title: Hepatic steatosis in Wilson disease--Role of copper and PNPLA3 mutations.
abstract: OBJECTIVE
  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.
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors: Albert Friedrich
authors: AF
authors: Stättermayer
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors: Stefan
authors: S
authors: Traussnigg
authors: Institute for Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors: Hans-Peter
authors: HP
authors: Dienes
authors: Department of Internal Medicine I, Paracelsus Private Medical University, Salzburg, Austria.
authors: Elmar
authors: E
authors: Aigner
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors: Rudolf
authors: R
authors: Stauber
authors: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors: Karoline
authors: K
authors: Lackner
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors: Harald
authors: H
authors: Hofer
authors: Institute for Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors: Judith
authors: J
authors: Stift
authors: Institute for Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors: Friedrich
authors: F
authors: Wrba
authors: Department of Internal Medicine, KH Oberndorf, Oberndorf, Austria.
authors: Andreas
authors: A
authors: Stadlmayr
authors: Department of Internal Medicine, KH Oberndorf, Oberndorf, Austria.
authors: Christian
authors: C
authors: Datz
authors: Department of Internal Medicine I, Paracelsus Private Medical University, Salzburg, Austria.
authors: Michael
authors: M
authors: Strasser
authors: Department of Internal Medicine IV, KH der Elisabethinen, Linz, Austria.
authors: Andreas
authors: A
authors: Maieron
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors: Michael
authors: M
authors: Trauner
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: peter.ferenci@meduniwien.ac.at.
authors: Peter
authors: P
authors: Ferenci
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003300:Copper / Q000378:metabolism*; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006527:Hepatolenticular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D003300:Copper; D004247:DNA; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: ATP7B; Copper; PNPLA3; Steatohepatitis; Steatosis; Wilson disease