Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes

Abstract

Objective: There are limited data comparing hepatic phenotype among hemochromatosis patients with different HFE genotypes. The goal of this study was to compare hepatic histopathologic features and hepatic iron concentration (HIC) among patients with phenotypic hemochromatosis and different HFE genotypes.

Methods: We studied 182 US patients with phenotypic hemochromatosis. Degree of hepatic fibrosis, pattern of iron deposition, presence of steatosis or necroinflammation, and HIC were compared among different HFE genotypes.

Results: C282Y/H63D compound heterozygotes and patients with HFE genotypes other than C282Y/C282Y were more likely to have stainable Kupffer cell iron (31.1% vs. 9.5%; P=0.02), portal or lobular inflammation (28.9% vs. 15.6%; P=0.03), and steatosis (33.3% vs. 10.2%; P<0.01) on liver biopsy than C282Y homozygotes. Mean log10 HIC (P<0.05) and log10 ferritin (P<0.05) were higher among C282Y homozygotes than in patients with other HFE genotypes. In a logistic regression analysis using age, sex, HFE genotype, log10 ferritin, and log10 HIC as independent variables, log10 serum ferritin (P=0.0008), male sex (P=0.0086), and log10 HIC (P=0.047), but not HFE genotype (P=0.0554) were independently associated with presence or absence of advanced hepatic fibrosis.

Conclusions: C282Y/H63D compound heterozygotes and other non-C282Y homozygotes which express the hepatic hemochromatosis phenotype frequently have evidence of steatosis or chronic hepatitis and lower body iron stores than C282Y homozygotes. These data suggest that presence of concomitant liver disease may explain expression of the hemochromatosis phenotype among non-C282Y homozygotes. Increased age, HIC, and ferritin are associated with advanced hepatic fibrosis, regardless of HFE genotype.

Figure 1

HFE C282Y/H63D compound heterozygotes were more likely to have to have Kupffer cell iron staining (26.7 vs 9.5%; p=0.04), portal or lobular inflammation (40% vs 15.6%; p=0.03) and steatosis (46.7% vs 10.2% p<0.01) than C282Y homozygotes. Patients with other HFE genotypes (C282Y/wt, H63D/wt, H63D/H63D, or wt/wt) also had a higher prevalence of Kupffer cell iron staining (50% vs 9.5%; p<.01), inflammation (35% vs 15.6%; p=0.03) and steatosis (40% vs 10.2%; p<0.01) than C282Y homozygotes. There were no significant differences between C282Y/H63D compound heterozygotes and patients with other HFE genotpes in prevalence of Kupffer cell staining (26.7% vs 50%; p=.16), inflammation (40% vs 35%; p=.76) or steatosis (46.7% vs 40%; p=.69).

Figure 2

Mean hepatic iron concentration in C282Y homozygotes was significantly higher than that in C282Y/H63D compound heterozygotes with cirrhosis (23,719 ± 14,991 mcg/g vs 18,300 ± 98 mcg/g, respectively; p=0.05) and without cirrhosis (10,700 ± 6,282 mcg/g vs 5,869 ± 1,817 mcg/g, respectively; p<0.01).