Anemia in Children JOSEPH J. IRWIN, M.D., and JEFFREY T. KIRCHNER, D.O., Lancaster General Hospital, Lancaster, Pennsylvania Anemia in children is commonly encountered by the family physician. Multiple causes exist, but with a thorough history, a physical examination and limited laboratory evaluation a specific diagnosis can usually be established. The use of the mean corpuscular volume to classify the ane- mia as microcytic, normocytic or macrocytic is a standard diagnostic approach. The most common form of microcytic anemia is iron deficiency caused by reduced dietary intake. It is easily treat- able with supplemental iron and early intervention may prevent later loss of cognitive function. Less common causes of microcytosis are thalassemia and lead poisoning. Normocytic anemia has many causes, making the diagnosis more difficult. The reticulocyte count will help narrow the differential diagnosis; however, additional testing may be necessary to rule out hemolysis, hemoglobinopathies, membrane defects and enzymopathies. Macrocytic anemia may be caused by a deficiency of folic acid and/or vitamin B12, hypothyroidism and liver disease. This form of anemia is uncommon in children. (Am Fam Physician 2001;64:1379-86.) nemia is a frequent laboratory in developing humans: the embryonic, abnormality in children. As Gower-I, Gower-II, Portland, fetal hemoglo- many as 20 percent of children bin (HbF) and normal adult hemoglobin in the United States and 80 per- (HbA and HbA2). HbF is the primary hemo- cent of children in developing globin found in the fetus. It has a higher affin- Acountries will be anemic at some point by the ity for oxygen than adult hemoglobin, thus age of 18 years.1 increasing the efficiency of oxygen transfer to the fetus. The relative quantities of HbF Physiology of Hemoglobin Production rapidly decrease to trace levels by the age of six Erythropoietin is the primary hormone to 12 months and are ultimately replaced by regulator of red blood cell (RBC) production. the adult forms, HbA and HbA2. In the fetus, erythropoietin comes from the monocyte/macrophage system of the liver. General Approach to Management Postnatally, erythropoietin is produced in the Most children with anemia are asymptomatic peritubular cells of the kidneys. Key steps in and have an abnormal hemoglobin or hemat- red blood cell differentiation include conden- ocrit level on routine screening (Table 1).2 Infre- sation of red cell nuclear material, production quently, a child with anemia may have pallor, of hemoglobin until it amounts to 90 percent fatigue and jaundice but may or may not be of the total red blood cell mass and the extru- critically ill. Key historical points and findings sion of the nucleus that causes loss of RBC on physical examination can reveal the under- synthetic ability. Normal RBCs survive an lying cause of the anemia. average of 120 days, while abnormal RBCs can The newborn’s body reclaims and stores survive as little as 15 days.1 iron as the hematocrit levels decrease during The hemoglobin molecule is a heme-pro- the first few months of life. Therefore, in full- tein complex of two pairs of similar polypep- term infants, iron deficiency is rarely the cause tide chains. There are six types of hemoglobin of anemia until after six months of age. In pre- mature infants, iron deficiency can occur only after the birth weight has been doubled. Iron deficiency anemia is rarely found in full-term infants X-linked causes of anemia, such as glucose-6- phosphate dehydrogenase (G6PD) deficiency, younger than six months and in premature infants before should be considered in males. Pyruvate they have doubled their birth weight. kinase deficiency is autosomal recessive and associated with chronic hemolytic anemia of OCTOBER 15, 2001 / VOLUME 64, NUMBER 8 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1379 TABLE 1 Screening Recommendations for Anemia in Children 1. U.S. Preventive Services Task Force recommends screening hemoglobin or hematocrit between the ages of six to 12 months in high-risk infants. High- risk includes the following: blacks, Native Americans, Alaska natives, infants living in poverty, immigrants from developing countries, preterm and lowbirth- weight infants and infants whose principle dietary intake is unfortified cow’s Laboratory Evaluation milk. Newborns should be screened for hemoglobinopathies with hemoglobin Anemia is defined as a decreased concentra- electrophoresis. Selective screening is appropriate in areas of low prevalence. tion of hemoglobin and RBC mass compared 2. The recommendations of the American Academy of Family Physicians are with that in age-matched controls. In screen- the same as the U.S. Preventive Services Task Force. ing situations, such as the one-year check-up, 3. American Academy of Pediatrics recommends screening hemoglobin or only a hemoglobin level is usually obtained. hematocrit at the six-, nine-, or 12-month visit for all infants. Universal When anemia is encountered during this screening for anemia in newborns is not warranted. screening, the specimen should be upgraded to a complete blood cell count (CBC), because Information from U.S. Preventive Services Task Force. Guide to clinical preventive services: report of the U.S. Preventive Services Task Force. 