Anaemia, iron homeostasis and pulmonary hypertension: a review.

Anaemia is a highly prevalent condition, which negatively impacts on patients' cardiovascular performance and quality of life. Anaemia is mainly caused by disturbances of iron homeostasis. While absolute iron deficiency mostly as a consequence of chronic blood loss or insufficient dietary iron absorption results in the emergence of iron deficiency anaemia, inflammation-driven iron retention in innate immune cells and blockade of iron absorption leads to the development of anaemia of chronic disease. Both, iron deficiency and anaemia have been linked to the clinical course of pulmonary hypertension. Various mechanistic links between iron homeostasis, anaemia, and pulmonary hypertension have been described and current treatment guidelines suggest regular iron status assessment and the implementation of iron supplementation strategies in these patients. The pathophysiology, diagnostic assessment as well as current and future treatment options concerning iron deficiency with or without anaemia in individuals suffering from pulmonary hypertension are discussed within this review.

Iron deficiency in non-anemic chronic obstructive pulmonary disease in a predominantly male population: an ignored entity.

Non-anemic iron deficiency has been studied in heart failure, but studies are lacking in chronic obstructive pulmonary disease (COPD). The potential clinical implications of association of iron deficiency with the severity of COPD warrant research in this direction. This was an observational, cross-sectional study on patients with COPD to compare disease severity, functional status and quality of life in non-anemic patients with COPD between two groups - iron deficient and non-iron deficient. Stable non-anemic COPD with no cause of bleeding were evaluated for serum iron levels, ferritin levels, TIBC, 6MWD, SGRQ, spirometry, and CAT questionnaire. The study patients were divided into iron replete (IR) and iron deficient (ID) groups. A total of 79 patients were studied, out of which 72 were men and seven were women. The mean age was 61.5±8.42 years. Of these, 36 (45.5%; 95% CI, 34.3-56.8%) had iron deficiency. Mean 6-minute-walk distance was significantly shorter in ID (354.28±82.4 meters vs 432.5±47.21 meters; p=0.001). A number of exacerbations in a year were more in ID group (p=0.003), and more patients in ID had at least two exacerbations of COPD within a year (p=0.001). However, the resting pO2, SaO2, and SpO2 levels did not differ significantly between the two groups (p=0.15 and p=0.52, respectively). Also, there was no significant difference in the distribution of patients of a different class of airflow limitations between the two groups. Non-anemic iron deficiency (NAID) is an ignored, yet easily correctable comorbidity in COPD. Patients with iron deficiency have a more severe grade of COPD, had lesser exercise capacity and more exacerbations in a year as compared to non-iron deficient patients. So, foraying into the avenue of iron supplementation, which has shown promising results in improving functional capacity in heart failure and pulmonary hypertension, may well lead to revolutionary changes in the treatment of COPD.

Iron deficiency during pregnancy and lactation modifies the fatty acid composition of the brain of neonatal rats.

Iron deficiency is common in pregnant and lactating women and is associated with reduced cognitive development of the offspring. Since iron affects lipid metabolism, the availability of fatty acids, particularly the polyunsaturated fatty acids required for early neural development, was investigated in the offspring of female rats fed iron-deficient diets during gestation and lactation. Subsequent to the dams giving birth, one group of iron-deficient dams was recuperated by feeding an iron-replete diet. Dams and neonates were killed on postnatal days 1, 3 and 10, and the fatty acid composition of brain and stomach contents was assessed by gas chromatography. Changes in the fatty acid profile on day 3 became more pronounced on day 10 with a decrease in the proportion of saturated fatty acids and a compensatory increase in monounsaturated fatty acids. Long-chain polyunsaturated fatty acids in the n-6 family were reduced, but there was no change in the n-3 family. The fatty acid profiles of neonatal brain and stomach contents were similar, suggesting that the change in milk composition may be related to the changes in the neonatal brain. When the dams were fed an iron-sufficient diet at birth, the effects of iron deficiency on the fatty acid composition of lipids in both dam's milk and neonates' brains were reduced. This study showed an interaction between maternal iron status and fatty acid composition of the offspring's brain and suggests that these effects can be reduced by iron repletion of the dam's diet at birth.

