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Iron Deficiency and Iron-Related Disorders

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Micronutrients and Human Health".

Deadline for manuscript submissions: closed (25 April 2024) | Viewed by 35206

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Dr. Phu V. Tran

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Guest Editor

Department of Pediatrics, University of Minnesota at Twin Cities, Minneapolis, MN 55455, USA
Interests: developmental neuroscience; epigenetics; fetal-neonatal nutrition; neurobehavioral development; DOHaD

Prof. Dr. Barbara True Felt

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Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
Interests: developmental pediatrics; disorders of elimination; parent–child interaction difficulties; sleep problems; school problems and attention deficit disorder

Dr. Yue Chen

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Guest Editor

Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota at Twin Cities, Minneapolis, MN 55455, USA
Interests: functional proteomics; epigenetics; cell signaling; cancer biology; metabolic diseases
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Dear Colleagues,

Increasing evidence indicates that early life exposures (e.g., malnutrition, toxins, stress) can have a lasting impact on physiological and mental health—a central concept of the developmental origins of health and disease (DOHaD). These lasting effects are a burden to society. Iron deficiency (ID) is the foremost micronutrient deficiency, affecting 40–50% of pregnant women and preschool-aged children worldwide. There are a multitude of both controllable and uncontrollable factors that contribute to poor iron status during fetal and early childhood periods, including anemia, maternal obesity, maternal diabetes, placental dysfunction, intrauterine growth restriction, and socioeconomic status. ID during the fetal and early childhood periods (developmental ID) has a significant effect on neurodevelopment, resulting in cognitive, socio-emotional, and learning and memory deficits that continue into adulthood despite prompt iron therapy after diagnosis. Developmental ID also carries long-term health risks including increased risk for neuropsychiatric disorders, such as autism and schizophrenia. Parallel studies in pre-clinical models have shown that early-life ID results in abnormal brain structure, function, and gene expression, occurring acutely during rapid neurodevelopment then continuing persistently through to adulthood. The persistent and widespread changes in gene networks implicated in psychopathologies are a likely major cause of adult neurobehavioral abnormalities.

This Special Issue will publish original research and reviews of developmental ID on health outcomes and risks, as well as mechanisms (e.g., iron trafficking and metabolism, maternal-fetal/infant iron transport, microbiota, epigenetics, iron-dependent gene regulation and post-translational modifications), by which developmental ID determines the long-term health outcomes.

Dr. Phu V. Tran
Prof. Dr. Barbara True Felt
Dr. Yue Chen
Guest Editors

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Keywords

iron deficiency
iron metabolism
neurodevelopment
behavior
cognition
learning and memory
microbiota
iron-trafficking
epigenetics
maternal–fetal iron

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Published Papers (14 papers)

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Editorial

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5 pages, 148 KiB

Open AccessEditorial

Maternal–Infant Iron Deficiency and Neurologic Sequelae

by Barbara T. Felt and Phu V. Tran

Nutrients 2025, 17(5), 841; https://doi.org/10.3390/nu17050841 - 28 Feb 2025

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15 pages, 1390 KiB

Open AccessArticle

Influence of Biological Sex and Congenital Iron Deficiency on Neonatal Cytokine Responses

