Residency · Residency · Medicine-Pediatrics

Anemia: A Diagnostic Framework Across Ages

Overview

Anemia is defined as hemoglobin below normal for age, sex, and physiologic state. Age-specific normal values are critical: neonatal Hgb is high (14-24 g/dL), drops to nadir at 6-9 weeks (physiologic anemia of infancy), then gradually rises to adult values. Iron deficiency anemia (IDA) is the most common cause globally across all ages. The Med-Peds approach requires mastery of age-specific differentials and evaluation algorithms.

Age-Specific Hemoglobin Norms

Classification by Mechanism

Decreased Production

Iron deficiency, B12/folate deficiency; Anemia of chronic disease/inflammation; Lead poisoning (children); Aplastic anemia, pure red cell aplasia (Diamond-Blackfan, transient erythroblastopenia of childhood) Bone marrow infiltration (leukemia, metastatic disease); Chronic kidney disease (erythropoietin deficiency); Hypothyroidism.

Increased Destruction (Hemolytic)

Intrinsic RBC defects: hereditary spherocytosis, G6PD deficiency, sickle cell disease, thalassemia. Extrinsic: autoimmune hemolytic anemia, microangiopathic hemolytic anemia (HUS, TTP, DIC), mechanical (prosthetic valves) Hemolytic labs: elevated LDH, indirect bilirubin, reticulocyte count; decreased haptoglobin.

Blood Loss

Acute: trauma, GI bleeding, surgical. Chronic: GI (occult in adults, Meckel diverticulum in children), menorrhagia in adolescents/women, parasitic infections globally.

Classification by MCV

Microcytic (Low MCV)

Iron deficiency: most common cause across ages. Thalassemia trait: disproportionately low MCV relative to degree of anemia; RBC count often elevated; Mentzer index (MCV/RBC) <13 suggests thalassemia. Lead poisoning: basophilic stippling, elevated lead level; screen at 1 and 2 years per AAP. Anemia of chronic disease: can be microcytic or normocytic. Sideroblastic anemia: rare; ring sideroblasts on marrow biopsy.

Normocytic

Anemia of chronic disease/inflammation; Acute blood loss; Hemolytic anemias (reticulocytes are large, so MCV may be falsely elevated); Early iron deficiency; Mixed deficiency (iron + B12/folate); Bone marrow failure, aplastic anemia; CKD.

Macrocytic

Megaloblastic: B12 deficiency, folate deficiency (hypersegmented neutrophils on smear) Non-megaloblastic: hypothyroidism, liver disease, myelodysplastic syndrome, medications (methotrexate, hydroxyurea, antiretrovirals), reticulocytosis. B12 deficiency in infants of vegan/vegetarian mothers is a unique pediatric concern.

<image>Diagnostic algorithm for anemia classification by MCV showing stepwise approach from CBC with differential through reticulocyte count, iron studies, peripheral smear, and further workup</image>

Iron Deficiency Anemia

Pediatric IDA

Infants/toddlers (6-24 months): most vulnerable age group; term infants exhaust iron stores by 4-6 months. Risk factors: exclusive breastfeeding without iron supplementation after 4 months, excessive cow's milk intake (>24 oz/day — causes occult GI blood loss and displaces iron-rich foods), prematurity, low socioeconomic status. AAP recommends universal screening with hemoglobin at 12 months. Iron-fortified formula or iron supplementation (1 mg/kg/day) for breastfed infants starting at 4 months. Adolescents: menstrual blood loss in females, growth spurts, poor diet.

Adult IDA

Premenopausal women: menorrhagia is the leading cause. Postmenopausal women and men: GI blood loss until proven otherwise — requires upper and lower endoscopy. Celiac disease screening (tTG-IgA) in unexplained IDA. Consider H. pylori (impairs iron absorption)

Iron Studies Interpretation

Ferritin: best single test for iron deficiency; <15 ng/mL is diagnostic in adults; <12 in children. Ferritin is an acute phase reactant — can be normal/elevated despite iron deficiency in inflammation; consider ferritin <30-50 in inflammatory states. Serum iron: decreased in IDA. TIBC: elevated in IDA (reflects increased transferrin production) Transferrin saturation: <20% suggests iron deficiency. Soluble transferrin receptor: elevated in IDA, normal in anemia of chronic disease — helpful distinguishing marker. Reticulocyte hemoglobin (CHr): <28 pg suggests functional iron deficiency; useful in CKD.

Treatment of IDA

Oral iron: ferrous sulfate preferred (3-6 mg/kg/day elemental iron in children; 325 mg [65 mg elemental] 1-3 times daily in adults) Every-other-day dosing may improve absorption via hepcidin kinetics. Take on empty stomach with vitamin C; avoid with calcium, antacids, PPIs. Reticulocyte response expected in 5-7 days; hemoglobin rise in 2-4 weeks. Continue 3-6 months after hemoglobin normalizes to replenish stores. IV iron: indicated for intolerance, malabsorption, ongoing losses, severe anemia, CKD, IBD; ferric carboxymaltose, iron sucrose, or ferumoxytol.

<image>Comparison of iron studies patterns in iron deficiency anemia, anemia of chronic disease, thalassemia trait, and combined iron deficiency with chronic disease showing ferritin, serum iron, TIBC, and transferrin saturation</image>

Anemia of Chronic Disease/Inflammation

Pathophysiology

Hepcidin (produced by the liver in response to IL-6) is the key mediator. Hepcidin blocks ferroportin, trapping iron in macrophages and enterocytes. Results in functional iron deficiency despite adequate or elevated iron stores. Also: blunted erythropoietin response, shortened RBC survival.

