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    • In the present referred patients with hemochromatosis

    2022-05-17

    In the present referred patients with hemochromatosis and HFE p.C282Y homozygosity, eight of the ten patients with HCV infection were men. In another US cohort of ten patients with HFE p.C282Y homozygosity, chronic HCV infection, and stage 3 or 4 fibrosis, all were men [30]. In the present post-screening examination participants, the prevalence of anti-HCV was significantly greater in men than women. In National Health and Nutrition Examination Survey 2003–2010, the prevalence of chronic hepatitis C infection was significantly greater in men than women [20]. In this study, the odds ratio of anti-HCV in post-screening examination participants with elevated screening SF levels was more than nine-fold higher than that of participants whose screening SF levels were not elevated. Case participants without HFE p.C282Y homozygosity were invited to the post-screening examination solely because they SCH772984 had elevated screening TS and SF. These selection criteria would account in part for the strong positive association of anti-HCV and elevated screening SF levels we observed. These results are also consistent with previous observations of SF and liver disease in HEIRS Study participants [31] and SF levels in non-Hispanic white participants with chronic HCV infection who participated in the 1988–1994 National Health and Nutrition Examination Survey [32]. In a study performed in Italy before HFE was discovered, Piperno et al. reported that most patients with hemochromatosis and chronic HCV infection also had cirrhosis, and that their mean SF levels and quantities of iron removed by phlebotomy to achieve iron depletion were significantly lower than those of hemochromatosis patients without chronic HCV infection and fibrosis/cirrhosis [33]. In three of the present referred patients with HFE p.C282Y homozygosity, chronic HCV infection, and stage 4 fibrosis/cirrhosis, SF was 303–994μg/L. In contrast, stage 4 fibrosis/cirrhosis in a large series of Alabama and Ontario p.C282Y homozygotes was significantly associated with SF >1000μg/L, after adjustment for other variables [34]. In another study from the US, ten p.C282Y homozygotes with chronic HCV infection were diagnosed to have stage 3 or 4 fibrosis at a lower mean age and had a significantly lower mean hepatic iron concentration than 13 p.C282Y homozygotes with stage 3 or 4 fibrosis who did not have chronic HCV infection [30]. These findings support the postulate that the combination of hemochromatosis-associated iron overload and chronic HCV infection are synergistic in causing hepatic fibrogenesis. In contrast, each of five Austrian patients with p.C282Y homozygosity and chronic HCV infection had elevated SF levels, but only one of the five patients had hepatic iron index >1.9mmolFe/g dry weight/y and histologic abnormalities of liver typical of hemochromatosis [27]. This report is consistent with observations in patients with chronic HCV infection that hepatic iron overload is uncommon and hepatic iron concentration is unassociated with inflammation grade and fibrosis stage [35]. The proportion of patients with chronic HCV infection who have elevated hepatic iron levels measured by atomic absorption spectrometry is 5–14% [35], [36]. Elevated hepatic iron levels in patients with chronic HCV infection are incompletely explained by p.C282Y and p.H63D alleles [27], [37]. Serum hepcidin levels are lower in patients with chronic HCV infection than control subjects [38], [39]. Hepcidin expression is suppressed in persons with chronic HCV infection via multiple control pathways [40] and HCV-induced oxidative stress [41]. Decreased hepcidin expression may increase iron absorption via up-regulation of ferroportin in patients with chronic HCV infection [42]. The expression of many iron-related genes is increased in chronic HCV infection and could lead to hepatocyte iron deposition and retention [43]. Hepatic iron levels were higher in patients with chronic HCV infection due to genotype 1b than those with genotypes 2a or 2b [44], indicating that HCV genotype influences liver iron deposition and retention. Low concentrations of free or transferrin-bound iron reduced interferon-gamma signaling in the human myelomonocytic cell line THP-1 [45], suggesting that iron overload could reduce in vivo macrophage antiviral activity. Other “immunologic” mechanisms by which iron may decrease resistance to HCV infection have been reviewed [46].