by Narmin Mukhtarova, Anthony Babu, Christopher L. Coe and Pamela J. Kling

Nutrients 2024, 16(23), 4203; https://doi.org/10.3390/nu16234203 - 5 Dec 2024

Viewed by 1057

Abstract

Background/Objectives: Stimulated cord blood mononuclear cell (CBMC) cytokine responses were previously shown to predict the risk of childhood atopic disease. Iron deficiency (ID) at birth may also program atopic disease. Males are at a higher risk of pediatric atopic disease, but it is not known whether congenital ID impacts CBMC immune responses differentially by sex. Methods: Cord blood (CB) samples were collected from healthy term or near-term neonates after elective cesarean deliveries. A transferrin saturation ≤ 25% defined congenital ID. CBMCs were stimulated with either phytohemagglutinin (PHA) or PHA plus an iron chelator. Results: Of the 85 neonates, the 26 neonates with congenital ID exhibited lower plasma tumor necrosis factor-α (TNF-α), as well as higher CBMC TNF-α and IL-8 responses than iron-sufficient neonates (p = 0.017, p = 0.013, and p = 0.007, respectively). Higher CBMC TNF-α responses were seen in both males and females with congenital ID. However, females with congenital ID also had lower plasma IL-6, lower plasma TNF-α, and higher CBMC interleukin (IL)-8 responses. Additionally, iron chelation during culture influenced stimulated CBMC IFN-γ and CBMC TNF-α responses. Discussion: Congenital ID may influence stimulated CBMC cytokine responses, but results point to a sex-specific regulation of immune balance at birth. Because males are more prone to infantile ID and more likely to develop early childhood asthma, future studies should further investigate how fetal sex and congenital iron status impacts childhood immune responsiveness to infections and antigenic stimulation from the rearing environment. Full article

(This article belongs to the Special Issue Iron Deficiency and Iron-Related Disorders)

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12 pages, 293 KiB

Open AccessArticle

Iron Deficiency and Internalizing Symptoms Among Adolescents in the National Health and Nutrition Examination Survey

by Dimitri Fiani, Solangia Engler, Yang Ni, Sherecce Fields and Chadi Calarge

Nutrients 2024, 16(21), 3643; https://doi.org/10.3390/nu16213643 - 26 Oct 2024

Cited by 1 | Viewed by 2100

Abstract

Background: Iron Deficiency (ID) affects two billion people worldwide, predominantly adolescent girls, and may be associated with increased psychopathology. The associations between ID and symptoms of depression and anxiety in adolescents were examined using data from the National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey of a nationally representative sample of non-institutionalized Americans. Methods: The current analysis included survey cycles where both iron-related markers and mental health-related outcomes were collected in adolescents 12 to 17 years old. Acute and serious medical conditions, acute inflammation, and abnormal birth weight led to exclusion. Linear multivariable regression analyses examined the association between ID status (defined based on the total body iron model) and (1) total Patient Health Questionnaire (PHQ-9) score, (2) one item examining anxiety severity, and (3) one item examining overall mental well-being. Covariates included age, sex, race and ethnicity, body mass index, household income, head-of-household marital status, and psychotropic medication use. Sensitivity analyses examined the robustness of the findings when ID was defined based on the ferritin model. Results: In 1990 adolescents (age [mean ± SD]: 14.5 ± 1.7 years; 85.7% females), ID with and without anemia was significantly associated with a higher PHQ-9 score in multiracial adolescents (Cohen’s d = 1.09, p = 0.0005 for ID without anemia; d = 0.92, p = 0.0395 for ID with anemia). Moreover, ID with anemia was associated with more severe anxiety (d = 3.00, p = 0.0130) and worse mental well-being (d = 2.75, p = 0.0059) in multiracial adolescents. The findings remained significant after adjusting for psychotropic use and in the sensitivity analyses. Conclusions: Iron deficiency is associated with poorer mental health in adolescents of multiracial background. Future studies should confirm these findings prospectively and examine the underlying mechanism. Full article

(This article belongs to the Special Issue Iron Deficiency and Iron-Related Disorders)

19 pages, 3806 KiB

Open AccessArticle

Normalization of Fetal Cerebral and Hepatic Iron by Parental Iron Therapy to Pregnant Rats with Systemic Iron Deficiency without Anemia

by Annette Burkhart, Kasper Bendix Johnsen, Tina Skjørringe, Asbjørn Haaning Nielsen, Lisa Juul Routhe, Sandra Hertz, Lisbeth Birk Møller, Lars Lykke Thomsen and Torben Moos

