Basics
Description
Microcytic anemia is hemoglobin 2 standard deviations (SD) below the mean as well as an abnormally low mean corpuscular volume. Use of age-based norms for both indices is critical.
Epidemiology
- In pediatrics, the most common cause of microcytic anemia is iron deficiency anemia (IDA).
- IDA incidence by age:
- 1 " 2 years, 14%
- Adolescent females, 9%
- Hemoglobinopathies causing microcytic anemia are common in Mediterranean countries, Southeast Asia, China, Africa, and India. Incidence in the United States is currently increasing due to increasing immigration.
Risk Factors
Prematurity, breastfeeding, lower socioeconomic class, and overweight infants are more likely to have IDA. Certain ethnic groups such as African Americans and Hispanics have higher rates of iron deficiency. These groups also have a higher incidence of hemoglobinopathies, which can complicate the clinical picture.
Pathophysiology
- Iron homeostasis in the body is primarily regulated through mechanisms of iron absorption.
- Iron is absorbed through duodenal enterocytes and then transported to the liver. Hepcidin is synthesized by the liver and is the major regulator of iron absorption. The amount of dietary iron that is absorbed is relatively low but varies depending on the patient 's iron stores.
- The body loses about 1 " 2 mg/day of iron through loss of intestinal epithelia. This amount is higher in menstruating females.
- IDA usually develops from absorption that is inadequate to compensate for excretion and the demands required for growth (in children).
- Hemoglobin is made up of two alpha globin chains and two beta globin chains. Abnormalities in the production of these chains can lead to microcytic anemia. Anemia can develop either through inadequate production of one of these chains or through increased clearance of red blood cells (RBC) with mutated globin chains.
Etiology
- The most common cause of microcytic anemia is iron deficiency.
- Hemoglobinopathies are the next most common cause in childhood. Of the hemoglobinopaties, hemoglobin E and alpha- and beta-thalassemias most commonly cause microcytic anemia.
- Rarely, disorders of heme synthesis such as dyserythropoietic anemias and sideroblastic anemia can be a cause of microcytic anemia.
- Anemia of chronic disease can occasionally be microcytic, although more frequently is normocytic.
Diagnosis
History
- Age of onset: Iron deficiency is most common in infancy and menstruating females. A teenage male with iron deficiency anemia should be a red flag and an alert to look for ongoing occult blood loss.
- Ethnic background
- Dietary history, including
- Breast- versus formula-fed in infancy
- Daily milk consumption of greater than 24 oz is associated with IDA.
- Lack of red meat consumption
- Pica
- Lead exposure (often paint in older homes, mini blinds, ceramic dishware, or toys)
- GI symptoms including diarrhea/constipation
- Blood loss (can be from GI, urinary, epistaxis, menstruation, and rarely pulmonary causes)
- Weight loss/fever/malaise or other symptoms of systemic disease
- Family members who have needed transfusions. In pubertal females, a maternal menstrual history may be informative.
- Special questions: Children with behavioral problems, including breath-holding spells, have higher rates of iron deficiency.
Physical Exam
- Most children with iron deficiency are well appearing with a normal physical exam. They may be somewhat irritable.
- Frontal bossing or malocclusion of the teeth can be seen in children with thalassemia due to expansion of the bone marrow compartment.
- Pallor is the most common finding.
- Evaluate in the face, conjunctiva, gums, and nail beds. Palmar crease becomes pale with a hemoglobin less than 7 g/dL.
- Blue sclera can be occasionally observed in iron deficiency. Scleral icterus may be seen in patients with hemoglobinopathies.
- Glossitis may be seen in patients with chronic iron deficiency.
- Cardiovascular examination
- Auscultate for tachycardia and flow murmurs. However, often, children with chronic IDA may not have tachycardia.
- Cardiac instability is rare but does occur.
- Splenomegaly: The spleen enlarges in some patients with thalassemia as a site of extramedullary hematopoiesis. This is a rare finding in IDA, although it has been reported.
- Nail abnormalities: Spoon nails (koilonychia) can be seen in long-standing iron deficiency.
Diagnostic Tests & Interpretation
- No single test identifies all the causes of microcytic anemia. Children are often identified through routine screening at well-child exams.
- CBC: low hemoglobin level and low mean corpuscular volume for age (lower limit of normal can be estimated by 70+ age in years)
- Red cell distribution width (RDW) is increased in IDA and normal in thalassemia.
- RBC count is elevated in thalassemia. Mentzer index: MCV/RBC count in millions: <13 points, toward thalassemia; >13 points, toward IDA
- Reticulocyte count: reticulocytopenia in IDA, reticulocytosis in hemoglobinopathies
- Thrombocytosis is often seen in IDA (can appear prior to microcytosis). In severe, prolonged iron deficiency, thrombocytopenia eventually develops.
- Peripheral blood smear
- Hypochromia and bizarre forms in IDA
- Target cells are seen in patients with thalassemia.
- Basophilic stippling with lead poisoning
- Iron studies: Ferritin, serum iron, transferrin saturation, and TIBC must be interpreted together. In the face of iron deficiency, the body 's iron stores are first mobilized. It is only once these iron stores are depleted that microcytosis develops.
- Ferritin
- Decreased in iron deficiency
- Most sensitive index for iron deficiency. A ferritin of less than 30 is over 90% sensitive and specific for IDA.
- As a measure of iron stores in the liver, it is one of the earliest indices to change in IDA.