Irritability and Perceived Expressed Emotion in Adolescents With Iron Deficiency and Iron Deficiency Anemia: A Case-Control Study.

The objective of this study was to assess the difference in irritability and perceived expressed emotion (EE) between adolescents with iron deficiency (ID) or iron deficiency anemia (IDA) and their healthy peers. In addition, we aimed to investigate the relationship between hemogram parameters, irritability, and perceived EE in adolescents with ID and IDA. The sample of this single-center cross-sectional case-control study consisted of 89 adolescents from 12 to 17 years of age. Of the participants, 19 had been diagnosed with ID, 31 had IDA, and 39 were healthy controls. Significant differences in the self-reported and parent-reported irritability scores were observed between the ID group and the control group and between the IDA group and the control group. There was also a significant difference in the subscale of irritability between the ID group and the control group. The difference between the IDA and control groups in the intrusiveness subscale was found to be significant as well. Adolescents with IDA and ID exhibited significantly perceived irritability compared with the control group. In terms of irritability, adolescents with IDA and ID revealed greater irritability than their healthy peers. The results of this study suggest that irritability and perceived EE should be investigated in cases of ID, whether with or without anemia. As chronic diseases may benefit substantially from psychiatric consultation, psychosocial evaluation and intervention should be considered a complementary treatment option in the management of ID and IDA.

Iron and Zinc Homeostasis and Interactions: Does Enteric Zinc Excretion Cross-Talk with Intestinal Iron Absorption?

Iron and zinc are essential micronutrients required for growth and health. Deficiencies of these nutrients are highly prevalent among populations, but can be alleviated by supplementation and food fortification. Cross-sectional studies in humans showed positive association of serum zinc levels with hemoglobin and markers of iron status. Dietary restriction of zinc or intestinal specific conditional knock out of ZIP4 (SLC39A4), an intestinal zinc transporter, in experimental animals demonstrated iron deficiency anemia and tissue iron accumulation. Similarly, increased iron accumulation has been observed in cultured cells exposed to zinc deficient media. These results together suggest a potential role of zinc in modulating intestinal iron absorption and mobilization from tissues. Studies in intestinal cell culture models demonstrate that zinc induces iron uptake and transcellular transport via induction of divalent metal iron transporter-1 (DMT1) and ferroportin (FPN1) expression, respectively. It is interesting to note that intestinal cells are exposed to very high levels of zinc through pancreatic secretions, which is a major route of zinc excretion from the body. Therefore, zinc appears to be modulating the iron metabolism possibly via regulating the DMT1 and FPN1 levels. Herein we critically reviewed the available evidence to hypothesize novel mechanism of Zinc-DMT1/FPN1 axis in regulating intestinal iron absorption and tissue iron accumulation to facilitate future research aimed at understanding the yet elusive mechanisms of iron and zinc interactions.

Comparative liver function assessment of natural and available drug (Ferrous sulfate) for iron-deficiency anemia in rat model.

To assess the comparative effect of anti-anaemic drug (ferrous sulfate) with naturally occurring anti-anaemic compound (Illicium verum commonly called star anise) on liver in rat model. Model and both test groups were made anaemic. Ferrous sulfate was given to T1 group of rats as 30mg/kg body weight (b.w) and Illicium verum to T2 group of rats with dose of 80mg/kg b.w for six weeks. Illicium verum treated group (T2 rats) produced depression, decreased anxiety and enhanced short-term memory, whereas ferrous sulfate treated group (T1 rats) enhanced long term memory. The liver function test of T2 rats showed that the total bilirubin was in normal range, but direct bilirubin, SGPT, ALP and GGT were significantly decreased in T2 rats in comparison with T1 and also from model group of rats. It was concluded in this study that by comparing the effect of ferrous sulfate with naturally occurring Illicium verum on iron-defficiency anaemia, illicium verum produces same effects and can be used to treat iron-defficiency anaemia without affecting liver function.

Iron Deficiency, Cognitive Functions, and Neurobehavioral Disorders in Children.

