Hepatic steatosis in Wilson disease – Role of copper and PNPLA3 mutations

Background & Aims The earliest characteristic alterations of the liver pathology in Wilson disease (WD) include steatosis, which is sometimes indistinguishable from non-alcoholic fatty liver disease (NAFLD). Steatosis in WD may reflect copper-induced mitochondrial dysfunction. A genetic polymorp...

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Published in:Journal of hepatology 2015-07, Vol.63 (1), p.156-163
Main Authors: Stättermayer, Albert Friedrich, Traussnigg, Stefan, Dienes, Hans-Peter, Aigner, Elmar, Stauber, Rudolf, Lackner, Karoline, Hofer, Harald, Stift, Judith, Wrba, Friedrich, Stadlmayr, Andreas, Datz, Christian, Strasser, Michael, Maieron, Andreas, Trauner, Michael, Ferenci, Peter
Format: Article
Language:English
Subjects:
Adolescent
Adult
Alleles
ATP7B
Biopsy
Child
Child, Preschool
Copper
Copper - metabolism
DNA - genetics
DNA Mutational Analysis
Female
Gastroenterology and Hepatology
Genetic Predisposition to Disease
Genotype
Hepatolenticular Degeneration - genetics
Hepatolenticular Degeneration - metabolism
Hepatolenticular Degeneration - pathology
Humans
Lipase - genetics
Lipase - metabolism
Liver - metabolism
Liver - pathology
Male
Membrane Proteins - genetics
Membrane Proteins - metabolism
Middle Aged
Mutation
PNPLA3
Steatohepatitis
Steatosis
Wilson disease
Young Adult
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Summary:Background & Aims The earliest characteristic alterations of the liver pathology in Wilson disease (WD) include steatosis, which is sometimes indistinguishable from non-alcoholic fatty liver disease (NAFLD). Steatosis in WD may reflect copper-induced mitochondrial dysfunction. A genetic polymorphism in rs738409, in the patatin-like phospholipase domain-containing 3 gene ( PNPLA3 ), is strongly associated with appearance of in NAFLD. This study evaluated the role of PNPLA3 and hepatic copper content for development of steatosis in patients with WD. Methods Liver biopsies obtained at diagnosis and the PNPLA3 genotype were analyzed in 98 Caucasian patients with WD (male: 52 [53.1%]; mean age: 27.6 years [CI 95%: 24.8–30.4, range: 5.8–61.5]). Steatosis was graded as percentage of lipid containing hepatocytes by an expert hepatopathologist unaware of the results of genetic testing. Results Moderate/severe steatosis (>33% of hepatocytes) was observed in 28 patients (pediatric: n = 13/26 [50.0%], adult: n = 15/72 [20.8%]; p = 0.01). Forty-six patients (46.9%; pediatric: n = 7, adult: n = 39; p = 0.022) had cirrhosis. Multivariate logistic regression identified PNPLA3 G allele (OR: 2.469, CI 95%: 1.203–5.068; p = 0.014) and pediatric age (OR: 4.348; 1.577–11.905; p = 0.004) as independent variables associated with moderate/severe steatosis. In contrast, hepatic copper content did not impact on moderate/severe steatosis (OR: 1.000, CI 95%: 1.000–1.001; p = 0.297). Conclusions Steatosis is common in WD and the PNPLA3 G allele contributes to its pathogenesis. The role of hepatic copper concentration and ATP7B mutations in steatosis development deserve further investigations.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2015.01.034