- May be elevated out of proportion to iron stores because it is an acute-phase reactant and will rise with infection, inflammation, malignancy, or liver disease
- Can be increased in patients with thalassemia who have not received transfusion because ineffective erythropoiesis leads to increased GI absorption of iron
- Serum iron
- Measures transferrin-associated ferric iron and fluctuates with daily iron intake
- Normal in thalassemia (unless chronically transfused, which leads to increased iron levels)
- Normal or reduced in infection or inflammatory states
- TIBC
- Elevated in IDA but can be normal to decreased in anemia of chronic disease
- Oral contraceptives can increase TIBC.
- Liver disease and malnutrition can decrease TIBC.
- Transferrin saturation
- Calculated value (serum iron/TIBC 100)
- Low in IDA
- Soluble transferrin receptor
- Newer test used to determine iron status. It is increased in iron deficiency anemia and also in thalassemia syndromes but not with the anemia of chronic disease.
- Unlike ferritin, it is not an acute phase reactant and does not increase with inflammation or infection.
- Should not be used routinely in patients in the evaluation of IDA but only in patients with other illnesses that make the interpretation of ferritin levels difficult
- Lead level and free erythrocyte protoporphyrin (FEP) are both elevated in lead intoxication. Lead poisoning and IDA can exist together.
- Hemoglobin electrophoresis with quantitation
- Decreased hemoglobin A and increased hemoglobin A2 in beta-thalassemia trait
- Normal hemoglobin electrophoresis in patients with one (silent carrier) and two (trait) alpha-globin thalassemic mutations
- Hemoglobin H consists of tetramers of beta globin chains and is seen in patients with three alpha-globin mutations.
- If a patient has been transfused or labs cannot be drawn, labs on the parents may be helpful. A CBC, peripheral smear, and a hemoglobin electrophoresis are usually sufficient.
Diagnostic Procedures/Other
- Bone marrow aspirate is rarely indicated but can be performed if malignancy or disorders of heme synthesis are in the differential.
- Recurrent iron deficiency despite treatment raises suspicion for ongoing blood loss. Hemoccult stools to look for occult GI bleeding, common in children with milk protein allergy. Urinalysis for evidence of renal RBC loss. Pulmonary hemosiderosis can present as recurrent pneumonias.
Alert
Results of hemoglobin electrophoresis are only reliable in patients with normal iron stores. If patients have abnormal iron studies, repeat hemoglobin electrophoresis after adequate period of iron supplementation.
Differential Diagnosis
- Iron deficiency
- Hemoglobinopathies
- Chronic lead poisoning
- Anemia of chronic disease
- Sideroblastic anemia
Treatment
Medication
- Ferrous sulfate or ferrous gluconate at 6 mg/kg of elemental iron per day in divided doses. Iron salts should be taken with orange juice, as ascorbic acid increases absorption. It should NOT be taken with milk. Milk intake should be stopped completely. Patients on proton pump inhibitors may have decreased absorption.
- Intravenous iron is reserved for patients with malabsorption. Iron sucrose, ferric gluconate, and iron dextran are available in the United States. Anaphylaxis is the primary adverse reaction; iron sucrose and ferric gluconate have lower rates of anaphylaxis.
General Measures
- Many patients are identified on routine well-child screening. Consider therapeutic trial of iron supplementation without further workup if history is suspicious.
- Oral iron supplementation and altered dietary practices improves anemia in almost all patients.
- Parents should be able to report seeing dark black iron in the stool. Iron can cause nausea, GI discomfort, and constipation. Stool softeners can help.
- Transfusion of RBCs is rarely indicated and is only needed in patients with cardiovascular instability.
- Treatment of lead intoxication is achieved through chelation and removal of environmental exposures.
- In patients with microcytic anemia from hemoglobinopathies, but normal iron indices, iron therapy is not indicated.
Ongoing Care
Follow-up Recommendations
- Repeat laboratory evaluation can be done in 1 month. Reticulocyte count is the first laboratory value to change and begins to increase within a week after the initiation of iron therapy. Hemoglobin levels take at least 2 " 3 weeks to respond. MCV is the last index to improve.
- Poor adherence to therapy is the most common cause of treatment failure.
- Children with IDA are more likely to have more difficulties with learning and behavioral problems.
- Children with other hemoglobinopathies should be referred to a hematologist. They do not need further treatment with iron.
Additional Reading
- Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassemia. Lancet. 2012;379(9813):373 " 383. [View Abstract]
- Janus J, Moerschel SK. Evaluation of anemia in children. Am Fam Physician. 2010;81(12):1462 " 1471. [View Abstract]
- McCann JC, Ames BN. An overview of evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioral function. Am J Clin Nutr. 2007;85(4):931 " 945. [View Abstract]
- Walters MC, Abelson HT. Interpretation of the complete blood count. Pediatr Clin North Am. 1996;43(3):599 " 622. [View Abstract]
- Wang B, Zhan S, Gong T, et al. Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anemia. Cochrane Database Syst Rev. 2013;6:CD001444. [View Abstract]
Codes
ICD09
- 280.9 Iron deficiency anemia, unspecified
- 282.7 Other hemoglobinopathies
- 280.8 Other specified iron deficiency anemias
ICD10
- D50.9 Iron deficiency anemia, unspecified
- D58.2 Other hemoglobinopathies
- D50.8 Other iron deficiency anemias
SNOMED
- 234349007 Microcytic anemia (disorder)
- 80141007 Hemoglobinopathy (disorder)
- 87522002 Iron deficiency anemia (disorder)