Over 30 years ago, Dr. Jerome Sullivan hypothesized that the differences in incidence of heart disease between the sexes could be attributed to differences in stored iron. He suggested that phlebotomy to deplete iron might be a reasonable clinical experiment to potentially modify this risk factor.1 Dr. Zacharski proposed the feasibility of such a study in 2000 and then demonstrated correlations between levels of ferritin, inflammatory biomarkers, and mortality in a subset of patients with peripheral arterial disease.2 However, this hypothesis has been challenged by studies in hemochromatosis patients with HFE mutations, which have failed to demonstrate an association with coronary artery disease. So Dr. Sullivan recently described the “hepcidin” hypothesis to reconcile this paradox.3 In most patients with HFE mutations and iron overload, hepcidin levels are low. Atherosclerosis is an inflammatory process, and cytokines such as IL-6 can increase hepcidin, which in turn can regulate macrophage iron content.
Valenti et al. from Milan now enter this debate by demonstrating that hepcidin and macrophage iron correlate with both MCP-1 release and vascular damage in highrisk individuals with metabolic syndrome, including hyperlipidemia, Type 2 diabetes, and hypertension. Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic alterations and elevated ferritin levels were compared to patients with C282Y HFE homozygosity or heterozygosity with C282Y or H63D. The researchers used monocyte activation, serum hepcidin, and carotid artery intima media thickness to determine the extent of vascular damage. In response to iron, monocytes with HFE genotypes had a partial defect in iron retention. Iron treatment increased MCP-1 and IL-6 in normal monocytes, especially those in patients with advanced carotid vascular disease, but not in monocytes with HFE mutations. Hepcidin and iron added to normal monocytes, which blocked ferroportin and allowed monocyte iron accumulation, progressively increased MCP-1 mRNA and protein. In 130 patients with NAFLD, hepcidin levels correlated with serum ferritin and MCP-1 levels. In addition, serum MCP-1 levels were higher in patients with carotid plaques than in those without such plaques. In multivariate analysis, the presence of carotid plaques was significantly associated with ferritin and MCP-1 serum levels, independent of classic risk factors and HFE mutations.
In Brief
There is a strong association between NAFLD and cardiovascular risk with metabolic syndrome. The role of inflammation and oxidative stress underpins this risk and suggests the rationale for antioxidant or cytokine therapies. Most of these patients have elevated serum ferritin, suggesting that iron may be driving oxidative stress. In Dr. Valenti’s study, patients with NAFLD/metabolic syndrome and iron overload related to the presence or absence of HFE mutations were phlebotomized. Should the Sullivan and Zarcharski hypotheses regarding phlebotomy in certain patients with iron overload in the absence of HFE mutations be revisited? Would drugs lowering hepcidin levels be beneficial in NAFLD? Do patients with homozygosity for C282Y with inflammation or NAFLD have an even greater risk of cardiovascular disease? In plaques, there are frequently hemorrhaging red cells that can provide heme-derived iron, but is heme-derived iron in the artery wall more atherogenic? Although not resolved, the possibility that iron promotes rusting of vessels remains intriguing.
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Competing Interests
Dr. Vercellotti indicated no relevant conflicts of interest.