More than 25% of the world's population is affected by anemia, of which more than 50% suffers from iron deficiency anemia (IDA). Children below 7 years of age are the population group that is most vulnerable to iron deficiency. Iron is an essential element in brain metabolism. Iron deficiency can cause changes in neurotransmitter homeostasis, decrease myelin production, impair synaptogenesis, and decline the function of the basal ganglia. Therefore, IDA adversely affects cognitive functions and psychomotor development. Research has shown that iron deficiency is a frequent comorbidity in attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder. Iron deficiency may also induce or exacerbate deficiency of other essential nutrients, which may have a negative impact on the developing brain and other organs in infants. Many nations of the world have programs to control IDA based on the use of iron supplementation, intake of fortified food and drinks, improved food safety, and monitoring of dietary diversity. Based on the current recommendations of the World Health Organization on cost-effectiveness (WHO-CHOICE), iron fortification and iron supplementation programs can be considered cost-effective or even highly cost-effective in most countries of the world to averting cognitive impairment.

A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment.

BACKGROUND: The fetal brain starts developing early and animal studies have suggested that iron plays several roles for the development, but results from epidemiological studies investigating associations between gestational iron and offspring neurodevelopment are inconsistent. OBJECTIVE: To systematically examine results from observational studies and RCTs on gestational iron and offspring neurodevelopment, with focus on the importance of four domains: iron status indicators, exposure timing, neurodevelopmental outcomes, and offspring age. METHODS: PRISMA guidelines were followed. Embase, PsychInfo, Scopus, and The Cochrane library were searched in September 2017 and February 2018. Overall, 3307 articles were identified and 108 retrieved for full-text assessment. Pre-specified eligibility criteria were used to select studies and 27 articles were included;19 observational and 8 RCTs. RESULTS: Iron status in pregnancy was associated with offspring behavior, cognition, and academic achievement. The direction of associations with behavioral outcomes were unclear and the conclusions related to cognition and academic achievement were based on few studies, only. Little evidence was found for associations with motor development. Observed associations were shown to persist beyond infancy into adolescence, and results depended on iron status indicator type but not on the timing of exposure. CONCLUSION: We conclude that there is some evidence that low pregnancy iron, possibly particularly in the 3rd trimester, may be associated with adverse offspring neurodevelopment. As most previous research used Hemoglobin, inferring results to iron deficiency should be done with caution. No conclusions could be reached regarding associations beyond early childhood, and supplementation with iron during pregnancy did not seem to influence offspring neurodevelopment.

Safety and efficacy of sucrosomial iron in inflammatory bowel disease patients with iron deficiency anemia.

Iron deficiency anemia (IDA) is one of the most common complications of inflammatory bowel disease (IBD). We planned a prospective study to address tolerability and efficacy of sucrosomial iron, a new oral formulation of ferric pyrophosphate, in IBD patients. Thirty patients with a confirmed diagnosis of Crohn's Disease (CD) or ulcerative colitis (UC) and mild IDA were enrolled. Patients with severe IBD were excluded. All patients underwent 12 weeks of oral treatment with 30 mg/day of sucrosomial iron. Treatment compliance and adverse events were investigated every 4 weeks. Iron status, hematological parameters and IBD activity scores were determined at baseline and at the end of treatment, as well as serum hepcidin and non-transferrin bound iron (NTBI) levels. Twenty-four (80%) patients took more than 90% of the prescribed regimen. Forty-four adverse events (AEs) were recorded, but none of them is considered certainly or probably related to the study treatment. Interestingly, only eleven gastrointestinal events were recorded in 9 (30%) patients. At the end of treatment, all iron parameters improved significantly and Hb increased in 86% of patients (from 11.67 to 12.37 g/dl, p = 0.001). Serum hepcidin showed a significant increase in 79% of patients and became positively correlated with C-reactive protein (CRP) at the end of the study, while NTBI remained below the detection threshold after iron supplementation. The IBD activity scores improved in both CD and UC. This pilot interventional study supports the therapeutic use of sucrosomial iron in IBD and paves the way for future studies in larger or more difficult IBD populations.

Iron therapy substantially restores qEEG maturational lag among iron-deficient anemic infants.

