- Email: [email protected]
Hereditary hemochromatosis, iron, hepcidin, and coronary heart disease
402
Correspondence / Medical Hypotheses 82 (2014) 401–404
[3] Kirschvink JL, Kirschvink AK, Woodford BJ. Magnetic biomineralization in the human brain. Proc Nat Acad Sci 1992;89:7683–7. [4] Pankhurst Q, Hautot D, Khan N, Dobson J. Increased levels of magnetite iron compounds in Alzheimer’s disease. J Alz Dis 2008;13:49–52. [5] Størmer FC, Laane CMM. Is magnetite involved in the formation of neurogenerative diseases? Med Hypotheses 2009;74:391. [6] Størmer FC. Is memory stored in the brain neurons and is magnetite involved? Med Hypotheses 2013;81:1170.
Fredrik Carl Størmer Norwegian Institute of Public Health, Fuglehauggaten 10, 0260 0403, Norway Tel.: +47 92268576. E-mail address: [email protected] doi:http://dx.doi.org/10.1016/j.mehy.2014.01.005
Hereditary hemochromatosis, iron, hepcidin, and coronary heart disease Luca Mascitelli a,⇑, Mark R. Goldstein b a b
Comando Brigata alpina ‘‘Julia’’/Multinational Land Force, Medical Service, 8 Via S. Agostino, Udine 33100, Italy NCH Physicians Group, 1845 Veterans Park Drive, Suite 110, Naples, FL 34109, USA
a r t i c l e
i n f o
Article history: Received 26 November 2013 Accepted 18 December 2013
a b s t r a c t 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. Ó 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+2) and ferric (Fe+3) 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 restric⇑ Corresponding author. Tel.: +39 0432584140; fax: +39 0432584053. E-mail address: [email protected] (L. Mascitelli). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.12.013
tion 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
Correspondence / Medical Hypotheses 82 (2014) 401–404
macrophages. Hepcidin binds ferroportin on cell membranes, causing its internalization and degradation. Hepcidin levels are upregulated by iron intake and inflammation and markedly downregulated by iron deficiency anemia. Insufficient hepcidin production, regardless of iron overload, is also the key pathogenic feature of most types of HH. Because of the low hepcidin levels in the two conditions, iron deficiency anemia and HH are both characterized by macrophages with little or no iron. The failure of vascular wall macrophages to retain iron in cases of inherited iron overload accompanied by a lower production of hepcidin may prevent progression and destabilization of atherosclerotic plaque [10]. Indeed, hepcidin has been recently confirmed to represent a positive regulator of atherosclerotic plaque destabilization via regulating iron homeostasis in macrophages [12]. A recent meta-analysis involving studies on single nucleotide polymorphisms has found a significant association between CHD risk and H63D mutation; however no association has been shown between other HFE gene variants and CHD risk [13]. Notably, C282Y/H63D heterozygous may develop a milder form of hemochromatosis [14], and are still be able to produce hepcidin, whose values are in fact slightly higher than normal individuals (without HFE mutations) [15]. The different behaviour of C282Y/H63D heterozygous (who retain a relative ability to increase hepcidin production in response to iron, even if still inadequate for iron stores) as compared to C282Y homozygous (who produce very low hepcidin levels), likely related to the different impact of the two mutations on HFE function, may influence the different relationship with CHD risk. Therefore, the controversial results of the association between HH and CHD does not exclude a key role for iron in atherogenesis in subjects without inherited deficiencies of hepcidin. Future studies should be conducted to find out whether iron depletion or hepcidin regulators might reduce CHD risk.