Diagnosis

Normocytic or microcytic anemia with low serum iron but low/normal TIBC and normal/elevated ferritin. Distinguishing from concurrent true iron deficiency is challenging — consider soluble transferrin receptor, ferritin/log ferritin, or bone marrow iron staining.

Management

Treat the underlying disease; Avoid oral iron if ferritin is elevated (will not be absorbed due to hepcidin); EPO-stimulating agents in CKD (target Hgb 10-11.5 g/dL); IV iron may be beneficial if concurrent true iron deficiency.

Hemolytic Anemias Across Ages

Hereditary Spherocytosis

Most common inherited hemolytic anemia in Northern Europeans. Autosomal dominant (75%); presents with anemia, jaundice, splenomegaly. Diagnosis: spherocytes on smear, elevated MCHC, positive osmotic fragility or eosin-5-maleimide (EMA) binding test. Management: folic acid supplementation, splenectomy for severe cases (delay until age >5 for infection risk; vaccinate pre-splenectomy)

G6PD Deficiency

X-linked; most common enzymopathy worldwide. Episodic hemolysis triggered by oxidative stress: infections, fava beans, medications (sulfonamides, dapsone, primaquine, nitrofurantoin) Diagnosis: G6PD enzyme level (may be falsely normal during acute hemolysis due to reticulocyte release — recheck 2-3 months later) Smear: bite cells, Heinz bodies (special stain)

Autoimmune Hemolytic Anemia (AIHA)

Warm AIHA (IgG-mediated): most common; positive DAT (Coombs test); treat with steroids, rituximab. Cold AIHA (IgM-mediated): cold agglutinin disease; associated with Mycoplasma, EBV in children; lymphoproliferative disorders in adults. In children: often post-infectious, self-limited; in adults: consider underlying lymphoma or autoimmune disease.

<image>Peripheral blood smear composite showing characteristic findings in different anemias: spherocytes, target cells in thalassemia, schistocytes in microangiopathic hemolytic anemia, and hypersegmented neutrophils in megaloblastic anemia</image>

Special Pediatric Considerations

Physiologic Anemia of Infancy

Nadir at 6-9 weeks in term infants (Hgb 9-11 g/dL), 4-8 weeks in preterm (Hgb can drop to 7-8 g/dL — "anemia of prematurity") Caused by decreased erythropoietin production after transition to extrauterine oxygen levels. No treatment needed in term infants; preterm infants may require EPO or transfusion.

Transient Erythroblastopenia of Childhood (TEC)

Temporary suppression of erythropoiesis, typically ages 6 months - 3 years. Post-viral, self-limited (resolves in 1-2 months) Must distinguish from Diamond-Blackfan anemia (DBA): DBA presents earlier (<1 year), has elevated fetal hemoglobin and eADA, and congenital anomalies.

Diamond-Blackfan Anemia

Congenital pure red cell aplasia; presents in first year of life. Associated with short stature, craniofacial anomalies, thumb abnormalities. Macrocytic anemia with reticulocytopenia; elevated HbF and erythrocyte adenosine deaminase (eADA) Treatment: steroids (60-70% respond), chronic transfusion, hematopoietic stem cell transplant.

Clinical Pearls

In a child with microcytic anemia and a normal or elevated RBC count, think thalassemia trait before iron deficiency. Cow's milk should not be introduced before 12 months and should be limited to <20-24 oz/day in toddlers to prevent IDA. A trial of iron therapy is both diagnostic and therapeutic in young children with suspected IDA — response confirms the diagnosis. In adults over 50 with new IDA, GI malignancy workup is mandatory even in the absence of GI symptoms. Reticulocyte production index (RPI) >2 indicates an appropriate marrow response to anemia (hemolysis or blood loss); RPI <2 suggests underproduction. Ferritin <30 ng/mL has better sensitivity (92%) than <15 ng/mL (59%) for iron deficiency, especially in the setting of concurrent inflammation.

<image>Age-specific differential diagnosis of anemia showing the most common etiologies by age group from neonate through elderly adult with key distinguishing features</image>

References

• Baker RD, Greer FR; Committee on Nutrition. Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0-3 Years of Age). Pediatrics. 2010;126(5):1040-1050.
• Camaschella C. Iron-Deficiency Anemia. N Engl J Med. 2015;372(19):1832-1843.
• Powers JM, Buchanan GR. Diagnosis and Management of Iron Deficiency Anemia. Hematol Oncol Clin North Am. 2019;33(3):393-408.
• Means RT. Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood Parameters. Nutrients. 2020;12(2):447.

How to think about this

Anemia presents differently across the lifespan, but a core framework of mechanism (production, destruction, loss) and red blood cell size (microcytic, normocytic, macrocytic) remains constant. The Med-Peds approach emphasizes understanding age-specific norms for hemoglobin, recognizing common etiologies unique to pediatric and adult populations, and interpreting lab values like iron studies in context. For instance, iron deficiency in a toddler often stems from dietary factors, whereas in a postmenopausal adult, it warrants investigation for gastrointestinal blood loss. Hemolytic anemias, while sharing common laboratory findings, manifest with different underlying conditions at different ages, from inherited disorders in childhood to autoimmune processes or drug-induced causes in adults.

Check yourself with 2 bullets.

• What's the first step in evaluating microcytic anemia in a 65-year-old male versus an 18-month-old?
• How would you differentiate anemia of chronic disease from iron deficiency in a patient with rheumatoid arthritis and microcytic anemia?

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