anemia microcitica

DOI: 10.1542/pir.28-1-52007;28;5Pediatrics in Review

Matthew RichardsonMicrocytic Anemia

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Microcytic AnemiaMatthew Richardson,

MD*

Author Disclosure

Dr Richardson did not

disclose any financial

relationships relevant

to this article.

Objectives After completing this article, readers should be able to:

1. Discuss the common causes of microcytic anemia in children.2. Define the most common cause of microcytic anemia in children.3. Distinguish iron deficiency anemia from beta thalassemia trait.4. Recognize when disorders of beta-globin may present in infants.

Microcytic AnemiaAnemia is the most common hematologic abnormality that pediatricians encounter. Thedifferential diagnosis for anemia in children includes congenital, acquired, benign, malig-nant, common, and extraordinarily rare disorders. Thankfully, most conditions causeconsistent changes in the mean cell volume (MCV) of red blood cells (RBCs) and can begrouped by using this parameter. In children, anemia is caused most often by disorders thatresult in smaller-than-normal RBCs (microcytosis) (Table 1). With a thorough history, agood physical examination, and perhaps some additional blood work, the correct cause ofa child’s microcytic anemia can be discovered.

Is It Anemia? Is It Microcytic?Automated blood counters may not take into account the normal variations inhemoglobin/hematocrit and MCV that are seen throughout childhood. Results reportedas abnormal must be compared with age-specific values (Table 2). Values that are 2standard deviations below the age-appropriate mean can be considered abnormal.

Hemoglobin OverviewBecause disorders of heme metabolism or globin synthesis can lead to microcytic anemia,an appreciation of hemoglobin structure and how it changes over the first few months afterbirth is important. Hemoglobin is produced by a multistep process involving severalenzymes in mitochondria and the cytosol. Hemoglobin consists of an iron-containingheme ring associated with four globin chains (Fig. 1). Except for the first few weeks afterconception, the dominant hemoglobin in utero is fetal hemoglobin (HbF), composed ofthe heme ring associated with two alpha-globin chains and two gamma-globin chains. Aspregnancy continues, the fetus transitions to an adult hemoglobin pattern, graduallydecreasing the amount of HbF and increasing the amounts of hemoglobin A (HbA) (hemering associated with two alpha-chains and two beta-chains [alpha2beta2]) and A2(HbA2) (heme ring with two alpha-chains and two delta-chains). At birth, HbF accountsfor approximately 80% of hemoglobin and HbA for 20%. Between 6 and 10 months afterbirth, most children have a distribution of hemoglobin types similar to that of adults. Thus,disorders of beta-globin genes, such as beta thalassemia or sickle cell disease, may notbecome apparent until partway through the first postnatal year.

History and Physical ExaminationKey aspects of the history and physical examination always should be addressed whenevaluating a child who has microcytic anemia.

*Section of Pediatric Hematology/Oncology, Baystate Children’s Hospital, Springfield, Mass.

Article blood/neoplasms

Pediatrics in Review Vol.28 No.1 January 2007 5



Signs, Symptoms, HistoryMany children who have microcytic anemia have nocomplaints. The disorder frequently is detected as part ofan office screening program or when a blood count isobtained for another illness. When evaluating a childwho has microcytic anemia, the results of the newbornscreen for hemoglobin disorders should be reviewed.Gestational age at time of birth should be determinedbecause infants born preterm are at higher risk for irondeficiency than are term infants. Older children maybecome noticeably tired. Significant iron deficiency cancause irritability. Family members, often those who seethe child only intermittently, sometimes note pallor.Pallor can be appreciated in the conjunctiva, gums, and

creases of the palms; in darker-pigmented patients, look-ing for pallor in the nailbeds is particularly helpful.

The physical examination may show tachycardia atrest and a flow murmur. The presence of splenomegalyshould raise the question of a hemoglobinopathy orthalassemia. Bony deformations such as frontal bossingor maxillary dysplasia suggest bone marrow hypertrophy,as seen in the major thalassemia syndromes.

DietBecause nutritional iron deficiency is the primary cause ofmicrocytic anemia in children, a dietary history is essen-tial. Particular attention should be given to the volume ofcow milk consumed and the amount and type of meatsand vegetables eaten. Pica may be either a sign or a causeof iron deficiency or lead poisoning. Craving and eatingice (pagophagia) is relatively common with iron defi-ciency.

Blood LossPotential signs of blood loss (and, thus, iron loss), such ashematochezia (bright red blood per rectum), melena,and heavy menses, should be investigated.