403
Acknowledgment None. References [1] Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:1986–95. [2] Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293–4. [3] Mascitelli L, Goldstein MR, Pezzetta F. Explaining sex difference in coronary heart disease: is it time to shift from the oestrogen hypothesis to the iron hypothesis? J Cardiovasc Med 2011;12:64–5. [4] Sullivan JL. Iron in arterial plaque: modifiable risk factor for atherosclerosis. Biochim Biophys Acta 2009;1790:718–23. [5] Mascitelli L, Pezzetta F, Goldstein MR. Reduced body iron stores and atherosclerosis in patients with cyanotic congenital heart disease. Int J Cardiol 2011;146:117. [6] Mascitelli L, Pezzetta F. Cardiovascular protections in severely impaired hemostasis. Circulation 2004;110:e39. [7] Lynch SR, Skikne BS, Cook JD. Food iron absorption in idiopathic hemochromatosis. Blood 1989;74:2187–93. [8] Benyamin B, McRae AF, Zhu G, et al. Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 2009;84:60–5. [9] Ellervik C, Tybjaerg-Hansen A, Grande P, Appleyard M, Nordestgaard BG. Hereditary hemochromatosis and risk of ischemic heart disease: a prospective study and a case-control study. Circulation 2005;112:185–93. [10] Sullivan JL. Macrophage iron, hepcidin, and atherosclerotic plaque stability. Exp Biol Med 2007;232:1014–20. [11] Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta 2012;1823:1434–43. [12] Li JJ, Meng X, Si HP, et al. Hepcidin destabilizes atherosclerotic plaque via overactivating macrophages after erythrophagocytosis. Arterioscler Thromb Vasc Biol 2012;32:e50. Erratum in: Arterioscler Thromb Vasc Biol 2012;32:e50. [13] Lian J, Xu L, Huang Y, et al. Meta-analyses of HFE variants in coronary heart disease. Gene 2013;527:167–73. [14] Pietrangelo A. Hereditary hemochromatosis – a new look at an old disease. N Engl J Med 2004;350:2383–97. [15] Bozzini C, Campostrini N, Trombini P, et al. Measurement of urinary hepcidin levels by SELDI-TOF-MS in HFE-hemochromatosis. Blood Cells Mol Dis 2008;40:347–52.
Disclosure None.
Mesogastrium recurrence as expression of the fifth metastatic route of gastric cancer
We commend Xie and colleagues [1] on their innovative hypothesis of Metastasis V as the new fifth route used by gastric cancer to develop local recurrence. We would like to lend more support to this topic by reporting our experience. In April 2007, a 70 year-old man was submitted to curative total gastrectomy for adenocarcinoma of stomach fundus staged as pT2b pN1 pM0 G1 according to the AJCC sixth edition. He received adjuvant radiochemotherapy. 6 years later, a 4 cm in length wall thickening of the left half of the transverse colon was evident on abdominal CT scan; endoscopic biopsy revealed adenocarcinoma. At laparotomy, the colonic lesion was observed infiltrating the Roux-en-Y entero-enteric anastomosis tailored 6 years before as well as the adjacent abdominal wall. En-bloc resection of the mass was performed along with restoration of small and large bowel continuity: definitive histology yielded the unsuspected diagnosis of peritoneal metastasis of gastric cancer invading transverse colon, intestine and abdominal wall. The patient died of acute respiratory failure on the fifth postoperative day.
Although performed with curative intent and combined with neoadjuvant chemotherapy, radical surgery for advanced gastric cancer (gastrectomy with D2 lymph node dissection) is often followed by locoregional recurrence (75–80% of cases) occurring at the anastomotic site, in the stomach bed, hepatoduodenal ligament, perigastric and retroperitoneal lymph nodes. Direct invasion, lymphatic drainage, hematogenous spread and peritoneal dissemination are the four classical routes through which gastric cancer cells can determine locoregional recurrence or distant implants. Recently, Xie et al. proposed a new fifth pathway of metastasis identified as Metastasis V pathway or mesogastrium dissemination [1,2]. In this case, tumor cells, migrating on the deep fascia of mesogastrium which lies between the stomach and mesentery, reach a bare area from which they spread among the fat cells in the mesentery adipose connective tissue. We do think this was the most likely path of recurrence occurring in our patient and agree with Xie and coworkers that complete mesogastrium excision (CME) should be always accomplished along with gastrectomy and D2 lymph node dissection in order to cut down this route and reduce the incidence of locoregional recurrence from gastric cancer [1,2].
