title: A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia.
abstract: OBJECTIVE
  To compare iron depletion to lifestyle changes alone in patients with severe nonalcoholic fatty liver disease (NAFLD) and hyperferritinemia, a frequent feature associated with more severe liver damage, despite at least 6 mo of lifestyle changes.
  
  
  METHODS
  Eligible subjects had to be 18-75 years old who underwent liver biopsy for ultrasonographically detected liver steatosis and hyperferritinemia, ferritin levels ≥ 250 ng/mL, and NAFLD activity score > 1. Iron depletion had to be achieved by removing 350 cc of blood every 10-15 d according to baseline hemoglobin values and venesection tolerance, until ferritin < 30 ng/mL and/or transferrin saturation (TS) < 25%. Thirty-eight patients were randomized 1:1 to phlebotomy (n = 21) or lifestyle changes alone (n = 17). The main outcome of the study was improvement in liver damage according to the NAFLD activity score at 2 years, secondary outcomes were improvements in liver enzymes [alanine aminotransferases (ALT), aspartate aminotransferase (AST), and gamma-glutamyl-transferases (GGT)].
  
  
  RESULTS
  Phlebotomy was associated with normalization of iron parameters without adverse events. In the 21 patients compliant to the study protocol, the rate of histological improvement was higher in iron depleted vs control subjects (8/12, 67% vs 2/9, 22%, P = 0.039). There was a better improvement in steatosis grade in iron depleted vs control patients (P = 0.02). In patients followed-up at two years (n = 35), ALT, AST, and GGT levels were lower in iron-depleted than in control patients (P < 0.05). The prevalence of subjects with improvement in histological damage or, in the absence of liver biopsy, ALT decrease ≥ 20% (associated with histological improvement in biopsied patients) was higher in the phlebotomy than in the control arm (P = 0.022). The effect of iron depletion on liver damage improvement as assessed by histology or ALT decrease ≥ 20% was independent of baseline AST/ALT ratio and insulin resistance (P = 0.0001).
  
  
  CONCLUSIONS
  Iron depletion by phlebotomy is likely associated with a higher rate of improvement of histological liver damage than lifestyle changes alone in patients with NAFLD and hyperferritinemia, and with amelioration of liver enzymes.
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Rovida
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Fatta
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Edoardo Alessandro
authors.initials: EA
authors.lastname: Pulixi
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.affiliation: Luca Valenti, Anna Ludovica Fracanzani, Paola Dongiovanni, Serena Rovida, Raffaela Rametta, Erika Fatta, Edoardo Alessandro Pulixi, Silvia Fargion, Department of Pathophysiology and Transplantation, Metabolic Liver Diseases Research Center, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Policlinico, via F Sforza 35, 20122, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D019189:Iron Metabolism Disorders / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D018962:Phlebotomy
keywords: Ferritin; Iron depletion; Nonalcoholic fatty liver disease; Randomized controlled trial