Open research questions in Iron Metabolism and Disorders

What the literature leaves open

• Future research should explore longitudinal effects of dietary inflammatory potential on iron biomarkers and investigate culturally relevant dietary interventions aimed at improving maternal nutritional and hematological outcomes. Despite these limitations, the significant association observed contributes meaningful evidence to the limited literature from Southeast Asia.

  Association Between Dietary Inflammatory Index Scores and Hemoglobin Levels Among Pregnant Women in Asahan Regency: A Cross-Sectional Study · 2026 · DOI

• BACKGROUND Gastrointestinal bleeding (GIB) is common in children and may lead to anemia, yet the risk factors for anemia in pediatric GIB remain poorly understood.

  Clinical characteristics of hospitalized children with gastrointestinal bleeding and risk factors for associated anemia · 2026 · DOI

• ConclusionVery low-certainty evidence suggests daily supplementation may produce a small increase in haemoglobin and serum ferritin compared with intermittent regimens, although the magnitude and clinical significance of these differences remain uncertain.

  Daily Versus Intermittent Oral Iron Supplementation for the Treatment of Anaemia in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis · 2026 · DOI

• 1. Anemia prevention programs should move beyond standalone awareness campaigns and embed structured, behaviorally informed education within existing health and school systems. Educational content should emphasize actionable knowledge, including locally available iron- rich foods, appropriate supplementation schedules, and management of side effects, and should be delivered alongside routine supplementation and screening services. Integrating education with service delivery will reduce the gap between knowledge acquisition and sustained preventive practice by aligning information with real-world access and follow-up. Health and nutrition programs should prioritize system-level supports that enable consistent practice, including reliable supply chains for iron supplements, routine monitoring and follow-up, and clear counseling protocols for managing side effects. Embedding supplementation into normalized settings such as schools, antenatal care services, and community health platforms can reduce stigma, improve adherence, and minimize reliance on individual motivation. Strengthened delivery systems are essential to ensure that biomedical interventions translate into long-term behavioral outcomes.

  Educational and Behavioral Factors Associated with Iron Deficiency Anemia: A Systematic Review and Bibliometric Synthesis · 2026 · DOI

• In Ethiopia, anemia prevalence among women of reproductive age has been increasing despite national nutrition strategies, yet aggregated, nationally representative data on PPA remain scarce.

  Prevalence of Anemia and Associated Factors Among Post-Partum Mothers in Public Health Facilities in Ethiopia: A Systematic Review and Meta-Analysis · 2026 · DOI

• Conclusion Evidence from this review is insufficient to support the widespread use of RHC as a standalone screening test for IDWA in blood donors.

  Diagnostic accuracy of reticulocyte haemoglobin content in detecting iron deficiency without anaemia in blood donors: A systematic review and meta‐analysis · 2026 · DOI

• Reticulocyte haemoglobin content (RHC) has been increasingly investigated as an alternative biomarker to evaluate iron status, but its diagnostic performance remains unclear.

  Diagnostic accuracy of reticulocyte haemoglobin content in detecting iron deficiency without anaemia in blood donors: A systematic review and meta‐analysis · 2026 · DOI

• The predictive value of elevated preoperative red cell distribution width (RDW), a marker of erythropoietic stress, for incident postoperative anemia in nonanemic patients remains unclear.

  Elevated preoperative red cell distribution width and incident anemia after metabolic and bariatric surgery: a cohort study · 2026 · DOI

• DECLARATION OF CONFLICTING INTEREST The limitation of this study was the difficulty of obtaining the research material (beetroot) directly, as it had to be ordered in advance.

  EFEKTIVITAS PEMBERIAN EKSTRAK BUAH BIT (Beta vulgaris) TERHADAP KENAIKAN HEMOGLOBIN (Hb)IBU HAMIL TRIMESTER III DENGAN ANEMIA DI KOTA BENGKULU · 2026 · DOI

• While IDA and MA have been extensively studied individually, few studies have examined the shared chemical pathways underlying ineffective erythropoiesis, oxidative stress, and nucleotide synthesis defects.