Correspondence / Medical Hypotheses 82 (2014) 401–404
[3] Kirschvink JL, Kirschvink AK, Woodford BJ. Magnetic biomineralization in the human brain. Proc Nat Acad Sci 1992;89:7683–7. [4] Pankhurst Q, Hautot D, Khan N, Dobson J. Increased levels of magnetite iron compounds in Alzheimer’s disease. J Alz Dis 2008;13:49–52. [5] Størmer FC, Laane CMM. Is magnetite involved in the formation of neurogenerative diseases? Med Hypotheses 2009;74:391. [6] Størmer FC. Is memory stored in the brain neurons and is magnetite involved? Med Hypotheses 2013;81:1170.
Fredrik Carl Størmer Norwegian Institute of Public Health, Fuglehauggaten 10, 0260 0403, Norway Tel.: +47 92268576. E-mail address: [email protected] doi:http://dx.doi.org/10.1016/j.mehy.2014.01.005
Hereditary hemochromatosis, iron, hepcidin, and coronary heart disease Luca Mascitelli a,⇑, Mark R. Goldstein b a b
Comando Brigata alpina ‘‘Julia’’/Multinational Land Force, Medical Service, 8 Via S. Agostino, Udine 33100, Italy NCH Physicians Group, 1845 Veterans Park Drive, Suite 110, Naples, FL 34109, USA
a r t i c l e
i n f o
Article history: Received 26 November 2013 Accepted 18 December 2013
a b s t r a c t 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. Ó 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+2) and ferric (Fe+3) 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 restric⇑ Corresponding author. Tel.: +39 0432584140; fax: +39 0432584053. E-mail address: [email protected] (L. Mascitelli). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.12.013
tion 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
Correspondence / Medical Hypotheses 82 (2014) 401–404
macrophages. Hepcidin binds ferroportin on cell membranes, causing its internalization and degradation. Hepcidin levels are upregulated by iron intake and inflammation and markedly downregulated by iron deficiency anemia. Insufficient hepcidin production, regardless of iron overload, is also the key pathogenic feature of most types of HH. Because of the low hepcidin levels in the two conditions, iron deficiency anemia and HH are both characterized by macrophages with little or no iron. The failure of vascular wall macrophages to retain iron in cases of inherited iron overload accompanied by a lower production of hepcidin may prevent progression and destabilization of atherosclerotic plaque [10]. Indeed, hepcidin has been recently confirmed to represent a positive regulator of atherosclerotic plaque destabilization via regulating iron homeostasis in macrophages [12]. A recent meta-analysis involving studies on single nucleotide polymorphisms has found a significant association between CHD risk and H63D mutation; however no association has been shown between other HFE gene variants and CHD risk [13]. Notably, C282Y/H63D heterozygous may develop a milder form of hemochromatosis [14], and are still be able to produce hepcidin, whose values are in fact slightly higher than normal individuals (without HFE mutations) [15]. The different behaviour of C282Y/H63D heterozygous (who retain a relative ability to increase hepcidin production in response to iron, even if still inadequate for iron stores) as compared to C282Y homozygous (who produce very low hepcidin levels), likely related to the different impact of the two mutations on HFE function, may influence the different relationship with CHD risk. Therefore, the controversial results of the association between HH and CHD does not exclude a key role for iron in atherogenesis in subjects without inherited deficiencies of hepcidin. Future studies should be conducted to find out whether iron depletion or hepcidin regulators might reduce CHD risk.
