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Immunohistochemical analysis of Mallory bodies in Wilsonian and non‐Wilsonian hepatic copper toxicosis
Author(s) -
Müller Thomas,
Langner Cord,
Fuchsbichler Andrea,
HeinzErian Peter,
Ellemunter Helmut,
Schlenck Barbara,
Bavdekar Ashish R.,
Pradhan Avinash M.,
Pandit Anand,
MüllerHöcker Josef,
Melter Michael,
Kobayashi Kunihiko,
Nagasaka Hironori,
Kikuta Hideaki,
Müller Wilfried,
Tanner M. Stuart,
Sternlieb Irmin,
Zatloukal Kurt,
Denk Helmut
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20108
Subject(s) - steatohepatitis , oxidative stress , cirrhosis , biology , autophagy , hepatocyte , microbiology and biotechnology , pathology , immunohistochemistry , copper toxicity , keratin 8 , cancer research , fatty liver , medicine , immunology , endocrinology , biochemistry , toxicity , disease , apoptosis , in vitro
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. (H EPATOLOGY 2004;39;963–969.)