OFFICIAL ABP TOPIC:

Understand the differential diagnosis, evaluation, and management of anemia

BACKGROUND

Anemia is a hemoglobin and hematocrit below the normal range according to age and sex. A wide range of diagnoses can lead to anemia in children. The patient’s age, gender, and ethnicity should be considered during the evaluation and workup.

EVALUATION OF ANEMIA

HISTORY

Anemia can cause pallor, lethargy, irritability, or poor PO intake. Hemolysis can cause jaundice, dark urine, or scleral icterus. GI bleeding can be associated with bloody stools, changes in stool color, or inflammatory bowel disease. Ask about symptoms of a bleeding disorder, such as epistaxis and heavy menstrual bleeding. Pica is associated with iron deficiency and lead poisoning.

Birth history should include history of jaundice or anemia as a newborn. Medications and diet should be reviewed; hemolysis in patients with G6PD deficiency can be caused by certain oxidant drugs and foods, such as sulfonylurea, fluoroquinolones, and fava beans. Consuming mostly goat’s milk may lead to folate deficiency anemia. Excessive cow’s milk intake or breastmilk without adequate iron supplementation can cause iron deficiency anemia. Toxin exposure should also be reviewed for lead.

PHYSICAL EXAMINATION

Pallor can be seen when examining the patient’s conjunctiva, nails, and palms. Jaundice, scleral icterus, and hepatosplenomegaly suggest hemolysis.

LABORATORY TESTS

To evaluate anemia, obtain a CBC with differential, reticulocyte count, and a blood smear. MCV (mean corpuscular volume) is used to classify the anemia as microcytic, normocytic, or macrocytic. RDW (red cell distribution width) measures how variable the sizes of the RBCs are. Reticulocyte count is used to determine the bone marrow’s response to anemia. A high reticulocyte count is an appropriate response to anemia from blood loss or hemolysis. A low reticulocyte count is not an appropriate response to anemia and indicates an issue with RBC production.

Once the initial evaluation suggests a possible etiology of anemia, further etiology-directed testing may help confirm the diagnosis:

• Bleeding: stool occult blood and PT/PTT
• Iron deficiency: iron, ferritin, TIBC, and transferrin saturation
• Hemoglobinopathy: hemoglobin electrophoresis to diagnose sickle cell anemia, thalassemia, hemoglobin C
• Hemolytic anemia: direct antiglobulin test, LDH, serum indirect bilirubin, haptoglobin levels, G6PD deficiency screening, osmotic fragility, and electrophoresis
• Macrocytic anemia: B12 and folate levels, thyroid and liver function tests
• Lead poisoning: lead level
• Hypothyroidism: TSH and free T4
• Nutritional deficiencies: vitamin B12 and folate levels
• Bone marrow failure or leukemia: bone marrow biopsy

DIFFERENTIAL DIAGNOSIS

DIFFERENTIAL DIAGNOSIS OF ANEMIA BASED ON CLINICAL FINDINGS

Finding	Possible etiology
Skin
Hyperpigmentation	Fanconi anemia
Petechiae, purpura	Autoimmune hemolytic anemia with thrombocytopenia, hemolytic-uremic syndrome, bone marrow failure, infiltration
Jaundice	Hemolytic anemia, hepatitis, aplastic anemia
Ulcers on extremities	Sickle cell disease, thalassemia
Facies
Frontal bossing, prominence of facial bones	Congenital hemolytic anemias, thalassemia major, severe iron deficiency
Eyes
Microcornea	Fanconi anemia
Tortuosity of conjunctival & retinal vessels	Sickle cell disease
Cataracts	G6PD deficiency, galactosemia in neonatal period
Vitreous hemorrhages	Sickle cell disease
Mouth
Glossitis	Vitamin B12 deficiency, iron deficiency
Angular stomatitis	Vitamin B12 deficiency, iron deficiency
Hands
Hypoplasia of thenar eminence	Fanconi anemia
Spoon nails	Iron deficiency
Spleen
Enlargement	Congenital hemolytic anemia, leukemia, lymphoma, infection, portal hypertension

Immune hemolytic disease, infection, and hereditary disorders are most common in neonates and infants. In older children, acquired iron deficiency is more likely.

