Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C

Abstract

Hepatic iron has been associated with more aggressive liver disease in chronic viral hepatitis. We evaluated whether the recently described C282Y mutation of the hemochromatosis gene, designated HFE (responsible for at least 83% of hereditary hemochromatosis), was associated with more advanced liver disease in chronic hepatitis C. One hundred thirty-seven patients with biopsy-proven chronic hepatitis C were studied and liver biopsies scored for necroinflammation (grade 0-18) and fibrosis (stage 0-6). Genomic DNA was amplified by polymerase chain reaction and the C282Y mutation identified by restriction with RsaI and electrophoretic separation of restriction fragments. Ten (7.3%) patients had the C282Y mutation. No C282Y homozygous patients were identified. Age, sex distribution, and estimated weekly alcohol consumption were not significantly different between those with and without the mutation. Serum ferritin was higher in the heterozygotes (mean, 339 g/L) compared with homozygous wild types (153 g/L; P ‫؍‬ .0005). In the majority of patients, liver iron was graded 0 out of 4, but hepatocyte iron staining was more commonly present in heterozygotes compared with homozygous normals (30% compared with 4% [P ‫؍‬ .02]). Liver disease was more advanced in those with the mutant allele (mean fibrosis stage: 3.6, compared with wild type: 1.5 [P ‫؍‬ .01]). Cirrhosis was found more often in those with the mutation (40%) compared with those without (8.7%) (P ‫؍‬ .01; odds ratio: 7.6 [1.9-31.2]). There was no significant difference in inflammation scores between heterozygotes and wild type (mean, 5.4 compared with 4

Host genetic determinants in hepatitis C virus infection

“…119 Given the observation that a number of individuals with chronic HCV infection have excess hepatic iron, 120 some investigators have examined whether possession of these variants is associated with advanced liver disease. The results of these studies have been discrepant, 119,121 with four studies suggesting an association between possession of HFE variants and increased fibrosis or cirrhosis, 80,92,101,109 and the other studies suggesting that there are no associations. Methodological differences may account for these differing observations.…”

“…80,92,93,97,98,102,109,111,101 Two major polymorphisms are recognised in the literature: Cys282Tyr and His63Asp (often abbreviated as C282Y and H63D, respectively, in single-letter amino-acid notation). Of these two polymorphisms, the Cys282Tyr has been of greater interest.…”

“…47,92,97,98,109,[122][123][124][125][126][127][128][129][130][131][132] Two studies observed an association between DRB1*11 and the presence of cryoglobulins (OR not reported in Amaroso study; OR ¼ 3.4 in Cacoub study). 122,123 Both studies examined Italian populations.…”

“…No consistent observations with respect to this locus have been observed, with several studies reporting no association between this variant and increased iron, 93,97,131 and another study reporting an association between this locus and higher mean ferritin levels. 109 Differences in study design-for example the definition of iron (ie, serum ferritin levels vs iron stains of liver biopsies)-may play a major role in these differences. Some studies employed use of the 5-point METVIR scoring system for liver fibrosis while others used the 7-point Knodell histological activity index.…”

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection

“…18 The degree of inflammation, the severity of fibrosis and response to therapy are likely to be influenced by host factors. Increasing research activity focuses on the elucidation of host genetic factors affecting disease progression in hepatitis C. 19,20 Case-control studies have identified associations with HCV persistence and polymorphisms in histocompatibility antigens (HLA), 20,21 cytokine genes such as TNF-␣, IL-10 and TGF-␤1 [22][23][24] as well as the hemochromatosis (HFE) gene [25][26][27] have been correlated with parameters of HCV infection.…”