  Linking Iron Deficiency and Megaloblastic Anaemia through Phytochemical Chemistry: Chemical Integration of Iron Redox Biology and One-Carbon Metabolism in Erythropoiesis · 2026 · DOI

• Abstract Background and Objectives Iron deficiency (ID) poses a non‐negligible risk for blood donors, yet longitudinal data on iron status and whether low‐dose iron‐containing supplements improve ID among Japanese donors are scarce.

  Iron recovery dynamics after whole blood donation and the effect of low‐dose iron supplementation in Japanese donors · 2026 · DOI

• This study has several limitations that warrant consideration. Adverse events, such as hypophosphatemia, hypersensitivity reactions, or infusion-related reactions, are not reliably captured in the TriNetX network. As such, event-level safety data could not be included in this 12 analysis. Instead, the study focused on major clinical outcomes (mortality, hemoglobin recovery, transfusion requirements, and hospital utilization) as indicators of safety and effectiveness. The study’s retrospective, observational design precludes definitive conclusions regarding causality. Detailed microbiologic information—including pathogen load, antimicrobial resistance profiles, and infection severity—was not consistently available, limiting the granularity of the subgroup analyses. Furthermore, variability in the timing and dosing of IV iron relative to infection onset may have affected the observed outcomes. Because antibiotic exposure was measured only during the 14 days after the index date, and the index date was defined as the later of infection or IDA diagnosis, some patients had already begun antibiotics before the index date and did not have their earlier antibiotic days reflected in this outcome. Additionally, clinical factors driving the decision to administer or withhold IV iron—particularly those documented only in narrative physician notes and not captured in structured EHR fields—could not be assessed. The generalizability of our findings to pediatric populations, immunocompromised patients, or critically ill patients requiring intensive care may also be limited, depending on cohort composition. IV iron exposure was analyzed asa binary variable, as detailed dosing information was not consistently available. We could not assess whether complete iron repletion was accomplished. Oral iron use could not be assessed because over-the-counter formulations are not reliably documented in structured EHR data; therefore, some patients may have received additional iron therapy beyond IV iron, either as supplementation or continuation therapy after incomplete repletion. Because hemoglobin was assessed out to 60-90 days, longer-term hemoglobin recovery may reflect the combined effects of IV iron and any additional iron therapy. However, in a supplemental analysis, hemoglobin improvement at 14 days was greater in the IV iron group, a time point at which oral iron would be unlikely to producea clinically meaningful hematologic response“’, supporting a direct, early effect of IV iron. Finally, while short-term mortality (14- and 90-day) was assessed, longer-term outcomes, such as recurrent infections, persistent anemia, and functional recovery, were not evaluated. 13 This study also has analytical limitations. First, most analyses were performed within the TriNetX platform, which provides only aggregate mean values. Median values were not available, which may have better suited non-normal data distributions. Reliance on means may therefore have introduced greater variance due to outliers. Second, length of stay could only be measured after the diagnosis of IDA and infection. Any hospitalization time prior to the index event was not captured, which may have underestimated total hospital stay for some patients. Third, as with all retrospective observational studies, residual confounding is possible despite propensity score matching. Unmeasured variables, such as illness severity scores, transfusion thresholds, nutritional status, or precise timing of infection onset, may have influenced outcomes. Fourth, TriNetX data is limited to structured EHR fields and has only limited inclusion of granular clinical details such as dosing and whether IV iron was given asa single treatment or a repeated course. So, although IV iron administration was required to occur within 7 days after the combined diagnosis of IDA and infection, the de-identified EHR timestamps in TriNetX do not allow verification of the precise sequence of events, so minor misclassification of event timing cannot be fully excluded. Additionally, outpatient antibiotic use may not have been recorded. Finally, given the missingness of laboratory hemoglobin data, a detailed exploration of the intermediate impact of IV iron on hemoglobin could not be performed, and the hemoglobin recovery observed at 60-90 days likely reflects a combination of recovery from acute illness, resolution of inflammation-associated anemia, and repletion of iron stores. Despite these limitations, this study provides important real-world evidence supporting the safety and potential clinical benefits of intravenous iron administration in hospitalized patients with acute infections.