403
Acknowledgment None. References [1] Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:1986–95. [2] Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293–4. [3] Mascitelli L, Goldstein MR, Pezzetta F. Explaining sex difference in coronary heart disease: is it time to shift from the oestrogen hypothesis to the iron hypothesis? J Cardiovasc Med 2011;12:64–5. [4] Sullivan JL. Iron in arterial plaque: modifiable risk factor for atherosclerosis. Biochim Biophys Acta 2009;1790:718–23. [5] Mascitelli L, Pezzetta F, Goldstein MR. Reduced body iron stores and atherosclerosis in patients with cyanotic congenital heart disease. Int J Cardiol 2011;146:117. [6] Mascitelli L, Pezzetta F. Cardiovascular protections in severely impaired hemostasis. Circulation 2004;110:e39. [7] Lynch SR, Skikne BS, Cook JD. Food iron absorption in idiopathic hemochromatosis. Blood 1989;74:2187–93. [8] Benyamin B, McRae AF, Zhu G, et al. Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 2009;84:60–5. [9] Ellervik C, Tybjaerg-Hansen A, Grande P, Appleyard M, Nordestgaard BG. Hereditary hemochromatosis and risk of ischemic heart disease: a prospective study and a case-control study. Circulation 2005;112:185–93. [10] Sullivan JL. Macrophage iron, hepcidin, and atherosclerotic plaque stability. Exp Biol Med 2007;232:1014–20. [11] Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta 2012;1823:1434–43. [12] Li JJ, Meng X, Si HP, et al. Hepcidin destabilizes atherosclerotic plaque via overactivating macrophages after erythrophagocytosis. Arterioscler Thromb Vasc Biol 2012;32:e50. Erratum in: Arterioscler Thromb Vasc Biol 2012;32:e50. [13] Lian J, Xu L, Huang Y, et al. Meta-analyses of HFE variants in coronary heart disease. Gene 2013;527:167–73. [14] Pietrangelo A. Hereditary hemochromatosis – a new look at an old disease. N Engl J Med 2004;350:2383–97. [15] Bozzini C, Campostrini N, Trombini P, et al. Measurement of urinary hepcidin levels by SELDI-TOF-MS in HFE-hemochromatosis. Blood Cells Mol Dis 2008;40:347–52.
Disclosure None.
Mesogastrium recurrence as expression of the fifth metastatic route of gastric cancer
We commend Xie and colleagues [1] on their innovative hypothesis of Metastasis V as the new fifth route used by gastric cancer to develop local recurrence. We would like to lend more support to this topic by reporting our experience. In April 2007, a 70 year-old man was submitted to curative total gastrectomy for adenocarcinoma of stomach fundus staged as pT2b pN1 pM0 G1 according to the AJCC sixth edition. He received adjuvant radiochemotherapy. 6 years later, a 4 cm in length wall thickening of the left half of the transverse colon was evident on abdominal CT scan; endoscopic biopsy revealed adenocarcinoma. At laparotomy, the colonic lesion was observed infiltrating the Roux-en-Y entero-enteric anastomosis tailored 6 years before as well as the adjacent abdominal wall. En-bloc resection of the mass was performed along with restoration of small and large bowel continuity: definitive histology yielded the unsuspected diagnosis of peritoneal metastasis of gastric cancer invading transverse colon, intestine and abdominal wall. The patient died of acute respiratory failure on the fifth postoperative day.
Although performed with curative intent and combined with neoadjuvant chemotherapy, radical surgery for advanced gastric cancer (gastrectomy with D2 lymph node dissection) is often followed by locoregional recurrence (75–80% of cases) occurring at the anastomotic site, in the stomach bed, hepatoduodenal ligament, perigastric and retroperitoneal lymph nodes. Direct invasion, lymphatic drainage, hematogenous spread and peritoneal dissemination are the four classical routes through which gastric cancer cells can determine locoregional recurrence or distant implants. Recently, Xie et al. proposed a new fifth pathway of metastasis identified as Metastasis V pathway or mesogastrium dissemination [1,2]. In this case, tumor cells, migrating on the deep fascia of mesogastrium which lies between the stomach and mesentery, reach a bare area from which they spread among the fat cells in the mesentery adipose connective tissue. We do think this was the most likely path of recurrence occurring in our patient and agree with Xie and coworkers that complete mesogastrium excision (CME) should be always accomplished along with gastrectomy and D2 lymph node dissection in order to cut down this route and reduce the incidence of locoregional recurrence from gastric cancer [1,2].