# 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

| Age/Group | Normal Hemoglobin (g/dL) |
|-----------|-------------------------|
| Newborn (term) | 14-24 |
| 2 months (physiologic nadir) | 9-14 |
| 6 months - 6 years | 11-14 |
| 6-12 years | 11.5-15.5 |
| Adult female | 12-16 |
| Adult male | 14-18 |
| Pregnancy | ≥11 (hemodilution) |

## 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

| Parameter | Iron Deficiency | Anemia of Chronic Disease | Thalassemia Trait |
|-----------|----------------|--------------------------|-------------------|
| Ferritin | Low (<15 adults, <12 children) | Normal/elevated | Normal |
| Serum iron | Low | Low | Normal |
| TIBC | Elevated | Low/normal | Normal |
| Transferrin saturation | <20% | Low/normal | Normal |
| Soluble transferrin receptor | Elevated | Normal | Normal |

**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.