α1-Antitrypsin mutations in NAFLD: High prevalence and association with altered iron metabolism but not with liver damage
✍ Scribed by Luca Valenti; Paola Dongiovanni; Alberto Piperno; Anna Ludovica Fracanzani; Marco Maggioni; Raffaela Rametta; Paola Loria; Maria Antonietta Casiraghi; Elda Suigo; Roberto Ceriani; Erica Remondini; Paola Trombini; Silvia Fargion
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 131 KB
- Volume
- 44
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Hyperferritinemia, a common feature of nonalcoholic fatty liver disease (NAFLD), has been associated with steatohepatitis and fibrosis. Heterozygosity for ␣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. (HEPATOLOGY 2006;44:857-864.)
N onalcoholic fatty liver disease (NAFLD), the leading cause of liver disease in Western countries, includes a spectrum of clinical entities ranging from pure fatty liver to nonalcoholic steatohepa-titis (NASH) with possible evolution to cirrhosis and hepatocarcinoma. Diabetes, obesity, and dyslipidemia are the main risk factors for NAFLD, with insulin resistance as the key pathogenic event. Hyperferritinemia associated with nonparenchymal iron overload in the presence of nearly normal transferrin saturation 6-8 represents a common clinical presentation of NAFLD, involving up to one third of unselected cases, 9 shares clinical features with the insulin resistance-hepatic iron overload syndrome (IR-HIO), and is related to mutations in the HFE gene responsible for hereditary hemochromatosis (HHC) only in a minority of cases. Although increased oxidative stress is possibly implicated, 12 the reasons why only a subset of subjects with metabolic liver disease shows alterations in iron parameters is at present unclear, but hyperferritinemia has bee reported to represent a risk factor for steatohepatitis and fibrosis. It can be speculated that genetic factors influencing hepatocellular damage, inflammation and iron handling result in hyperferritinemia and affect the progression of