title: Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Parenchymal liver siderosis is associated with increased fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to assess whether a panel of genetic variants previously reported to influence iron metabolism, including the C282Y/H63D HFE, the PiZ/PiS alpha1-antitrypsin, the IVS1-24 ferroportin polymorphisms, and the beta-thalassemia trait, may be able to predict the presence of parenchymal siderosis and of progressive fibrosis in NAFLD.
  
  
  METHODS
  We considered 274 Italian patients with biopsy-proven NAFLD. Genetic polymorphisms were searched for by sequence allele specific-polymerase chain reaction and restriction analysis, whereas beta-trait was determined according to blood count and HbA(2) determination.
  
  
  RESULTS
  Parenchymal iron deposition was predominantly observed in 32 (11.7%) patients. Heterozygosity for the C282Y (OR 1.87, 95% CI 1.04-3.25), homozygosity for the H63D HFE (OR 2.31, 95% CI 1.04-4) mutations, and the beta-thalassemia trait (OR 2.57 95% CI 1.49-4.47) were all predominantly associated with parenchymal siderosis, independently of age, sex, body mass index, alcohol intake, ferritin, and transferrin saturation. Sixty-three percent of patients with hepatocellular siderosis were positive for at least one of the aforementioned genetic variants. The beta-thalassemia trait had the highest positive and the lowest negative likelihood ratios for predominantly parenchymal iron accumulation (5.05 and 0.74, respectively), and was independently associated with moderate/severe fibrosis (OR 2.50, 95% CI 1.26-5.19).
  
  
  CONCLUSIONS
  In patients with NAFLD, predominant hepatocellular iron deposition is often related to genetic factors, among which beta-globin mutations play a major role, predisposing to parenchymal iron accumulation and to progressive liver fibrosis.
authors.affiliation: Department of Internal Medicine, Università degli Studi Milano, UO Medicina Interna 1B, Fondazione Ospedale Policlinico MaRE IRCCS, Milan, Italy. luca.valenti@unimi.it
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Elena
authors.initials: E
authors.lastname: Canavesi
authors.forename: Enrico
authors.initials: E
authors.lastname: Galmozzi
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Paolo
authors.initials: P
authors.lastname: Maggioni
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000328:Adult; D000368:Aged; D005234:Fatty Liver / Q000150:complications / Q000235:genetics; D005260:Female; D005293:Ferritins / Q000097:blood; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000209:etiology / Q000235:genetics*; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease; D055544:beta-Globins / Q000235:genetics*
chemical_list: D055544:beta-Globins; D005293:Ferritins; D007501:Iron