMed  Google Scholar 

  18. Coffey AJ, Durkie M, Hague S, et al. A genetic study of Wilson’s disease in the United Kingdom. Brain. 2013;136(Pt 5):1476–87.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wilson SA. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain. 1912;34:295–509.

    Article  Google Scholar 

  20. Cumings J. The effects of B.A.L. in hepatolenticular degeneration. Brain. 1951;74:10–22.

    Article  CAS  PubMed  Google Scholar 

  21. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5(4):327–37.

    Article  CAS  PubMed  Google Scholar 

  22. Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993;5(4):344–50.

    Article  CAS  PubMed  Google Scholar 

  23. Yamaguchi Y, Heiny ME, Gitlin JD. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochem Biophys Res Commun. 1993;197(1):271–7.

    Article  CAS  PubMed  Google Scholar 

  24. Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, De Jong GJ, Gitlin JD. Mechanisms of copper incorporation into human ceruloplasmin. J Biol Chem. 2002;277(48):46632–8.

    Article  CAS  PubMed  Google Scholar 

  25. Wilson Disease Mutation Database. http://www.medicalgenetics.med.ualberta.ca/wilson/index.php.

  26. Usta J, Wehbeh A, Rida K, et al. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype. PLoS One. 2014;9(11):e109727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu ZY, Lin MT, Murong SX, Wang N. Molecular diagnosis and prophylactic therapy for presymptomatic Chinese patients with Wilson disease. Arch Neurol. 2003;60(5):737–41.

    Article  PubMed  Google Scholar 

  28. Yoshida K, Furihata K, Takeda S, et al. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet. 1995;9(3):267–72.

    Article  CAS  PubMed  Google Scholar 

  29. Roeser HP, Lee GR, Nacht S, Cartwright GE. The role of ceruloplasmin in iron metabolism. J Clin Invest. 1970;49(12):2408–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gunther MR, Hanna PM, Mason RP, Cohen MS. Hydroxyl radical formation from cuprous ion and hydrogen peroxide: a spin-trapping study. Arch Biochem Biophys. 1995;316(1):515–22.

    Article  CAS  PubMed  Google Scholar 

  31. Mufti AR, Burstein E, Csomos RA, et al. XIAP is a copper binding protein deregulated in Wilson’s disease and other copper toxicosis disorders. Mol Cell. 2006;21(6):775–85.

    Article  CAS  PubMed  Google Scholar 

  32. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141(5):1572–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Min HK, Kapoor A, Fuchs M, et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 2012;15(5):665–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Paris I, Dagnino-Subiabre A, Marcelain K, et al. Copper neurotoxicity is dependent on dopamine-mediated copper uptake and one-electron reduction of aminochrome in a rat substantia nigra neuronal cell line. J Neurochem. 2001;77(2):519–29.

    Article  CAS  PubMed  Google Scholar 

  35. Tjaard Hoogenraad U. Wilson disease: major problems in neurology. Philadelphia: W .B. Saunders Company; 1996.

    Google Scholar 

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Authors and Affiliations

  1. Division of Digestive Diseases, Department of Medicine, Yale University, New Haven, CT, USA

    Uyen To

  2. Division of Digestive Diseases and Transplant and Immunology, Departments of Medicine and Surgery, Yale University, New Haven, CT, USA

    Michael L. Schilsky

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  1. Uyen To
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Correspondence to Michael L. Schilsky .

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  1. Yale New Haven Transplantation Center, Yale University, New Haven, Connecticut, USA

    Michael L. Schilsky

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To, U., Schilsky, M.L. (2018). Introduction to Copper Metabolism and Wilson Disease. In: Schilsky, M. (eds) Management of Wilson Disease . Clinical Gastroenterology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-91527-2_1

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  • DOI: https://doi.org/10.1007/978-3-319-91527-2_1

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  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-91526-5

  • Online ISBN: 978-3-319-91527-2

  • eBook Packages: MedicineMedicine (R0)

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