<i>HFE</i>mutations in nonalcoholic fatty liver disease
Authors: Luca Valenti, Paola Dongiovanni, Anna Ludovica Fracanzani, Silvia Fargion
Journal: Hepatology (2008)

We read with interest the article by Nelson et al.1 on the relationship between HFE (hemochromatosis) mutations and severity of liver damage in a North American cohort of 126 patients with nonalcoholic steatohepatitis (NASH). They found that heterozygosity for the C282Y mutation was associated with higher iron stores and prevalence of severe fibrosis compared to other genotypes, but diabetes was the only predictor of fibrosis at multivariate analysis considering demographic/anthropometric features and HFE status. These results are important, especially because iron overload is a treatable condition, and iron depletion improves the metabolic picture in patients with nonalcoholic fatty liver disease (NAFLD) and hyperferritinemia.2 Nelson et al. hypothesize that the C282Y mutation facilitates fibrogenesis by increasing iron stores and oxidative stress, but they did not report significant differences in the prevalence of HFE mutations between their cohort of patients with NASH and 2 recent North American studies in the general population.3, 4 However, it appears that in Caucasians the prevalence of the C282Y mutation, but not that of the H63D mutation, was significantly higher in patients with NASH (21.6%) compared to prevalence reported by Beutler et al.4 (11.4%, P = 0.002) and Adams et al.3 (12%, P = 0.006) in the general population. This was true for both the C282Y/H63D (5.1% versus 1.9%, P = 0.02 and versus 2%, P = 0.03, respectively), and the C282Y/wild-type (16.3% versus 9.5%, P = 0.03 and versus 10%, P = 0.006) genotypes. These results suggest increased susceptibility to NASH in patients carrying the C282Y mutation, although definite evidence is precluded by the lack of matched controls. Increased susceptibility to fatty liver in Caucasian subjects positive for the C282Y HFE mutation was previously demonstrated in Italian patients, with careful evaluation of ascertainment bias.5 Data obtained in studies of NAFLD also indicated that C282Y heterozygotes developed steatosis for a lower degree of overweight, and that the C282Y mutation and body iron stores were associated with a relative deficit of beta-cell function. These results provide possible mechanisms by which iron overload may indirectly promote fibrogenesis, that is, by interfering with lipid metabolism6 and by promoting hyperglycemia, which fit well with results of the multivariate analysis elaborated by Nelson et al.1 Interestingly, we also recently observed increased risk of steatosis in patients with chronic hepatitis C virus infection who were positive for HFE mutations, independently of age, sex, body mass index, and alcohol intake (odds ratio 1.59, 95% confidence interval 1.1–2.4, P = 0.02), suggesting that the effect of iron on steatosis development may extend to other liver diseases.7 Supporting the authors' results relative to fibrosis progression, in a cohort of 212 Italian patients with biopsy-proven NAFLD with complete characterization of iron status,8 HFE genotypes predisposing to iron overload (C282Y/H63D and H63D/H63D),3 though observed less frequently than in subjects of Northern European descent, were associated with higher iron stores and prevalence of severe fibrosis independently of confounders (Table 1). Taken together, these observations suggest that HFE mutations may promote fibrogenesis by inducing fatty liver and dysmetabolism. Additional studies are required to confirm this hypothesis. Luca Valenti*, Paola Dongiovanni*, Anna Ludovica Fracanzani*, Silvia Fargion*, * Department of Internal Medicine, Medicina Interna IB, Universita' di Milano, Ospedale Policlinico Mangiagalli Regina Elena IRCCS, Milan, Italy.