<i>HFE</i> Gene Mutations and Oxidative Stress Influence Serum Ferritin, Associated with Vascular Damage, in Hemodialysis Patients

Abstract

Background/Aims: Hyperferritinemia has been associated with cardiovascular mortality in hemodialysis patients. The aim of this study was to evaluate whether serum ferritin was affected by iron and oxidative status and by genetic factors (HFE mutations and the Ala9Val MnSOD polymorphism), and to assess the association between ferritin and cardiovascular damage evaluated by ecocolor-Doppler. Methods: 63 hemodialysis patients were tested for HFE and MnSOD genotype by restriction analysis and oxidative status; vascular damage was assessed by measuring intima-media thickness, and by detecting plaques at carotid and femoral arteries. Results: Ferritin was correlated with transferrin saturation (p = 0.003), decreased iron-specific serum antioxidant activity (p = 0.01), age (p = 0.03), and C282Y and H63D HFE mutations (p = 0.05), but not with the MnSOD polymorphism. Ferritin was associated with advanced vascular damage, as evaluated by the presence of plaques, both at carotid (p = 0.03) and femoral arteries (p = 0.001), the other risk factors being age and low albumin. Low iron-specific antioxidant activity was associated with carotid plaques (p = 0.03). Conclusion: In hemodialysis patients, hyperferritinemia reflects a relative increase in iron availability and a decrease in iron-specific antioxidant activity, is favored by HFE mutations, and represents a risk factor for advanced cardiovascular damage.

HFE Mutations Modulate the Effect of Iron on Serum Hepcidin-25 in Chronic Hemodialysis Patients

“…Exclusion criteria were active major infectious diseases (pneumonia, sepsis), neoplasia, congestive heart failure (NYHA stage III and IV), unstable ischemic heart disease, hepatic failure, and the ␤-thalassemic trait. Part of this series has previously been described elsewhere in detail (12,31).…”

“…However, recent data highlight that ferritin levels reflect also iron stores in CHD patients. Indeed, in these subjects ferritin correlated positively with transferrin saturation, with the presence of common mutations of the HFE gene of hereditary hemochromatosis (12), and with bone marrow iron stores (22).…”

“…Functional iron deficiency is a common finding, determining the need for high doses of ESAs and iron, both associated with adverse events. High doses of ESAs increase the risk of mortality due to cardiovascular events related to hypertension and hypercoagulability (9 -11), whereas excess iron promotes vascular damage by inducing oxidative stress and heightens the risk of infections (12)(13)(14)(15)(16). The mechanism proposed to explain refractoriness to i.v.…”

Modulation of Iron Metabolism and Hepcidin Release by HFE Mutations in Chronic Hemodialysis Patients: Pathophysiological and Therapeutic Implications

“…It has been suggested that iron overload may increase cardiovascular risk in the general population, by affecting LDL oxidation and endothelial dysfunction (Roest, van der Schouw et al 1999;Zacharski, Chow et al 2000;Wolff, Volzke et al 2004) and administration of intravenous iron has been associated with increased oxidative stress (Michelis, Gery et al 2003). In CHD patients, carotid intima media thickness (an early index of atherosclerosis and a strong predictor of cardiovascular events) and carotid plaques were positively correlated with serum ferritin and oxidative stress and reduced plasma anti-oxidant activity (Drueke, www.intechopen.com -Sarsat et al 2002;Valenti, Valenti et al 2007), and intima-media thickness was also associated with the dose of IV iron administered (Reis, Guz et al 2005). Furthermore, hepcidin and TNFα levels have also been correlated with vascular stiffness, another reliable predictor of cardiovascular events in CHD (Kuragano, Itoh et al 2011).…”

“…As mentioned above, although treatment with ESAs and IV iron formulations (Locatelli, Aljama et al 2004) are generally prescribed, functional iron deficiency is a common finding, determining the need for high doses of ESAs and iron, both associated with adverse events. Indeed, high ESAs doses have been associated with mortality due to cardiovascular events related to hypertension and hypercoagulability (Miyashita, Tojo et al 2004;Phrommintikul, Haas et al 2007;Strippoli, Tognoni et al 2007), whereas excess iron promotes vascular damage by inducing oxidative stress, and heightens the risk of infections (Seifert, von Herrath et al 1987;Jean, Charra et al 2002;Teehan, Bahdouch et al 2004;Kalantar-Zadeh, Regidor et al 2005;Valenti, Valenti et al 2007). The mechanism proposed to explain refractoriness to IV iron was previously related to the inhibition of erythropoiesis and iron recycling from macrophages by inflammation (Stenvinkel 2003).…”