Nutrients 2024, 16(19), 3264; https://doi.org/10.3390/nu16193264 - 27 Sep 2024

Viewed by 1499

Abstract

Background/Objectives: Iron (Fe) is a co-factor for enzymes of the developing brain necessitating sufficient supply. We investigated the effects of administering ferric derisomaltose/Fe isomaltoside (FDI) subcutaneously to Fe-deficient (ID) pregnant rats on cerebral and hepatic concentrations of essential metals and the expression of iron-relevant genes. Methods: Pregnant rats subjected to ID were injected with FDI on the day of mating (E0), 14 days into pregnancy (E14), or the day of birth (postnatal (P0)). The efficacy was evaluated by determination of cerebral and hepatic Fe, copper (Cu), and zinc (Zn) and gene expression of ferroportin, hepcidin, and ferritin H + L in pups on P0 and as adults on P70. Results: Females fed an ID diet (5.2 mg/kg Fe) had offspring with significantly lower cerebral and hepatic Fe compared to female controls fed a standard diet (158 mg/kg Fe). Cerebral Cu increased irrespective of supplying a standard diet or administering FDI combined with the standard diet. Hepatic hepcidin mRNA was significantly lower following ID. Cerebral hepcidin mRNA was hardly detectable irrespective of iron status. Conclusions: In conclusion, administering FDI subcutaneously to ID pregnant rats on E0 normalizes fetal cerebral and hepatic Fe. When applied at later gestational ages, supplementation with additional Fe to the offspring is needed to normalize cerebral and hepatic Fe. Full article

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16 pages, 875 KiB

Open AccessArticle

Iron Deficiency and Restless Sleep/Wake Behaviors in Neurodevelopmental Disorders and Mental Health Conditions

by Osman S. Ipsiroglu, Parveer K. Pandher, Olivia Hill, Scout McWilliams, Melissa Braschel, Katherine Edwards, Robin Friedlander, Elizabeth Keys, Calvin Kuo, Marion Suzanne Lewis, Anamaria Richardson, Alexandra L. Wagner and David Wensley

Nutrients 2024, 16(18), 3064; https://doi.org/10.3390/nu16183064 - 11 Sep 2024

Cited by 2 | Viewed by 4344

Abstract

Iron deficiency (ID) and restlessness are associated with sleep/wake-disorders (e.g., restless legs syndrome (RLS)) and neurodevelopmental disorders (attention deficit/hyperactivity and autism spectrum disorders (ADHD; ASD)). However, a standardized approach to assessing ID and restlessness is missing. We reviewed iron status and family sleep/ID history data collected at a sleep/wake behavior clinic under a quality improvement/quality assurance project. Restlessness was explored through patient and parental narratives and a ‘suggested clinical immobilization test’. Of 199 patients, 94% had ID, with 43% having a family history of ID. ADHD (46%) and ASD (45%) were common conditions, along with chronic insomnia (61%), sleep-disordered breathing (50%), and parasomnias (22%). In unadjusted analysis, a family history of ID increased the odds (95% CI) of familial RLS (OR: 5.98, p = 0.0002, [2.35–15.2]), insomnia/DIMS (OR: 3.44, p = 0.0084, [1.37–8.64]), and RLS (OR: 7.00, p = 0.01, [1.49–32.93]) in patients with ADHD, and of insomnia/DIMS (OR: 4.77, p = 0.0014, [1.82–12.5]), RLS/PLMS (OR: 5.83, p = 0.009, [1.54–22.1]), RLS (OR: 4.05, p = 0.01, [1.33–12.3]), and familial RLS (OR: 2.82, p = 0.02, [1.17–6.81]) in patients with ASD. ID and restlessness were characteristics of ADHD and ASD, and a family history of ID increased the risk of sleep/wake-disorders. These findings highlight the need to integrate comprehensive blood work and family history to capture ID in children and adolescents with restless behaviors. Full article