OBJECTIVE: To use quantitative electroencephalography (qEEG) to assess the impact of iron-deficiency anemia on central nervous system maturation in the first year of life. METHOD: Twenty-five infants (3-12 months old) presenting ferropenic anemia (IDA) and 25 healthy controls (CTL1), matched by age/gender with the former, were studied in two stages. Electroencephalogram during spontaneous sleep was recorded from all participants; the fast Fourier transform was calculated to obtain absolute power (AP) and relative power (RP) qEEG measures. In the first stage, a qEEG comparison between CTL1 and IDA was performed. Second stage consisted in comparing qEEG of the IDA infants before and after supplementation with iron (IDA-IS group), and comparing qEEG of the IDA-IS group with another control age-matched group (CTL2). Non-parametric multivariate permutation tests (NPT) were applied to assess differences between CTL1 and IDA groups, as well as IDA vs. IDA-IS, and IDA-IS vs. CTL2. RESULTS: More power in slow frequency bands and less power in fast frequency bands in 64% of IDA babies were observed. NPT evinced higher alpha AP and RP (P < 0.001), less theta AP, and less delta and theta RP in CTL1 than in IDA. After iron-restoration therapy, alpha AP and RP increased while theta AP and theta and delta RP decreased, reaching almost normal values. DISCUSSION: This work reveals CNS developmental delay through the study of qEEG (less rapid and more slow frequencies) which recovered significantly with iron supplementation. It is concluded that IDA constitutes a high risk factor for a lag of CNS maturation.

Effectiveness of a Program Intervention with Reduced-Iron Multiple Micronutrient Powders on Iron Status, Morbidity and Growth in Young Children in Ethiopia.

Despite the potential for improving iron status and child growth in low- and middle-income settings, concerns on the safety of high iron dosages of Micronutrient Powders (MNP currently limit their applicability in programs. We examined the effectiveness and risks of an integrated complementary feeding program with low iron dose (6 mg/serving) MNP among 6⁻23-month-old Ethiopian children using a quasi-experimental study design comparing children from five intervention districts (n = 1172) to those from four matched non-intervention districts (n = 1137). Haemoglobin concentrations increased in intervention and decreased in non-intervention children (group-difference +3.17 g/L), but without improvement in iron stores. Intervention children were 2.31 times more likely to have diarrhoea and 2.08 times more likely to have common cold and flu, but these differences decreased towards the end of the intervention. At end line, intervention children had higher mean Height-for-Age Zscore (HAZ) and a 51% reduced odds of being stunted compared to non-intervention children. MNP with low iron dose, when provided combined with other Infant and Young Child Feeding (IYCF) interventions, marginally improved haemoglobin status and resulted in a remarkable improvement in linear growth in 6⁻23-month-old children. These benefits likely outweigh the relatively small increase in the risk of diarrhoea.

Iron deficiency and iron treatment in the fetal developing brain - a pilot study introducing an experimental rat model.

BACKGROUND: Iron deficiency is especially common in women during the reproductive age and it is estimated that 52% of pregnant women have iron deficiency anemia. Maternal iron deficiency with or without anemia in pregnancy may have consequences for the fetus, where it may have an impact on the cerebral development of the brain. Both animals and adult human studies support that iron deficiency affects psychomotor development, behavioral traits, and cognitive functions in the offspring. However, it has not yet been established whether the availability of sufficient iron is particularly important in certain phases during brain development, and whether possible damages are reversible if iron supplementation is provided during pregnancy. Here we report results from a pilot study in an experimental rat model suitable for introducing iron deficiency in the fetal rat brain. METHODS: The model was utilized for examination of the potential to reverse changes in fetal brain iron by maternal parenteral iron administration. Fertilized females subjected to iron deficiency without anemia were subcutaneously injected with iron isomaltoside at the day of mating (E0), 14 days into pregnancy (E14), or at the day of birth (Postnatal (P) 0). Blood, brain and liver in the offspring were examined on P0 or in adulthood on postnatal day P70. RESULTS: Maternal iron restriction during pregnancy led to significantly lower levels of iron in the brains of newborn rats compared to levels in pups of iron sufficient mothers. Females fed ID diet (5.2 mg/kg Fe) had offspring with significantly lower cerebral iron compared to a control group fed a standard diet (158 mg/kg Fe). Injection of IIM to pregnant ID females on E0 or E14 yielded normalization of Fe in the developing brain known to express elevated levels of capillary transferrin receptors, indicating that the administered iron passed the placenta and fetal blood brain barrier. CONCLUSIONS: In future studies, this translational model may be applied to examine morphological and biochemical consequences of iron deficiency and iron deficiency treatment in the developing fetal brain.

