Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis

Abstract

The hypothesis of the role of iron overload associated with HFE gene mutations in the pathogenesis of nonalcoholic steatohepatitis (NASH) has been raised in recent years. In the present study, biochemical and histopathological evidence of iron overload and HFE mutations was investigated in NASH patients. Thirty-two NASH patients, 19 females (59%), average 49.2 years, 72% Caucasians, 12% Mulattoes and 12% Asians, were submitted to serum aminotransferase and iron profile determinations. Liver biopsies were analyzed for necroinflammatory activity, architectural damage and iron deposition. In 31 of the patients, C282Y and H63D mutations were tested by PCR-RFLP. Alanine aminotransferase levels were increased in 30 patients, 2.42 ± 1.12 times the upper normal limit on average. Serum iron concentration, transferrin saturation and ferritin averages were 99.4 ± 31.3 g/dl, 33.1 ± 12.7% and 219.8 ± 163.8 µg/dl, respectively, corresponding to normal values in 93.5, 68.7 and 78.1% of the patients. Hepatic siderosis was observed in three patients and was not associated with architectural damage (P = 0.53) or with necroinflammatory activity (P = 0.27). The allelic frequencies (N = 31) found were 1.6 and 14.1% for C282Y and H63D, respectively, which were compatible with those described for the local population. In conclusion, no evidence of an association of hepatic iron overload and HFE mutations with NASH was found. Brazilian NASH patients comprise a heterogeneous group with many associated conditions such as hyperinsulinism, environmental hepatotoxin exposure and drugs, but not hepatic iron overload, and their disease susceptibility could be related to genetic and environmental features other than HFE mutations.

Serum Ferritin Is a Clinical Biomarker in Japanese Patients with Nonalcoholic Steatohepatitis (NASH) Independent of HFE Gene Mutation

“…Hepatic iron overload thought to be associated with HFE gene mutations [10,11]. A significantly higher prevalence of HFE mutations in NASH patients has been reported as a factor responsible for liver fibrosis by increasing hepatic iron deposition [14,32], but recent studies have failed to confirm this [33][34][35]. In our study the prevalence of hyperferritinemia was significantly higher in the NASH patients than in patients with simple steatosis.…”

<i>SLC40A1</i> c.1402G→A Results in Aberrant Splicing, Ferroportin Truncation after Glycine 330, and an Autosomal Dominant Hemochromatosis Phenotype

“…Other members of this kinship presumed to have c.1402G→A on the basis of family history and pedigree analysis had been treated with phlebotomy, like the proband. Nonalcoholic hepatic steatosis, such as we observed in the present patient, does not cause iron overload [28,29,30,31,32,33,34], although it is unresolved whether iron overload may cause or exacerbate nonalcoholic steatosis [29, 30]. The present proband has diabetes mellitus like some other patients with SLC40A1 hemochromatosis [35], but it was not possible to determine if this was causally related to iron overload, mild hepatic steatosis, or other factors.…”

Prevalence of the hemochromatosis gene mutation in patients with nonalcoholic steatohepatitis and correlation with degree of liver fibrosis

“…These data are in agreement with those reported by CHITTURI et al (15) and BUGIANESI et al (11) . In Brazil, DEGUTI et al (16) studied the prevalence of HFE mutations in 31 patients with NASH, observing 1.6% and 14.1% for C282Y and H63D mutations respectively. In this study, there was no control group.…”