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26 pages, 1869 KiB

Open AccessArticle

Multiple Infections, Nutrient Deficiencies, and Inflammation as Determinants of Anemia and Iron Status during Pregnancy: The MINDI Cohort

by Doris González-Fernández, Elizabeta Nemeth, Emérita del Carmen Pons, Delfina Rueda, Odalis T. Sinisterra, Enrique Murillo, Veena Sangkhae, Lisa Starr, Marilyn E. Scott and Kristine G. Koski

Nutrients 2024, 16(11), 1748; https://doi.org/10.3390/nu16111748 - 2 Jun 2024

Cited by 2 | Viewed by 2447

Abstract

In pregnant women with multiple infections, nutrient deficiencies, and inflammation (MINDI), the study of anemia and iron status is limited. For this cross-sectional study (n = 213 Panamanian indigenous women), we investigated if hemoglobin, anemia (Hb < 110 g/L), ferritin, serum iron, serum transferrin receptor, and hepcidin were associated with (1) maternal nutritional status and supplementation practices, (2) biomarkers of inflammation, and (3) presence/absence of infections. Hierarchical generalized linear and logistic regression models and dominance analyses identified the relative importance of these predictors. Anemia (38%), which was likely underestimated due to low plasma volume (95%), was associated with lower ferritin, vitamin A, and weight-for-height, suggesting anemia of undernutrition. Inflammation was not associated with Hb or anemia; nevertheless, higher CRP was associated with increased odds of low serum iron and higher ferritin and hepcidin, indicating iron restriction due to inflammation. The length of iron supplementation did not enter models for anemia or iron indicators, but a multiple nutrient supplement was associated with higher ferritin and hepcidin. Moreover, iron supplementation was associated with higher odds of vaginal trichomoniasis but lower odds of caries and bacterial vaginosis. The complex pathogenesis of anemia and iron deficiency in MINDI settings may require other interventions beyond iron supplementation. Full article

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18 pages, 558 KiB

Open AccessArticle

Baby Food Pouches, Baby-Led Weaning, and Iron Status in New Zealand Infants: An Observational Study

by Neve H. McLean, Jillian J. Haszard, Lisa Daniels, Rachael W. Taylor, Benjamin J. Wheeler, Cathryn A. Conlon, Kathryn L. Beck, Pamela R. von Hurst, Lisa A. Te Morenga, Jenny McArthur, Rebecca Paul, Ioanna Katiforis, Kimberley J. Brown, Madeline C. Gash, Madeleine M. Rowan, Maria Casale, Alice M. Cox, Emily A. Jones, Rosario M. Jupiterwala, Bailey Bruckner, Liz Fleming and Anne-Louise M. Heath Show full author list Hide full author list

Nutrients 2024, 16(10), 1494; https://doi.org/10.3390/nu16101494 - 15 May 2024

Cited by 1 | Viewed by 2212

Abstract

Iron deficiency in infants can impact development, and there are concerns that the use of baby food pouches and baby-led weaning may impair iron status. First Foods New Zealand (FFNZ) was an observational study of 625 New Zealand infants aged 6.9 to 10.1 months. Feeding methods were defined based on parental reports of infant feeding at “around 6 months of age”: “frequent” baby food pouch use (five+ times per week) and “full baby-led weaning” (the infant primarily self-feeds). Iron status was assessed using a venepuncture blood sample. The estimated prevalence of suboptimal iron status was 23%, but neither feeding method significantly predicted body iron concentrations nor the odds of iron sufficiency after controlling for potential confounding factors including infant formula intake. Adjusted ORs for iron sufficiency were 1.50 (95% CI: 0.67–3.39) for frequent pouch users compared to non-pouch users and 0.91 (95% CI: 0.45–1.87) for baby-led weaning compared to traditional spoon-feeding. Contrary to concerns, there was no evidence that baby food pouch use or baby-led weaning, as currently practiced in New Zealand, were associated with poorer iron status in this age group. However, notable levels of suboptimal iron status, regardless of the feeding method, emphasise the ongoing need for paying attention to infant iron nutrition. Full article

(This article belongs to the Special Issue Iron Deficiency and Iron-Related Disorders)