Iron Promotes Intestinal Development in Neonatal Piglets.

Early nutrition is key to promoting gut growth and education of the immune system. Although iron deficiency anemia has long been recognized as a serious iron disorder, the effects of iron supplementation on gut development are less clear. Therefore, using suckling piglets as the model for iron deficiency, we assessed the impacts of iron supplementation on hematological status, gut development, and immunity improvement. Piglets were parenterally supplied with iron dextran (FeDex, 60 mg Fe/kg) by intramuscular administration on the third day after birth and slaughtered at the age of two days, five days, 10 days, and 20 days. It was expected that iron supplementation with FeDex improved the iron status with higher levels of serum iron, ferritin, transferrin, and iron loading in the liver by regulating the interaction of hepcidin and ferroportin (FPN). FeDex supplementation increased villus length and crypt depth, attenuated the pathological status of the duodenum, and was beneficial to intestinal mucosa. FeDex also influenced the intestinal immune development by stimulating the cytokines' production of the intestine and enhancing the phagocytotic capacity of monocytes. Overall, the present study suggested that iron supplementation helped promote the development of the intestine by improving its morphology, which maintains its mucosal integrity and enhances the expression of immuno-associated factors.

Approaches for Reducing the Risk of Early-Life Iron Deficiency-Induced Brain Dysfunction in Children.

Iron deficiency is the most common micronutrient deficiency in the world. Women of reproductive age and young children are particularly vulnerable. Iron deficiency in late prenatal and early postnatal periods can lead to long-term neurobehavioral deficits, despite iron treatment. This may occur because screening and treatment of iron deficiency in children is currently focused on detection of anemia and not neurodevelopment. Anemia is the end-stage state of iron deficiency. The brain becomes iron deficient before the onset of anemia due to prioritization of the available iron to the red blood cells (RBCs) over other organs. Brain iron deficiency, independent of anemia, is responsible for the adverse neurological effects. Early diagnosis and treatment of impending brain dysfunction in the pre-anemic stage is necessary to prevent neurological deficits. The currently available hematological indices are not sensitive biomarkers of brain iron deficiency and dysfunction. Studies in non-human primate models suggest that serum proteomic and metabolomic analyses may be superior for this purpose. Maternal iron supplementation, delayed clamping or milking of the umbilical cord, and early iron supplementation improve the iron status of at-risk infants. Whether these strategies prevent iron deficiency-induced brain dysfunction has yet to be determined. The potential for oxidant stress, altered gastrointestinal microbiome and other adverse effects associated with iron supplementation cautions against indiscriminate iron supplementation of children in malaria-endemic regions and iron-sufficient populations.

Nutritional Status of Bariatric Surgery Candidates.

Obesity is a global epidemic affecting populations globally. Bariatric surgery is an effective treatment for morbid obesity, and has increased dramatically. Bariatric surgery candidates frequently have pre-existing nutritional deficiencies that might exacerbate post-surgery. To provide better health care management pre- and post-bariatric surgery, it is imperative to establish the nutritional status of prospective patients before surgery. The aim of this study was to assess and provide baseline data on the nutritional status of bariatric candidates. A retrospective study was conducted on obese patients who underwent bariatric surgery from 2008 to 2015. The medical records of 1538 patients were reviewed for this study. Pre-operatively, the most commonly observed vitamin deficiencies were Vitamin D (76%) and Vitamin B12 (16%). Anemia and iron status parameters were low in a considerable number of patients before surgery, as follows: hemoglobin 20%, mean corpuscular volume (MCV) 48%, ferritin 28%, serum iron 51%, and transferrin saturation 60%. Albumin and transferrin were found to be low in 10% and 9% of the patients, respectively, prior to surgery. In addition to deficiencies, a great number of patients had hypervitaminosis pre-operatively. Excess levels of Vitamin B6 (24%) was the most remarkable. The findings in this study advocate a close monitoring and tailored supplementation pre- and post-bariatric surgery.