  A retrospective, real-world study of IV iron use to treat iron deficiency anemia during acute infection · 2026 · DOI

• A key strength of this study is the use of large, nationally representative NFHS‑5 data, which enabled precise estimates and adjustment for a broad range of biodemographic and socioeconomic covariates. The modeling strategy progressively adds blocks of variables and estimates predicted probabilities. It helps disentangle direct and confounded associations between morbidities and anaemia and offers interpretable effect sizes for policy audiences. However, the cross-sectional design of NFHS‑5 limits causal inference, as morbidity and haemoglobin were measured at roughly the same time, and bidirectional influences cannot be fully untangled. Morbidity data are based on maternal recall over the preceding two weeks and may be affected by misclassification and reporting bias. The haemoglobin measurement captures only a single point in time and does not distinguish between iron‑deficiency anaemia and other causes. Despite these limitations, the study adds important evidence that anaemia and common childhood infections coexist in substantial proportions of Indian children and are concentrated in socioeconomically and regionally disadvantaged groups.

  Coexistence of Anaemia and Common Morbidities Among Children in India Below the Age of Five Years: Evidence From the National Family Health Survey-5 (2019-21) · 2026 · DOI

• This approach addresses a key limitation of current diagnostic practice, which relies mainly on serum ferritin and identifies ID only after substantial iron depletion (18).

  Mean Corpuscular Hemoglobin and Red Cell Distribution Width for Early Screening of Non-Anaemic Iron Deficiency in Children: A Retrospective Study · 2026 · DOI

• The current investigation is limited by its relatively small samples size and its regional and ethnic context, which may influence the final interpretation of results. Future investigations should include larger, more diverse populations and inspect the functional impacts of TMPRSS6 polymorphism.

  Association of transmembrane protease serine 6 (TMPRSS6) gene Polymorphism with iron deficiency anemia in Iraqi women · 2026 · DOI

• The influence of IDNA on athletic performance varies between studies and appears to depend on baseline ferritin concentrations, training intensity and sex-specific factors, indicating heterogeneous…

  IRON DEFICIENCY WITHOUT ANEMIA IN ATHLETES: IMPLICATIONS FOR PERFORMANCE, HEALTH, AND TRAINING · 2026 · DOI

• Clinical ferritin cut-offs may underestimate functional deficiency in athletes, with performance-relevant zones between 30 and 50 µg/L proposed but potentially requiring modifications by age, sex…

  IRON DEFICIENCY WITHOUT ANEMIA IN ATHLETES: IMPLICATIONS FOR PERFORMANCE, HEALTH, AND TRAINING · 2026 · DOI

• While commending the authors for their important contribution to a relatively understudied area, we offer suggestions regarding the inclusion of additional exclusion criteria to account for factors that may influence ferritin levels and metabolic syndrome parameters, aiming to support further refinement and future research in this field.

  Comments on “Association of Serum Ferritin Levels with the Metabolic Syndrome in Postmenopausal Women between the Ages of 40 and 65 Years” · 2025 · DOI

• Hyaluronic acid (HA) and procollagen III N-terminal peptide (PIIINP) are potential biomarkers; however, their diagnostic utility in iron overload-induced liver fibrosis remains underexplored.

  Serum hyaluronic acid and procollagen type III N-terminal peptide as predictive biomarkers for iron overload-induced liver fibrosis in hemoglobinopathies · 2025 · DOI

• The effect of iron deficiency (ID) without anemia on the reproductive health of women in contrast to iron deficiency anemia is still insufficiently evaluated from a clinical point of view, despite a weighty theoretical basis and a large pool of clinical observations.

  Causes and consequences of iron deficiency without anemia in the practice of gynecologist · 2020 · DOI

• However, the obtained results suggest that this should be studied further in association with small intestine malabsorption, to determine the precise role of enteropathy in IDA patients.

  Iron Absorption Disturbances in Patients with Enteropathy: Interim Analysis of a Single Centre Study · 2020 · DOI

• While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful, ineffective erythropoiesis of an enormously expanded erythroid marrow.