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20 pages, 3504 KiB

Open AccessArticle

Maternal Iron Deficiency and Environmental Lead (Pb) Exposure Alter the Predictive Value of Blood Pb Levels on Brain Pb Burden in the Offspring in a Dietary Mouse Model: An Important Consideration for Cumulative Risk in Development

by Janine Cubello, Derick R. Peterson, Lu Wang and Margot Mayer-Proschel

Nutrients 2023, 15(19), 4101; https://doi.org/10.3390/nu15194101 - 22 Sep 2023

Cited by 5 | Viewed by 2166

Abstract

Maternal iron deficiency (ID) and environmental lead (Pb) exposure are co-occurring insults that both affect the neurodevelopment of offspring. Few studies have investigated how ID affects brain-region-specific Pb accumulations using human-relevant Pb concentrations. Furthermore, how these Pb exposures impact blood and brain Fe levels remains unclear. Importantly, we also wanted to determine whether the use of blood Pb levels as a surrogate for the brain Pb burden is affected by underlying iron status. We exposed virgin Swiss Webster female mice to one of six conditions differing by iron diet and Pb water concentration (0 ppm, 19 ppm, or 50 ppm lead acetate) and used Inductively Coupled Plasma Mass Spectrometry to measure the maternal and offspring circulating, stored, and brain Pb levels. We found that maternal ID rendered the offspring iron-deficient anemic and led to a region-specific depletion of brain Fe that was exacerbated by Pb in a dose-specific manner. The postnatal iron deficiency anemia also exacerbated cortical and hippocampal Pb accumulation. Interestingly, BPb levels only correlated with the brain Pb burden in ID pups but not in IN offspring. We conclude that ID significantly increases the brain Pb burden and that BPb levels alone are insufficient as a clinical surrogate to make extrapolations on the brain Pb burden. Full article

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13 pages, 289 KiB

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Examining the Double Burden of Underweight, Overweight/Obesity and Iron Deficiency among Young Children in a Canadian Primary Care Setting

by Sean A. Borkhoff, Patricia C. Parkin, Catherine S. Birken, Jonathon L. Maguire, Colin Macarthur and Cornelia M. Borkhoff

Nutrients 2023, 15(16), 3635; https://doi.org/10.3390/nu15163635 - 18 Aug 2023

Cited by 4 | Viewed by 1828

Abstract

There is little evidence on the prevalence of the double burden and association between body mass index (BMI) and iron deficiency among young children living in high-income countries. We conducted a cross-sectional study of healthy children, 12–29 months of age, recruited during health supervision visits in Toronto, Canada, and concurrently measured BMI and serum ferritin. The prevalence of a double burden of underweight (zBMI < −2) and iron deficiency or overweight/obesity (zBMI > 2) and iron deficiency was calculated. Regression models examined BMI and serum ferritin as continuous and categorical variables, adjusted for covariates. We found the following in terms of prevalence among 1953 children (mean age 18.3 months): underweight 2.6%, overweight/obesity 4.9%, iron deficiency 13.8%, iron-deficiency anemia 5.4%, underweight and iron deficiency 0.4%, overweight/obesity and iron deficiency 1.0%. The change in median serum ferritin for each unit of zBMI was −1.31 µg/L (95% CI −1.93, −0.68, p < 0.001). Compared with normal weight, we found no association between underweight and iron deficiency; meanwhile, overweight/obesity was associated with a higher odds of iron deficiency (OR 2.15, 95% CI 1.22, 3.78, p = 0.008). A double burden of overweight/obesity and iron deficiency occurs in about 1.0% of young children in this high-income setting. For risk stratification and targeted screening in young children, overweight/obesity should be added to the list of important risk factors. Full article

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15 pages, 5775 KiB

Open AccessArticle

Sex-Specific Effects of Early-Life Iron Deficiency and Prenatal Choline Treatment on Adult Rat Hippocampal Transcriptome

by Shirelle X. Liu, Tenille K. Fredrickson, Natalia Calixto Mancipe, Michael K. Georgieff and Phu V. Tran