The major categories of anemia in children based on pathophysiology include:

• Microcytic anemia (low MCV):
  • Iron deficiency (high RDW): Most common pediatric anemia, peaks at 6 months-5 years old.
  • Risk factors: Low birth weight, prematurity, excessive cow’s milk, poor diet
  • Low iron, low ferritin, high TIBC, low transferrin saturation
  • Thalassemia (normal RDW): Normal iron studies; hemoglobin analysis shows elevated hemoglobin A2 or F.
  • For persistent microcytic anemia despite iron therapy, consider thalassemia, sideroblastic anemia, lead poisoning, and gastrointestinal blood loss or malabsorption.
• Normocytic anemia (normal MCV): Acute blood loss, hemolytic anemia, infection, malignancy, bone marrow failure, pure red cell aplasia.
  • Hemolytic anemias  
    • Intrinsic RBC defects (membrane, enzymes, hemoglobin) or extrinsic factors (autoimmune, alloimmune, infection, microangiopathy)
    • High LDH, high indirect bilirubin, low haptoglobin, reticulocytosis, abnormalities on smear/hemoglobin analysis
  • Anemia of chronic disease/inflammation  
    • Associated with infection, autoimmune disease, malignancy, chronic illness
    • Normal or mildly decreased MCV, normal/low TIBC, low iron, normal/high ferritin
• Macrocytic anemia (high MCV): B12/folate deficiency, liver disease, hypothyroidism, medications, bone marrow failure, chronic kidney disease, endocrinopathies, lead poisoning, vitamin D deficiency.
  • Megaloblastic anemias  
    • Folate or vitamin B12 deficiency
    • Labs: High MCV, hypersegmented neutrophils, low B12/folate levels

MANAGEMENT OF ANEMIA

The treatment approach depends on the cause of anemia.

General Principles

• Eliminate any source of ongoing blood loss.
• Correct any nutrient deficiencies (iron, folate, B12 supplementation).
• Remove offending drugs in medication-induced anemias.
• Provide supportive transfusions for symptomatic anemia.
• Treat the underlying disease process.

Iron Deficiency Anemia

For children with proven or suspected IDA, treatment involves:

1. Oral iron therapy: Start ferrous sulfate 3 mg/kg elemental iron once daily for at least 3 months. Hemoglobin should rise >1 g/dL after 4 weeks of treatment. Continue iron for 1 month after Hgb normalizes to replenish stores.
2. Dietary modifications:
   • Infants: Breastfeed or use iron-fortified formula; avoid cow’s milk and low-iron formula.
   • 6+ months: Include iron-rich foods and sources of vitamin C; limit milk to <20 oz daily.
3. Address underlying cause: Treat cow’s milk protein colitis, celiac disease, or inflammatory bowel disease.
4. If anemia does not improve after iron therapy:
   • Assess adherence to therapy and dietary changes.
   • Obtain iron studies and hemoglobin analysis to exclude thalassemia.
   • Test stool for occult blood; consider cow’s milk colitis, celiac, or inflammatory bowel disease.

Parenteral iron may be needed if oral iron is not tolerated or effective. Transfusion is reserved for severe symptomatic cases (hemoglobin <5 g/dL).

Hemolytic Anemias

• Congenital hemolytic anemias: Patients should avoid oxidant drugs and take folate supplementation.
  • G6PD, pyruvate kinase deficiency: Avoid oxidant drugs, consider splenectomy.
  • Sickle cell disease: Hydroxyurea, transfusions, stem cell transplant.
  • Thalassemia: Transfusions, iron chelation; stem cell transplant can be curative.
• Autoimmune hemolytic anemia: Glucocorticoids are usually first-line treatment; other treatments include immunosuppressants, splenectomy, and stem cell transplant.

Anemia from Chronic Kidney Disease: Iron supplementation and erythropoiesis-stimulating agents are used for severe kidney disease.

Bone Marrow Failure or Infiltration

Conditions like Fanconi anemia, aplastic anemia, inherited bone marrow failure syndromes, and infiltrating malignancies require careful management:

• Consider erythropoiesis-stimulating agents.
• For malignancies, treat according to specific cancer diagnoses.
• Immunosuppressants may slow immune-mediated loss of hematopoietic cells in aplastic anemia.
• Provide transfusion support as needed and monitor for iron overload.
• Stem cell transplant may be needed for definitive cure.

REFERENCES

https://www.uptodate.com/contents/approach-to-the-child-with-anemia

https://www.uptodate.com/contents/sideroblastic-anemias-diagnosis-and-management/

https://www.uptodate.com/contents/iron-deficiency-in-infants-and-children-less-than12-years-treatment

https://www.uptodate.com/contents/iron-requirements-and-iron-deficiency-in-adolescents

https://www.uptodate.com/contents/overview-of-causes-of-anemia-in-children-due-to-decreased-red-blood-cell-production

https://www.uptodate.com/contents/anemia-of-chronic-disease-anemia-of-inflammation