Extrahepatic iron loading associates with the propensity to develop advanced hepatic fibrosis in hemochromatosis

Background and Aims: Hemostatic iron regulator-hemochromatosis can result in progressive iron-loading and advanced hepatic fibrosis in some individuals. We studied total body and hepatic iron loading to determine whether the distribution of iron-loading influences the risk of advanced fibrosis. Methods: One hundred thirty-eight men and 66 women with hemochromatosis who underwent liver biopsy for staging of hepatic fibrosis had evaluation of hepatic iron concentration (HIC), hepatic iron index (HIC/age), total body iron stores (mobilizable iron), and mobilizable iron/HIC ratio (a marker of total body iron relative to hepatic iron). The potential impact of liver volume on mobilizable iron stores was assessed using magnetic resonance imaging in a separate cohort of 19 newly diagnosed individuals with hemochromatosis. Results: Of 204 biopsied subjects, 41 had advanced fibrosis and exhibited 60% greater accumulation of mobilizable iron relative to HIC (mean 0.070 ± 0.008 g Fe/[μmol Fe/g]) compared with 163 subjects with low-grade fibrosis (mean 0.044 ± 0.002 g Fe/[μmol Fe/g], P < .0001). Linear regression modeling confirmed a discrete advanced hepatic fibrosis phenotype associated with greater mobilizable iron stores relative to HIC. The ratios of the upper to lower 95% limits of the distributions of liver volumes and the mobilizable iron/HIC ratios were 2.7 (95% confidence interval 2.3–3.0) and 9.7 (95% confidence interval 8.0–11.7), respectively, indicating that the distribution of liver volumes is not sufficiently wide to explain the variability in mobilizable iron/HIC ratios, suggesting that significant extrahepatic iron loading is present in those with advanced hepatic fibrosis. Conclusion: Advanced hepatic fibrosis develops in hemostatic iron regulator-hemochromatosis individuals who also have excessive extrahepatic mobilizable iron stores.