Nutrients 2023, 15(6), 1316; https://doi.org/10.3390/nu15061316 - 7 Mar 2023

Cited by 3 | Viewed by 2158

Abstract

Background: Fetal-neonatal iron deficiency (ID) causes long-term neurocognitive and affective dysfunctions. Clinical and preclinical studies have shown that early-life ID produces sex-specific effects. However, little is known about the molecular mechanisms underlying these early-life ID-induced sex-specific effects on neural gene regulation. Objective: To illustrate sex-specific transcriptome alterations in adult rat hippocampus induced by fetal-neonatal ID and prenatal choline treatment. Methods: Pregnant rats were fed an iron-deficient (4 mg/kg Fe) or iron-sufficient (200 mg/kg Fe) diet from gestational day (G) 2 to postnatal day (P) 7 with or without choline supplementation (5 g/kg choline) from G11–18. Hippocampi were collected from P65 offspring of both sexes and analyzed for changes in gene expression. Results: Both early-life ID and choline treatment induced transcriptional changes in adult female and male rat hippocampi. Both sexes showed ID-induced alterations in gene networks leading to enhanced neuroinflammation. In females, ID-induced changes indicated enhanced activity of oxidative phosphorylation and fatty acid metabolism, which were contrary to the ID effects in males. Prenatal choline supplementation induced the most robust changes in gene expression, particularly in iron-deficient animals where it partially rescued ID-induced dysregulation. Choline supplementation also altered hippocampal transcriptome in iron-sufficient rats with indications for both beneficial and adverse effects. Conclusions: This study provided unbiased global assessments of gene expression regulated by iron and choline in a sex-specific manner, with greater effects in female than male rats. Our new findings highlight potential sex-specific gene networks regulated by iron and choline for further investigation. Full article

(This article belongs to the Special Issue Iron Deficiency and Iron-Related Disorders)

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Review

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42 pages, 2427 KiB

Open AccessReview

Iron Deficiency and Sleep/Wake Behaviors: A Scoping Review of Clinical Practice Guidelines—How to Overcome the Current Conundrum?

by Scout McWilliams, Olivia Hill, Osman S. Ipsiroglu, Stefan Clemens, Alexander Mark Weber, Michael Chen, James Connor, Barbara T. Felt, Mauro Manconi, Andre Mattman, Rosalia Silvestri, Narong Simakajornboon, Susan M. Smith and Sylvia Stockler

Nutrients 2024, 16(15), 2559; https://doi.org/10.3390/nu16152559 - 3 Aug 2024

Cited by 3 | Viewed by 3879

Abstract

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes. Full article

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16 pages, 771 KiB

Open AccessReview

Biomarkers of Brain Dysfunction in Perinatal Iron Deficiency

by Raghavendra B. Rao

Nutrients 2024, 16(7), 1092; https://doi.org/10.3390/nu16071092 - 8 Apr 2024

Cited by 1 | Viewed by 2822

Abstract

Iron deficiency in the fetal and neonatal period (perinatal iron deficiency) bodes poorly for neurodevelopment. Given its common occurrence and the negative impact on brain development, a screening and treatment strategy that is focused on optimizing brain development in perinatal iron deficiency is necessary. Pediatric societies currently recommend a universal iron supplementation strategy for full-term and preterm infants that does not consider individual variation in body iron status and thus could lead to undertreatment or overtreatment. Moreover, the focus is on hematological normalcy and not optimal brain development. Several serum iron indices and hematological parameters in the perinatal period are associated with a risk of abnormal neurodevelopment, suggesting their potential use as biomarkers for screening and monitoring treatment in infants at risk for perinatal iron deficiency. A biomarker-based screening and treatment strategy that is focused on optimizing brain development will likely improve outcomes in perinatal iron deficiency. Full article

