Elsevier

Journal of Hepatology

Volume 38, Issue 3, March 2003, Pages 335-342
Journal of Hepatology

HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis

https://doi.org/10.1016/S0168-8278(02)00415-4Get rights and content

Abstract

Background/Aims: The impact of heterozygous HFE mutations on the course of chronic hepatitis C and iron indices was studied.

Methods: Ferritin, transferrin saturation (TS), serum iron, C282Y and H63D mutations were determined in 401 patients with chronic hepatitis C virus (HCV) infection and 295 healthy controls. Liver histologies were available in 217 and HCV genotypes in 339 patients.

Results: Allele frequencies of the C282Y and H63D mutation did not differ between HCV patients and healthy controls (6.95 vs. 6.2%; 14.75 vs. 16.4%; n.s.). HFE heterozygous HCV patients had higher ferritin (349±37 vs. 193±15 μg/l; P<0.0005), TS (38±2 vs. 32±1%; P<0.0005), serum iron (144±6 vs. 121±3 μg/dl; P<0.0005), semiquantitative liver iron staining (0.26±0.07 vs. 0.09±0.03; P<0.006) and fibrosis scores (1.9±0.2 vs. 1.4±0.1; P<0.003) compared to HFE wildtypes. By multivariate regression analysis odds ratios for liver cirrhosis were 5.9 (confidence interval (CI) 1.6–22.6; P<0.009) for C282Y heterozygotes and 2.9 (CI 1.0–8.4; P<0.05) for H63D heterozygotes compared to HFE wildtypes. Considering all HFE heterozygous HCV patients, odds ratios of 3.6 (CI 1.4–9.3; P<0.009) for cirrhosis and 3.1 (CI 1.3–7.3; P<0.009) for fibrosis were calculated.

Conclusions: C282Y or H63D heterozygosity is an independent risk factor for liver fibrosis and cirrhosis in HCV infected individuals. Screening for HFE mutations should be considered in HCV infection.

Introduction

Hepatitis C is one of the world's leading infectious diseases with more than 170 million chronically infected individuals [1]. Hereditary hemochromatosis (HH) is a frequent autosomal recessive genetic disorder of the caucasian population [2]. HH is characterized by an increased iron absorption from the small intestine and an increased iron deposition in parenchymal organs leading to multiorgan failure [3]. Iron parameters, especially ferritin, are frequently increased in patients with chronic hepatitis C [4], [5], [6] suggesting an association between chronic hepatitis C and iron overload. However, it is as yet unclear whether elevation of iron indices is an epiphenomenon of hepatitis C virus (HCV) induced liver injury, liver inflammation and virus replication or whether elevation of iron parameters and HFE mutations may play a role in the evolution of HCV induced liver disease [7].

Recently a candidate gene of HH, termed HFE, has been identified on chromosome 6, coding for a protein homologous to major histocompatibility complex (MHC) class I molecules [8]. Two major mutations of the HFE gene, an exchange of cysteine to tyrosine at amino acid 282 (C282Y) and histidine to aspartic acid at amino acid 63 (H63D), are thought to be responsible for about 90% of cases with hereditary hemochromatosis in western populations. Allele frequencies of 5–10% for the C282Y mutation and 6–30% for the H63D mutation have been determined in individuals of northern European descent [9], [10], [11]. The prevalence of homozygous carriers for the C282Y mutation varies between 0.25–1% [10]. The prevalence of HFE gene mutations among patients with chronic hepatitis C and healthy controls does not seem to differ [12], [13]. However, in the subgroup of HCV patients with elevated iron indices, representing 30–60% of all HCV patients, the prevalence of HFE-gene mutations has not yet been determined. Furthermore, C282Y heterozygosity, H63D heterozygosity or H63D homozygosity, usually not leading to clinically apparent iron overload in otherwise healthy patients, may achieve a clinical significance in chronic hepatitis C [14], [15].

Therefore, the aims of this study were to determine (i) the prevalence of HFE mutations among HCV patients (ii) whether elevation of iron indices is related to HFE gene mutations in patients with chronic hepatitis C (ii) the influence of HFE gene mutations on liver disease progression in patients with hepatitis C. We therefore evaluated HFE gene mutations and iron parameters in 401 patients with chronic hepatitis C and 295 healthy controls.

Section snippets

Patients and methods

The two main HFE mutations (C282Y and H63D) and biochemical iron indices were retrospectively assessed in a total of 401 caucasian patients with chronic replicative hepatitis C. All patients were naive to an antiviral therapy at the time of investigation of iron parameters. Liver histology, performed routinely before antiviral therapy, was available in 217 of 401 patients (54%). Patient's characteristics are shown in Table 1. Patients with or without liver biopsy did not differ in age (48 vs.

HFE gene mutations and iron parameters in healthy controls and patients with chronic hepatitis C

Clinical parameters of HCV patients and healthy controls are summarized in Table 1. No difference in the prevalence of HFE gene mutations was found between patients with chronic hepatitis C and control subjects. The allele frequency of the C282Y mutation was 6.95% in the HCV group and 6.2% in the control group. The allele frequency of the H63D mutation was 14.75% for patients with HCV and 16.4% for controls. The different constellations of HFE mutations were equally distributed between HCV

Discussion

It is yet unknown whether abnormal iron parameters in patients with hepatitis C are merely caused by chronic inflammation, decay of liver cells with release of iron, viral factors or whether they are due to a comorbid effect of HFE mutations. The pathogenetic impact of the two main HFE mutations in chronic hepatitis C is not fully understood [19].

Overt HH is associated with C282Y homozygosity in most of the cases, whereas only 1–2% C282Y/H63D compound heterozygotes will develop clinically

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