2d ed. Baltimore, Md.: some laboratories store blood samples for up Williams & Wilkins, 1996; American Academy of Family Physicians. Summary of to seven days. Physicians should first look at AAFP policy recommendations and age charts. Retrieved October 2000, from: the mean corpuscular volume (MCV), which http://www.aafp.org/exam; and the American Academy of Pediatrics. AAP policy allows placement of the anemia into one of statements, clinical practice guidelines, and model bills. Retrieved October 2000, the standard classifications of microcytic, nor- from: http://www.aap.org/policy/pcyhome.cfm. mocytic and macrocytic (Table 2).3,4 After narrowing the differential diagnosis based on the MCV,the clinician can proceed with addi- variable severity. A history of nutritional defi- tional diagnostic work-up. ciency, pica or geophagia suggests iron defi- The next step of the anemia work-up should ciency. Recent prescription drug use may sug- include a peripheral smear and a measurement gest G6PD deficiency or aplastic anemia. A of the reticulocyte count. Pathologic findings recent viral illness may suggest red cell aplasia. on the peripheral smear can indicate the etiol- Recurrent diarrhea raises suspicion of malab- ogy of the anemia based on red cell morphol- sorption and occult blood loss occurring in ogy. Basophilic stippling (Figure 1a) represent- celiac sprue and inflammatory bowel disease. ing aggregated ribosomes can be seen in The physical examination is important thalassemia syndromes, iron deficiency and but will be unremarkable in most children lead poisoning. Howell-Jolly bodies (Figure 1b) with anemia. Findings that suggest chronic are nuclear remnants seen in asplenia, perni- anemia include irritability, pallor (usually not cious anemia and severe iron deficiency. seen until hemoglobin levels are less than 7 g Cabot’s ring bodies (Figure 1c) are also nuclear per dL [70 g per L]), glossitis, a systolic mur- remnants and are seen in lead toxicity, perni- mur, growth delay and nail bed changes. Chil- cious anemia and hemolytic anemias. Heinz’s dren with acute anemia often present more bodies (Figure 1d) are from denatured aggre- dramatically with clinical findings including gated hemoglobin and can be seen in tha- jaundice, tachypnea, tachycardia, splenomeg- lassemia, asplenia and chronic liver disease. aly, hematuria and congestive heart failure. The reticulocyte count (or percentage) helps distinguish a hypoproductive anemia (de- creased RBC production) from a destructive The Authors process (increased RBC destruction). A low JOSEPH J. IRWIN, M.D., is in private practice in Ephrata, Pa. Dr. Irwin is a graduate of reticulocyte count may indicate bone marrow the University of Pennsylvania School of Medicine, Philadelphia, and completed a res- disorders or aplastic crisis, while a high count idency in family practice at Lancaster (Pa.) General Hospital. generally indicates a hemolytic process or active JEFFREY T. KIRCHNER, D.O., is associate director of the family practice residency pro- blood loss. The corrected reticulocyte count gram at Lancaster General Hospital. Dr. Kirchner is a graduate of the Philadelphia Col- corrects for differences in the hematocrit and is lege of Osteopathic Medicine and completed a residency in family practice at Abington (Pa.) Memorial Hospital. He is a former associate editor of American Family Physician. a more accurate indicator of erythropoietic activity. To calculate corrected reticulocyte Address correspondence to Joseph J. Irwin, M.D., Lancaster General Hospital, 555 W. Trout Run Rd., Ephrata, PA 17522 (e-mail: [email protected]). Reprints are not available count, multiply the patient’s reticulocyte count from the authors. (or percentage) by the result of dividing the 1380 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 64, NUMBER 8 / OCTOBER 15, 2001 TABLE 2 Classification of Anemias Based on Size of Red Blood Cells A C The rightsholder did not B D grant rights to reproduce FIGURE 1. Depiction of red blood cell mor- phologies that may appear on a peripheral this item in electronic smear, showing: (A) basophilic stippling, (B) media. For the missing Howell-Jolly bodies, (C) Cabot’s ring bodies and (D) Heinz’s bodies. item, see the original print version of this publication. patient’s hematocrit level by the normal hema- tocrit level. A corrected reticulocyte count above 1.5 suggests increased RBC production. In the case of decreased RBC survival, the bone marrow normally responds with increased reticulocyte production, usually greater than 2 percent or with an absolute count of greater than 100,000 cells per mm3 (100 ϫ 106 per L). This is presumptive evidence of chronic hemolysis if the reticulocytosis is sustained. If, after analysis of the initial laboratory find- ings, the diagnosis is still unclear, other confir- matory studies may be required. Tests to deter- mine if the MCV is too low include serum iron level, total iron binding capacity (TIBC) and lead level.