Alpha 1-antitrypsin mutations in NAFLD: high prevalence and association with altered iron metabolism but not with liver damage.
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.
Valenti
Luca
L
Department of Internal Medicine, Ospedale Policlinico, Mangiagalli e Regina Elena Fondazione IRCCS, Universita' di Milano, Italy.
Dongiovanni
Paola
P
Piperno
Alberto
A
Fracanzani
Anna Ludovica
AL
Maggioni
Marco
M
Rametta
Raffaela
R
Loria
Paola
P
Casiraghi
Maria Antonietta
MA
Suigo
Elda
E
Ceriani
Roberto
R
Remondini
Erica
E
Trombini
Paola
P
Fargion
Silvia
S
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*
D000515:alpha 1-Antitrypsin; D005293:Ferritins