Wilson's disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Copper is one of the essential elements for the human body. Copper must be absorbed and transported in order to function properly. Copper is transported bound to metallothionein or carried by ATOX1 to the trans-Golgi network. Impairment of copper incorportation in formation of ceruloplasmin will lead to increase the serum level of the copper. The increase of copper level will lead to accumulation of the excess amount in the liver and other organs. ATP7B gene mutation is found in the majority of the patients with Wilson's disease.

Pathophysiology

Normal copper transportation and metabolism

Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper. Source:By en:User:Jfdwolff - Copper Metabolism, English Wikipedia, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7777267

Pathogenesis

  • The following table includes the main mechanisms that play an important role in pathogenesis of Wilson's disease.
Impaired copper metabolism Role in Wilson's disease pathogenesis
Impaired copper incorporation
  • Failure of the copper to be incorporated into apoceruloplasmin leads to accumulation of the copper in the hepatocytes and different body tissues and organs.
  • Ceruloplasmin level may be decreased as a result of impaired copper incorporation. However, it is not required to diagnose Wilson's disease.
Copper accumulation in hepatocytes
Extrahepatic copper accumulation
  • Copper accumulation will eventually lead to copper deposition in other organs like the brain.
  • The urinary excretion of the copper will not be able to decrease the serum levels and the deposition increases over time ending by the damage of the other organs especially the brain.

Genetics

Associated conditions

Gross pathology

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic pathology

  • Histological examination of a liver biopsy may show the following:[6]
    • Mild steatosis which is considered an early histological feature
    • Glycogenated hepatic nuclei
    • Hepatocellular necrosis
    • Autoimmune hepatitis histologic features
    • Fibrosis and cirrhosis (macronodular or micronodular) in advanced cases
    • Fulminant liver falilure features which include:
      • Hepatocellular degenration
      • Parenchymal collapse

References

  1. Sandstead HH (1982). "Copper bioavailability and requirements". Am J Clin Nutr. 35 (4): 809–14. PMID 6280488.
  2. Sandstead HH (1982). "Copper bioavailability and requirements". Am J Clin Nutr. 35 (4): 809–14. PMID 6280488.
  3. Pfeiffer RF (2007). "Wilson's Disease". Semin Neurol. 27 (2): 123–32. doi:10.1055/s-2007-971173. PMID 17390257.
  4. Hung IH, Suzuki M, Yamaguchi Y, Yuan DS, Klausner RD, Gitlin JD (1997). "Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae". J Biol Chem. 272 (34): 21461–6. PMID 9261163.
  5. de Bie, P; Muller, P; Wijmenga, C; Klomp, L W J (2007). "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes". Journal of Medical Genetics. 44 (11): 673–688. doi:10.1136/jmg.2007.052746. ISSN 1468-6244.
  6. Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW; et al. (2006). "MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation". AJNR Am J Neuroradiol. 27 (6): 1373–8. PMID 16775300.

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