title: Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis.
abstract: Patients with Wilson's disease (WD), Indian childhood cirrhosis (ICC), and idiopathic copper toxicosis (ICT) develop severe liver disease morphologically characterized by ballooning of hepatocytes, inflammation, cytoskeletal alterations, and Mallory body (MB) formation, finally leading to mostly micronodular cirrhosis. The pathogenesis of MBs in copper toxicosis is still unresolved. Immunohistochemical analysis of MBs in different types of copper intoxication revealed that keratin, p62, and ubiquitin are integral components. Thus MBs associated with copper intoxication resemble those present in alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). p62 is a multifunctional immediate early gene product that, on the one hand, is involved in stress-induced cell signaling (particularly that of oxidative stress) by acting as an adapter protein linking receptor-interacting protein (RIP) with the atypical protein kinase C. On the other hand, p62 binds with high affinity to polyubiquitin and ubiquitinated proteins. In conclusion, p62 accumulation in WD, ICC, and ICT and deposition in MBs indicates a central role of protein misfolding induced by oxidative stress in copper-induced liver toxicity. By sequestering potentially harmful misfolded ubiquitinated proteins as inert cytoplasmic inclusion bodies (e.g., as MBs), p62 may be a major player in an important cellular rescue mechanism in oxidative hepatocyte injury.
authors.affiliation: Department of Pediatrics, University of Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Cord
authors.initials: C
authors.lastname: Langner
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuchsbichler
authors.forename: Peter
authors.initials: P
authors.lastname: Heinz-Erian
authors.forename: Helmut
authors.initials: H
authors.lastname: Ellemunter
authors.forename: Barbara
authors.initials: B
authors.lastname: Schlenck
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Bavdekar
authors.forename: Avinash M
authors.initials: AM
authors.lastname: Pradhan
authors.forename: Anand
authors.initials: A
authors.lastname: Pandit
authors.forename: Josef
authors.initials: J
authors.lastname: Müller-Höcker
authors.forename: Michael
authors.initials: M
authors.lastname: Melter
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hironori
authors.initials: H
authors.lastname: Nagasaka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kikuta
authors.forename: Wilfried
authors.initials: W
authors.lastname: Müller
authors.forename: M Stuart
authors.initials: MS
authors.lastname: Tanner
authors.forename: Irmin
authors.initials: I
authors.lastname: Sternlieb
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003300:Copper / Q000378:metabolism; D005260:Female; D006527:Hepatolenticular Degeneration / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000473:pathology; D007223:Infant; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology
chemical_list: D003300:Copper