Micronutrient Status and Dietary Intake of Iron, Vitamin A, Iodine, Folate and Zinc in Women of Reproductive Age and Pregnant Women in Ethiopia, Kenya, Nigeria and South Africa: A Systematic Review of Data from 2005 to 2015.

A systematic review was conducted to evaluate the status and intake of iron, vitamin A, iodine, folate and zinc in women of reproductive age (WRA) (≥15-49 years) and pregnant women (PW) in Ethiopia, Kenya, Nigeria and South Africa. National and subnational data published between 2005 and 2015 were searched via Medline, Scopus and national public health websites. Per micronutrient, relevant data were pooled into an average prevalence of deficiency, weighted by sample size (WAVG). Inadequate intakes were estimated from mean (SD) intakes. This review included 65 surveys and studies from Ethiopia (21), Kenya (11), Nigeria (21) and South Africa (12). In WRA, WAVG prevalence of anaemia ranged from 18-51%, iron deficiency 9-18%, and iron deficiency anaemia at 10%. In PW, the prevalence was higher, and ranged from 32-62%, 19-61%, and 9-47%, respectively. In WRA, prevalence of vitamin A, iodine, zinc and folate deficiencies ranged from 4-22%, 22-55%, 34% and 46%, while in PW these ranged from 21-48%, 87%, 46-76% and 3-12% respectively. Inadequate intakes of these micronutrients are high and corresponded with the prevalence figures. Our findings indicate that nationally representative data are needed to guide the development of nutrition interventions and public health programs, such as dietary diversification, micronutrient fortification and supplementation.

[Iron and Neurodevelopment]. / Fer et neurodéveloppement.

In the central nervous system, iron is a cofactor of many metabolic processes and synthesis of aminergic neurotransmitters. Iron plays an major function on brain development from the prenatal period to teenage years. The blood-brain barrier modulates concentration of iron in the brain. In case of iron deficiency in the child, the negative impact on the myelinogenesis and synaptogenesis are well proven, with negative effects on psychomotor and cognitive functions. Iron supplementation has a beneficial effect, even if there is no anemia. The consequences of iron deficiency are more harmful as deficiency is early. The main mechanisms involved about iron and brain are reviewed.

Iron Deficiency Treatment in Patients with Heart Failure.

Iron deficiency (ID) is one of the major risk factors for disability and mortality worldwide, and it was identified as a common and ominous comorbidity in patients with heart failure (HF), both with and without anaemia. Based on two clinical trials (FAIR-HF and CONFIRM-HF) and other epidemiological evidence, ID has been recognized as an important therapeutic target in symptomatic patients with HF and LVEF ≤45%.Intravenous iron supplementation has been demonstrated to be safe and effective for iron repletion and related with an improvement in clinical status, exercise capacity, and quality of life. Ongoing trials are testing the hypothesis that such a therapy may also reduce the risk of HF hospitalizations and cardiovascular death.

Anemia in Peritoneal Dialysis Patients; Iron Repletion, Current and Future Therapies.

Iron deficiency, both functional and absolute, is common in patients with chronic kidney disease (CKD), especially those requiring dialysis. Guidelines advocate treatment of iron-deficiency anemia in patients with CKD and those on peritoneal dialysis (PD). Oral iron is often insufficient and slow to improve hemoglobin concentrations because of high hepcidin levels causing impaired absorption and mobilization, while intravenous (IV) supplementation replenishes and maintains iron stores more effectively and is now standard practice (Kidney Disease Improving Global Outcomes [KDIGO] 2012 guidelines). However, there still remain concerns about the effects of labile iron and possible increased risk of infections for this group of patients.To date, the majority of published studies have focused on hemodialysis (HD) patients; very limited data are available regarding patients on PD. This review summarizes the rationale for iron therapy, methods of treatment, potential adverse effects, and long-term concerns in PD patients. In addition we highlight some interesting potential future therapies under study.