Influence of heterozygous HFE gene mutations on fibrosis progression in chronic hepatitis C virus (HCV) infected patients – a meta-analysis

Introduction: Several lines of evidence suggest that iron overload might promote hepatic fibrogenesis in HCV-infected patients. Consequently, recent studies focussed on the impact of common HFE gene variants (C282Y; H63D) on liver fibrosis in chronic HCV infection, yielding contradictory results. To clarify this issue, our aim was to analyse the available data on the relationship between C282Y and H63D mutations and stages of liver fibrosis.

Methods: Studies with data on HFE genotypes and histological stage of liver fibrosis in HCV-infected patients were identified via Medline search. To assess the effect of different genotypes on fibrosis we set up three scenarios: (1) influence of any HFE genotype on fibrosis stage; (2) exclusion of homozygous C282Y/C282Y patients. Patients with C282Y/H63D and H63D/H63D mutations were still included, assuming that they are not at increased risk for haemochromatosis; (3) inclusion of heterozygous (ht) patients only. Point estimates (odds ratios) and 95% CI were calculated using a fixed model with Mantel-Haenszel statistics.

Results: Six studies fulfilled the selection criteria. Scenario 1: The meta-analysis of the combined data showed an increased OR for the development of severe fibrosis (cirrhosis or one stage less) for any HFE genotype (OR: 1.66; 95% CI: 1.15–2.30; p=0.007). Scenario 2: The OR for the development of severe fibrosis in compound ht or ht patients was also significantly increased (OR 1.67; 95% CI: 1.13–2.56; p=0.009). Although there was a trend for an influence of the HFE genotype on fibrosis stage in scenario 3, no significant effects were detected. When a random model was used for the analysis, none of the scenarios showed a significant effect of the HFE status on fibrosis stage.

Conclusions: There is not enough evidence that common heterozygous HFE mutations confer a significant increase in risk for the development of a severe fibrosis in HCV patients. In part the reported effects of HFE genotypes on fibrosis stage might be due to inclusion of patients fulfilling the genetic criteria of haemochromatosis, and exclusion of these patients and ‘compound heterozygotes’ abolishes any significant effect.