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15 pages, 774 KiB

Open AccessReview

The Interaction between Psychological Stress and Iron Status on Early-Life Neurodevelopmental Outcomes

by Brie M. Reid and Michael K. Georgieff

Nutrients 2023, 15(17), 3798; https://doi.org/10.3390/nu15173798 - 30 Aug 2023

Cited by 11 | Viewed by 4745

Abstract

This review presents evidence from animal and human studies demonstrating the possible connection and significant impact of poor iron status and psychological distress on neurocognitive development during pregnancy and the neonatal period, with implications for long-term cognition. Stress and iron deficiency are independently prevalent and thus are frequently comorbid. While iron deficiency and early-life stress independently contribute to long-term neurodevelopmental alterations, their combined effects remain underexplored. Psychological stress responses may engage similar pathways as infectious stress, which alters fundamental iron metabolism processes and cause functional tissue-level iron deficiency. Psychological stress, analogous to but to a lesser degree than infectious stress, activates the hypothalamic–pituitary–adrenocortical (HPA) axis and increases proinflammatory cytokines. Chronic or severe stress is associated with dysregulated HPA axis functioning and a proinflammatory state. This dysregulation may disrupt iron absorption and utilization, likely mediated by the IL-6 activation of hepcidin, a molecule that impedes iron absorption and redistributes total body iron. This narrative review highlights suggestive studies investigating the relationship between psychological stress and iron status and outlines hypothesized mechanistic pathways connecting psychological stress exposure and iron metabolism. We examine findings regarding the overlapping impacts of early stress exposure to iron deficiency and children’s neurocognitive development. We propose that studying the influence of psychological stress on iron metabolism is crucial for comprehending neurocognitive development in children exposed to prenatal and early postnatal stressors and for children at risk of early iron insufficiency. We recommend future directions for dual-exposure studies exploring iron as a potential mediating pathway between early stress and offspring neurodevelopment, offering opportunities for targeted interventions. Full article

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8 pages, 948 KiB

Open AccessBrief Report

LRG1 Associates with Iron Deficiency Anemia Markers in Adolescents

by Rashed Alhammad, Mohamed Abu-Farha, Abdur Rahman, Thangavel Alphonse Thanaraj, Lemia Shaban, Reem Alsabah, Samar Hamad, Maha M. Hammad, Arshad Channanath, Fahd Al-Mulla and Jehad Abubaker

Nutrients 2023, 15(14), 3100; https://doi.org/10.3390/nu15143100 - 11 Jul 2023

Cited by 1 | Viewed by 1913

Abstract

Leucine-rich α-2 glycoprotein1 (LRG1) has been shown to be associated with several health conditions; however, its association with iron deficiency anemia, especially in children, has not been previously explored. In this study, we investigated the association between LRG1 and several iron deficiency anemia markers, including hemoglobin (Hb), albumin, red cell distribution width (RDW), iron, ferritin, and Hb transferrin saturation. A total of 431 participants were included in this analysis aged between 11 and 14 years. Higher LRG1 levels were observed in children diagnosed with anemia [31.1 (24.6, 43.2) µg/mL] compared to non-anemic children [29.2 (22.7–35.95) µg/mL]. Statistically significant differences of LRG1 level across the three groups (tertiles) of Hb, iron, transferrin saturation, albumin, RDW, ferritin, and WBC were observed. Strong negative correlations were observed between LRG1 and Hb (Spearman’s rho = −0.11, p = 0.021), albumin (Spearman’s rho = −0.24, p < 0.001), iron (Spearman’s rho = −0.25, p < 0.001), and Hb transferrin saturation (Spearman’s rho = −0.24, p < 0.001), whereas circulating LRG1 levels were positively associated with RDW (Spearman’s rho = 0.21, p < 0.001). In conclusion, our findings demonstrate for the first time the strong association between iron deficiency anemia markers and LRG1 in otherwise healthy school-aged children. However, further studies are needed to corroborate those results and to look for similar associations in other population subgroups. Full article

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