The complex relationship between iron status and anemia in pregnant and postpartum women in India: analysis of two Indian study cohorts of uncomplicated pregnancies

Low hemoglobin is widely used as an indicator of iron deficiency anemia in India and other low-and-middle income counties, but anemia need not accurately reflect iron deficiency. We examined the relationship between hemoglobin and biomarkers of iron status in antenatal and postnatal period. Secondary analysis of uncomplicated singleton pregnancies in two Indian study cohorts: 1132 antenatal women in third trimester and 837 postnatal women 12–72 h after childbirth. Associations of hemoglobin with ferritin in both data sets, and with sTfR, TSAT, and hepcidin in the postnatal cohort were examined using multivariable linear regression. Multinomial logistic regression was used to examine the association between severity of anemia and iron status. Regression models were adjusted for potential confounders. Over 55% of the women were anemic; 34% of antenatal and 40% of postnatal women had low ferritin, but 4% antenatal and 6% postnatal women had high ferritin. No evidence of association between hemoglobin and ferritin was observed (antenatal: adjusted coefficient [aCoef] −0.0004, 95% confidence interval [CI] −0.001, 0.001; postnatal: aCoef −0.0001, 95% CI −0.001, 0.001). We found a significant linear association of hemoglobin with sTfR (aCoef −0.04, 95% CI −0.07, −0.01), TSAT (aCoef −0.005, 95% CI −0.008, −0.002), and hepcidin (aCoef 0.02, 95% CI 0.02, 0.03) in postnatal women. Likelihood of low ferritin was more common in anemic than non-anemic women, but high ferritin was also more common in women with severe anemia in both cohorts. Causes of anemia in pregnant and postpartum women in India are multifactorial; low hemoglobin alone is not be a useful marker of iron deficiency

Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells

Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours

Maternal iron deficiency perturbs embryonic cardiovascular development in mice.

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women

Maternal iron deficiency perturbs embryonic cardiovascular development in mice.

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Funder: Novo Nordisk; doi: https://doi.org/10.13039/501100004191Funder: National Heart Foundation of Australia (Heart Foundation); doi: https://doi.org/10.13039/501100001030Funder: NSW Health; doi: https://doi.org/10.13039/501100009287Funder: Oxford University | John Fell Fund, University of Oxford (John Fell OUP Research Fund); doi: https://doi.org/10.13039/501100004789Funder: The Federated FoundationAbstract: Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women

Mechanisms of cardiac iron homeostasis and their importance to heart function

Heart disease is a common manifestation in conditions of iron imbalance. Normal heart function requires coupling of iron supply for oxidative phosphorylation and redox signalling with tight control of intracellular iron to below levels at which excessive ROS are generated. Iron supply to the heart is dependent on systemic iron availability which is controlled by the systemic hepcidin/ferroportin axis. Intracellular iron in cardiomyocytes is controlled in part by the iron regulatory proteins IRP1/2. This mini-review summarises current understanding of how cardiac cells regulate intracellular iron levels, and of the mechanisms linking cardiac dysfunction with iron imbalance. It also highlights a newly-recognised mechanism of intracellular iron homeostasis in cardiomyocytes, based on a cell-autonomous cardiac hepcidin/ferroportin axis. This new understanding raises pertinent questions on the interplay between systemic and local iron control in the context of heart disease, and the effects on heart function of therapies targeting the systemic hepcidin/ferroportin axis

Iron Deficiency as a Therapeutic Target in Cardiovascular Disease

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on their effectiveness in other cardiovascular diseases are lacking or conflicting. Realising the potential of iron therapies in cardiovascular disease requires understanding of the mechanisms through which iron deficiency affects cardiovascular function, and the cell types in which such mechanisms operate. That understanding has been enhanced by recent insights into the roles of hepcidin and iron regulatory proteins (IRPs) in cellular iron homeostasis within cardiovascular cells. These studies identify intracellular iron deficiency within the cardiovascular tissue as an important contributor to the disease process, and present novel therapeutic strategies based on targeting the machinery of cellular iron homeostasis rather than direct iron supplementation. This review discusses these new insights and their wider implications for the treatment of cardiovascular diseases, focusing on two disease conditions: chronic heart failure and pulmonary arterial hypertension

The interplay between iron and oxygen homeostasis with a particular focus on the heart

Iron is subject to tight homeostatic control in mammals. At the systemic level, iron homeostasis is controlled by the liver-derived hormone hepcidin acting on its target ferroportin in the gut, spleen and liver, which form the sites of iron uptake, recycling and storage, respectively. At the cellular level, iron homeostasis is dependent on the iron regulatory proteins IRP1/IRP2. Unique chemical properties of iron underpin its importance in biochemical reactions involving oxygen. As such, it is not surprising that there are reciprocal regulatory links between iron and oxygen homeostasis, operating both at the systemic and cellular levels. Hypoxia activates the IRP pathway, and in addition suppresses liver hepcidin through endocrine factors that have yet to be fully elucidated. This review summarises current knowledge on the interplay between oxygen and iron homeostasis, and describes recent insights gained into this interaction in the context of the heart. These include the recognition that the hepcidin/ferroportin axis plays a vital role in the regulation of intracellular iron homeostasis as well as regulating systemic iron availability. As is the case for other aspects of iron homeostasis, hypoxia significantly modulates the function of the hepcidin/ferroportin pathway in the heart. Key areas still to understand are the interactions between cardiac iron and diseases of the heart where hypoxia is a recognised component

The interplay between iron and oxygen homeostasis with a particular focus on the heart

Iron is subject to tight homeostatic control in mammals. At the systemic level, iron homeostasis is controlled by the liver-derived hormone hepcidin acting on its target ferroportin in the gut, spleen and liver, which form the sites of iron uptake, recycling and storage, respectively. At the cellular level, iron homeostasis is dependent on the iron regulatory proteins IRP1/IRP2. Unique chemical properties of iron underpin its importance in biochemical reactions involving oxygen. As such, it is not surprising that there are reciprocal regulatory links between iron and oxygen homeostasis, operating both at the systemic and cellular levels. Hypoxia activates the IRP pathway, and in addition suppresses liver hepcidin through endocrine factors that have yet to be fully elucidated. This review summarises current knowledge on the interplay between oxygen and iron homeostasis, and describes recent insights gained into this interaction in the context of the heart. These include the recognition that the hepcidin/ferroportin axis plays a vital role in the regulation of intracellular iron homeostasis as well as regulating systemic iron availability. As is the case for other aspects of iron homeostasis, hypoxia significantly modulates the function of the hepcidin/ferroportin pathway in the heart. Key areas still to understand are the interactions between cardiac iron and diseases of the heart where hypoxia is a recognised component