Hereditary hemochromatosis , iron , hepcidin , and coronary heart disease

Mounting evidence suggests that a state of sustained iron depletion may exert a primary protective action against coronary heart disease. A persistent criticism of the iron hypothesis has been that atherosclerosis may not be a prominent feature of hereditary hemochromatosis. The essence of this criticism is that iron cannot be a significant factor in atherogenesis in those unaffected by inherited iron overload unless an increase in atherosclerosis is observed in hereditary hemochromatosis. However, the emerging details of the physiology of hepcidin, the key hormone in iron recycling, suggest a resolution of the apparent paradox of an important role for iron in atherogenesis in the possible absence of increased plaque burden in most types of hereditary hemochromatosis. 2013 Elsevier Ltd. All rights reserved. Iron is an essential nutrient in humans, and states of both iron deficiency and iron excess result in deviation from optimal health [1]. Iron is a fundamental cofactor for several enzymes involved in oxidation–reduction reactions due to its ability to exist in two ionic forms: ferrous (Fe) and ferric (Fe) iron. The ability of iron to be converted between these oxidation states through the acceptance or donation of an electron is a key factor in allowing it to perform a range of biological functions. While the presence of iron in the body is essential in the context of oxygen transport, it is also important to note the potentially damaging consequences that result from interactions between these two molecular forms. In 1981, it was proposed that a state of sustained iron depletion or mild iron deficiency exerts a primary protective action against coronary heart disease (CHD) – the so called ‘‘iron hypothesis’’[2]. In late adolescence, men begin a steady accumulation of storage iron with age, but women fail to acquire significant iron stores because of their continual losses of iron in menstrual blood, pregnancies and deliveries. An escalation of risk follows initial acquisition of significant stored iron after cessation of menses due to natural menopause, or to surgical removal of the uterus and/or the ovaries [3]. A protective effect of iron depletion that may have multiple beneficial consequences is decreased availability of redox-active iron in vivo. The amount of free iron available at sites of oxidative or inflammatory injury appears to be a function of the stored iron level. Removal of stored iron from the body by phlebotomy, systemic iron chelation treatment or dietary iron restriction has been shown to decrease the amount of iron deposition within atherosclerotic lesions in animal studies [4]. Also epidemiological observations suggest a role of iron depletion in cardiovascular protection: (1) lower stored iron level mediated by cyanosisinduced hypoxia may explain why cyanotic patients with congenital heart disease might be protected from atherosclerosis [5]; (2) the protection against ischemic cardiovascular disease in individuals with impaired haemostasis might be related to the decrease of stored tissue iron caused by recurrent bleeding [6]. A persistent criticism of the iron hypothesis has been that atherosclerosis may not be a prominent feature of hereditary hemochromatosis (HH). The essence of this criticism is that iron cannot be a significant factor in atherogenesis in those unaffected by inherited iron overload unless an increase in atherosclerosis is observed in HH. HH is a late-onset autosomal recessive disorder, clinically and genetically heterogeneous, that leads to excess iron accumulation in multiple tissues including the heart [7]. Sequence variations in HFE gene, especially the most common variations of C282Y and H63D, have been associated with excess body iron stores [8] and contributed to HH development. Epidemiological evidence on a possible effect of HFE gene variations on CHD is inconclusive [9]. However, the emerging details of the physiology of hepcidin, the key hormone in iron recycling, suggest a resolution of the apparent paradox of an important role for iron in atherogenesis in the possible absence of increased plaque burden in most types of HH [10]. Hepcidin acts to block both iron absorption in the gut and iron release from macrophages through a common mechanism [11]. Ferroportin is the sole known iron exporter in enterocytes and 0306-9877/$ see front matter 2013 Elsevier Ltd. All rights reserved. http://dx.doi. org/10.1016/j.mehy. 2013.12. 013 ⇑ Corresponding author. Tel. : +39 0432584140; fax: +39 0432584053. E-mail address: lumasci@libero.it (L. Mascitelli). 402 Correspondence / Medical Hypotheses 82 (2014) 401–404