Abstract
Iron-deficiency anemia (IDA) remains the most prevalent nutritional disorder affecting pediatric populations worldwide, while protein and vitamin deficiency anemias—encompassing deficiencies in folate, vitamin B12, and protein-energy malnutrition—represent critical overlapping conditions in resource-limited settings. This article synthesizes current evidence on the etiopathogenesis, clinical manifestations, diagnostic approaches, differential diagnosis, therapeutic strategies, and preventive measures for these anemias in children aged 0–18 years. IDA arises primarily from inadequate iron intake, increased physiological demands during growth spurts, or chronic blood loss, leading to impaired hemoglobin synthesis and microcytic hypochromic anemia. Protein-vitamin deficiency anemias stem from dietary insufficiencies, malabsorption syndromes, or metabolic disruptions, resulting in macrocytic or normocytic anemias with systemic complications. Clinical features range from pallor and fatigue to developmental delays and organ dysfunction. Diagnosis relies on hematological indices, serum biomarkers, and exclusion of underlying pathologies. Treatment emphasizes targeted nutrient repletion, addressing root causes, and supportive care, whereas prevention focuses on dietary diversification, fortification programs, and public health interventions. Early recognition and management are pivotal to avert long-term neurocognitive sequelae.
Keywords
Iron-deficiency anemia; protein-energy malnutrition; folate deficiency; vitamin B12 deficiency; pediatric anemia; etiopathogenesis; clinical features; diagnosis; differential diagnosis; treatment; prevention
Introduction
Anemia in childhood constitutes a major public health challenge, with the World Health Organization estimating that approximately 40% of children under five years suffer from anemia globally, predominantly attributable to nutritional deficits (World Health Organization, 2023, https://www.who.int/publications/i/item/9789240073616). Iron-deficiency anemia (IDA) accounts for over half of these cases, driven by rapid growth, inadequate dietary iron bioavailability, and socioeconomic factors (Pasricha et al., 2021, https://doi.org/10.1016/S0140-6736(21)00521-4). Concurrently, protein and vitamin deficiency anemias, including those from folate, vitamin B12, and protein shortages, often coexist in malnourished populations, exacerbating morbidity through impaired erythropoiesis and multisystem effects (Green et al., 2019, https://doi.org/10.1182/blood-2018-05-815951). This review delineates the multifaceted aspects of these conditions, drawing from peer-reviewed literature to provide a comprehensive framework for clinicians and researchers.
Etiopathogenesis
Iron-Deficiency Anemia
The pathogenesis of IDA in children involves a sequential depletion of iron stores, culminating in erythropoietic failure. Physiologically, infants are born with hepatic iron reserves sufficient for 4–6 months in term babies, but preterm or low-birth-weight infants exhaust these earlier due to lower accretion (Domellöf, 2022, https://doi.org/10.3390/nu14102151). Postnatally, iron requirements surge during infancy (1–3 years) and adolescence, reaching 0.9–1.8 mg/day absorbable iron, yet typical diets provide only 5–15% bioavailable non-heme iron from plant sources (Lynch et al., 2018, https://doi.org/10.1182/bloodadvances.2018017818).
Key etiological factors include:
• Inadequate intake: Exclusive breastfeeding beyond 6 months without iron-fortified complements, or reliance on cow’s milk (which inhibits iron absorption via casein and calcium).
• Increased losses: Hookworm infestations in endemic areas cause chronic gastrointestinal bleeding; celiac disease or inflammatory bowel disorders impair absorption.
• Physiological demands: Pubertal growth in adolescents doubles iron needs, particularly in females with menarche.
Hepcidin, a liver-derived peptide, regulates iron homeostasis by inhibiting ferroportin-mediated release from enterocytes and macrophages; inflammation upregulates hepcidin, sequestering iron and mimicking deficiency (Nemeth et al., 2020, https://doi.org/10.1182/blood.2019004192).
Protein and Vitamin Deficiency Anemia
Protein-vitamin deficiency anemias encompass megaloblastic anemias from folate/B12 deficits and normocytic anemias from protein-energy malnutrition (PEM). Folate deficiency arises from low dietary greens, fruits, or legumes, compounded by increased requirements in hemolytic states or rapid growth (Bailey et al., 2015, https://doi.org/10.3945/an.114.007419). Vitamin B12 deficiency typically results from maternal depletion in vegan diets, pernicious anemia (rare in children), or ileal malabsorption in conditions like Crohn’s disease (O’Leary & Samman, 2010, https://doi.org/10.3390/nu2020160).
In PEM, hypoalbuminemia reduces oncotic pressure, while essential amino acid shortages impair globin synthesis. Kwashiorkor and marasmus represent extremes, with anemia reflecting combined micronutrient deficits (Golden, 2019, https://doi.org/10.1177/156482651904000101).