  Pathophysiology of Iron Overload^a · 1998 · DOI

• Although a single value for the toxic dose has not been established, significant gastrointestinal manifestations occur following the ingestion of 20 mg of elemental iron per kilogram of body weight while systemic toxicity may occur following the ingestion of at least 60 mg of elemental iron per kilogram of body weight.

  Acute Iron Poisoning · 1996 · DOI

• These persistent lower scores suggest either that iron therapy adequate for correcting anemia is insufficient to reverse behavioral and developmental disturbances in many infants or that certain ill effects are long-lasting, depending on the timing, severity, or chronicity of iron deficiency anemia in infancy.

  Iron Deficiency Anemia and Iron Therapy Effects on Infant Developmental Test Performance · 1987 · DOI

• Perhaps the most important learning point from this case is that chelation alone is insufficient if the environmental source of exposure is not identified and eliminated.

  A Case of Asymptomatic Lead Poisoning in a Two-Year-Old With a Background of Pica and Iron Deficiency Anaemia · 2026 · DOI

Most-cited papers in Iron Metabolism and Disorders

• Biological role of lactoferrin. · Archives of Disease in Childhood · 1992 · 377 citations
• Iron Deficiency Anemia and Iron Therapy Effects on Infant Developmental Test Performance · PEDIATRICS · 1987 · 339 citations
• Pathophysiology of Iron Overload^a · Annals of the New York Academy of Sciences · 1998 · 175 citations
• Non-invasive Anemia Detection and Prediagnosis · Journal of Pharmacology and Pharmacotherapeutics · 2024 · 139 citations
• Effects of Alcohol Consumption on Indices of Iron Stores and of Iron Stores on Alcohol Intake Markers · Alcoholism Clinical and Experimental Research · 2001 · 135 citations
• Association between depression and anemia in otherwise healthy adults · Acta Psychiatrica Scandinavica · 2016 · 101 citations
• Recommendations for diagnosis, treatment, and prevention of iron deficiency and iron deficiency anemia · HemaSphere · 2024 · 96 citations
• Silibinin attenuates ferroptosis in acute kidney injury by targeting FTH1 · Redox Biology · 2024 · 90 citations
• The Role of Iron in the Pathogenesis of Atherosclerosis · Physiological Research · 2017 · 68 citations
• The evaluation of iron deficiency and iron overload · Deutsches Ärzteblatt international · 2021 · 64 citations

Most recent work

• A retrospective, real-world study of IV iron use to treat iron deficiency anemia during acute infection · Blood · 2026
• Iron Deficiency in Vegetarian Athletes: A Narrative Review · Current Nutrition Reports · 2026
• Iron Deficiency in HFpEF: A True Clinical Divergence or a Competing Risk Artifact? · European Journal of Heart Failure · 2026
• IRON DEFICIENCY WITHOUT ANEMIA IN ATHLETES: IMPLICATIONS FOR PERFORMANCE, HEALTH, AND TRAINING · International Journal of Innovative Technologies in Social Science · 2026
• Predicting iron folic acid utilization among pregnant women in Ethiopia leveraging machine learning · Discover Artificial Intelligence · 2026
• Prevalence of Anemia in Pregnancy in Second and Third Trimester at BeniSuef Governorate · International Journal of Drug Delivery Technology · 2026
• Computer-Vision–Based Non-Invasive Detection of Anemia from Medical Images: A Scoping Review of Artificial Intelligence with Applications in Drug Delivery and Therapeutic Monitoring · International Journal of Drug Delivery Technology · 2026
• Changes in Anemia and Iron Biomarkers among Pregnant Women Receiving Care at Primary Health Centers in Puducherry, India: A Prospective Cohort Study · Annals of African Medicine · 2026
• Oral iron supplementation as a public health intervention in children aged 6 to 23 months for preventing iron deficiency and anaemia: Economic evaluation for the South African health system · African Journal of Primary Health Care & Family Medicine · 2026
• Iron Biology in Acute Kidney Injury: Catalytic Iron, Hepcidin–Ferroportin Axis, and NGAL—A Narrative Review · International Journal of Molecular Sciences · 2026

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