title: Alpha 1-antitrypsin mutations in NAFLD: high prevalence and association with altered iron metabolism but not with liver damage.
abstract: Hyperferritinemia, a common feature of nonalcoholic fatty liver disease (NAFLD), has been associated with steatohepatitis and fibrosis. Heterozygosity for alpha 1-antitrypsin (AAT) mutations is a cofactor of liver damage, and AAT influences inflammation and iron metabolism. This study evaluated the prevalence of the common AAT PiS/PiZ mutants in 353 patients with NAFLD, 195 of whom had hyperferritinemia, versus 114 matched controls and their influence on iron metabolism and the severity of liver damage in the 212 patients submitted to biopsy. PiS and PiZ alleles were searched for by restriction analysis. Thirty-eight patients (10.8%) carried non-MM genotypes versus 4/114 (3.5%) controls (P = .02). Patients carrying AAT mutations had higher ferritin (573 [454-966] vs. 348 [201-648]; P = .001) with similar transferrin saturation. The difference was more evident in males (P < .0001) and significant in patients not carrying HFE genotypes associated with iron overload (P = .015). The prevalence of non-MM genotypes was higher in patients with hyperferritinemia than in those without (28/195, 14% vs. 10/158, 6%, P = .016), and AAT mutations were associated with higher prevalence of sinusoidal siderosis (17/27, 63% vs. 70/180, 39%; P = .02), and sinusoidal/total iron score (46.3 +/- 38% vs. 25.1 +/- 35%, P = .01). Although ferritin was independently associated with fibrosis (P = .047), AAT mutations favoring sinusoidal iron deposition did not affect liver damage. In conclusion, AAT mutations are associated with hyperferritinemia and sinusoidal iron accumulation, but not with more severe liver damage in NAFLD.
authors.affiliation: Department of Internal Medicine, Ospedale Policlinico, Mangiagalli e Regina Elena Fondazione IRCCS, Universita' di Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Alberto
authors.initials: A
authors.lastname: Piperno
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Paola
authors.initials: P
authors.lastname: Loria
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Casiraghi
authors.forename: Elda
authors.initials: E
authors.lastname: Suigo
authors.forename: Roberto
authors.initials: R
authors.lastname: Ceriani
authors.forename: Erica
authors.initials: E
authors.lastname: Remondini
authors.forename: Paola
authors.initials: P
authors.lastname: Trombini
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D005234:Fatty Liver / Q000097:blood / Q000235:genetics*; D005260:Female; D005293:Ferritins / Q000097:blood / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D019190:Iron Overload / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009765:Obesity / Q000235:genetics; D011446:Prospective Studies; D012806:Siderosis; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000235:genetics*
chemical_list: D000515:alpha 1-Antitrypsin; D005293:Ferritins