Clinic (Clinical Manifestations)
Iron-Deficiency Anemia
Early symptoms are insidious: pallor (especially conjunctival), irritability, and pica (craving non-food items). Progressive fatigue, tachycardia, and systolic murmurs occur due to compensatory cardiac output. Neurodevelopmental impacts include cognitive deficits, reduced attention, and motor delays, persisting despite correction (Grantham-McGregor & Ani, 2001, https://doi.org/10.1093/jn/131.2.649S). In severe cases (<7 g/dL hemoglobin), high-output heart failure ensues.
Protein and Vitamin Deficiency Anemia
Folate/B12 deficiencies present with megaloblastic features: glossitis, angular stomatitis, and neurological symptoms (B12-specific: subacute combined degeneration, paresthesia). PEM anemia accompanies edema (kwashiorkor), growth faltering, and immune compromise, increasing infection susceptibility (Black et al., 2013, https://doi.org/10.1016/S0140-6736(13)60937-X). Systemic signs include dermatosis, hepatomegaly, and apathy.
Diagnosis
Iron-Deficiency Anemia
Hematology reveals microcytic (MCV <70 fL), hypochromic (MCH <25 pg) anemia with RDW >15%. Serum ferritin <15 ng/mL confirms depletion (absence of inflammation); transferrin saturation <10% and elevated soluble transferrin receptor support diagnosis (Camaschella, 2015, https://doi.org/10.3324/haematol.2014.121340). Bone marrow Prussian blue stain shows absent iron stores (gold standard, rarely needed).
Protein and Vitamin Deficiency Anemia
Macrocytic anemia (MCV >100 fL) with hypersegmented neutrophils; serum folate <3 ng/mL or red cell folate <140 ng/mL; B12 <200 pg/mL with elevated methylmalonic acid/homocysteine. In PEM, normocytic anemia with low retinol-binding protein; Schilling test (historical) for B12 absorption.
Differential Diagnosis
IDA must be distinguished from anemia of chronic disease (normal/high ferritin, low transferrin), thalassemia trait (normal RDW, elevated HbA2), and sideroblastic anemia (ringed sideroblasts). Protein-vitamin anemias overlap with myelodysplastic syndromes (dysplastic changes), drug-induced megaloblastosis (antifolates), or hypothyroidism. Combined deficiencies require sequential biomarker assessment; lead poisoning mimics IDA but with basophilic stippling (Barbui et al., 2019, https://doi.org/10.1182/blood-2018-10-879726).
Treatment
Iron-Deficiency Anemia
Oral ferrous sulfate (3–6 mg/kg/day elemental iron) for 3 months, achieving 1 g/dL hemoglobin rise weekly; parenteral iron (e.g., iron dextran) for intolerance or malabsorption. Transfusion reserved for hemoglobin <4–5 g/dL with symptoms. Address etiology: deworming, dietary counseling (heme iron from meat, vitamin C enhancers) (Powers & Buchanan, 2021, https://doi.org/10.1542/peds.2020-049749).
Protein and Vitamin Deficiency Anemia
Folic acid 1–5 mg/day orally; B12 100–1000 mcg intramuscular weekly then monthly if absorption-impaired. PEM mandates ready-to-use therapeutic foods (RUTF) with micronutrient premix, gradual refeeding to avoid refeeding syndrome (WHO, 2013, https://www.who.int/publications/i/item/9789241506328). Multidisciplinary support for underlying disorders.
Prevention
Universal iron supplementation (drops for infants 4–6 months) in high-prevalence areas; food fortification (cereals, salt). Promote breastfeeding with timely complementary foods rich in bioavailable iron. For protein-vitamin anemias: diversified diets, antenatal maternal supplementation, vaccination against enteric pathogens. Community programs like micronutrient powders yield 30–50% anemia reduction (Dewey & Vitta, 2019, https://doi.org/10.1159/000503672).
Conclusion
Iron-deficiency anemia and protein-vitamin deficiency anemias in children represent interconnected nutritional challenges with profound implications for physical growth, cognitive development, and long-term health outcomes. Their etiopathogenesis underscores the interplay of dietary inadequacies, physiological demands, and socioeconomic determinants, while clinical presentations highlight the need for vigilant screening in vulnerable populations. Accurate diagnosis, informed by hematological profiles and specific biomarkers, facilitates timely differentiation from mimicking conditions and guides targeted interventions. Therapeutic success hinges on nutrient repletion alongside etiology-specific management, with oral supplementation serving as the cornerstone for most cases. Preventive efforts—encompassing dietary diversification, fortification initiatives, maternal education, and public health policies—offer the most cost-effective means to reduce prevalence, as evidenced by successful programs in low-resource settings (Bhutta et al., 2013, https://doi.org/10.1016/S0140-6736(13)60937-X; Eichler et al., 2012, https://doi.org/10.1002/14651858.CD009000.pub2). Ultimately, a multisectoral approach integrating clinical care, community nutrition, and policy advocacy is imperative to eradicate these preventable anemias and secure equitable health for future generations.
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