Family HistorySome causes of microcytic anemia are inherited. Physi-cians should ask about a diagnosis of anemia in otherfamily members. Because certain disorders are morecommon in particular ethnic or racial groups, it is appro-

Table 1. Causes of MicrocyticAnemiaCommon

● Iron deficiency● Thalassemia trait (alpha or beta)

Less Common

● Hemoglobinopathy (with or without thalassemia)● Inflammation● Thalassemia major● Lead toxicity● Sideroblastic anemia

Table 2. Hemoglobin and Mean Cell Volume Throughout Childhood*

Age

MeanHemogobin(g/dL) (g/L) “�2SD”

MeanHematocrit (%)(Proportion of 1.0) “�2SD”

Mean CellVolume(mcm3) “�2SD”

Birth 16.5 (165) 13.5 (135) 51 (0.51) 42 (0.42) 108 981 to 3 d 18.5 (185) 14.5 (145) 56 (0.56) 45 (0.45) 108 951 mo 14.0 (140) 10.0 (100) 43 (0.43) 31 (0.31) 104 852 mo 11.5 (115) 9.0 (90) 35 (0.35) 28 (0.28) 96 773 to 6 mo 11.5 (115) 9.5 (95) 35 (0.35) 29 (0.29) 91 746 mo to 2 y 12.0 (120) 10.5 (105) 36 (0.36) 33 (0.33) 78 702 to 6 y 12.5 (125) 11.5 (115) 37 (0.37) 34 (0.34) 81 756 to 12 y 13.5 (135) 11.5 (115) 40 (0.40) 35 (0.35) 86 7712 to 18 y

Female 14.0 (140) 12.0 (120) 41 (0.41) 36 (0.36) 90 78Male 14.5 (145) 13.0 (130) 43 (0.43) 37 (0.37) 88 78

18 to 49 yFemale 14.0 (140) 12.0 (120) 41 (0.41) 36 (0.36) 90 80Male 15.5 (155) 13.5 (135) 47 (0.47) 41 (0.41) 90 80

*Adapted from Nathan DG, Orkin SH, Look AT, Ginsburg D, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 6th ed. Philadelphia, Pa:Saunders; 2003, with permission from Elsevier.

blood/neoplasms microcytic anemia

6 Pediatrics in Review Vol.28 No.1 January 2007



priate to ask about the patient’s ancestry. Most familiesare not offended if the physician explains the logic forasking about racial or national background. Sickle hemo-globinopathies are more prevalent in African-Americansand Hispanics; hemoglobin E disorder is seen most oftenin Southeast Asians. The thalassemias are most commonin African-Americans and people whose ancestry is fromthe Mediterranean region or southeast Asia. A negativereport of lineage from these regions/ethnicities/races,however, does not rule out any given disorder.

Iron DeficiencyIron is necessary for the production of hemoglobin,myoglobin, and cytochrome enzymes, which are presentin all tissues. Iron deficiency, thus, affects all organsystems. Low concentrations of iron, even without ane-mia, have been associated with poor cognitive achieve-ment, poor school performance, and behavioral prob-lems. Dietary iron is absorbed in the duodenum, butnot all sources of iron are absorbed equally well. Hemeiron, found in meats and shellfish, is absorbed morereadily than is the nonheme iron of beans, grains, andvegetables. Although the concentration of iron inhuman milk is similar to that of formula, human milkiron is absorbed more readily than formula iron. Thepresence of acidic food enhances the absorption ofdietary iron.

Children become iron deficient from either inade-quate dietary intake (the most common cause) or fromblood loss, usually gastrointestinal (GI) or, in olderfemales, menstrual bleeding. Infants and children who

consume large amounts of cowmilk are particularly prone to irondeficiency. Cow milk iron is poorlyabsorbed and filling and slows gas-tric emptying, thus preventing theconsumption of heme-containingfoods; calcium inhibits iron absorp-tion; and cow milk may cause aprotein allergy with GI bleeding(microscopic or gross). Ideally,children should be limited to fewerthan 16 oz of cow milk each day.The finding of iron deficiency in apatient who has a normal dietaryhistory should prompt an evalua-tion for a source of bleeding, suchas occult or overt GI bleeding ormenorrhagia.

Laboratory FindingsIn addition to microcytosis, iron deficiency results in anincrease in the red cell distribution width and decreases inthe reticulocyte count, RBC number, and mean cellularhemoglobin. Platelet number may be elevated. For pa-tients who have a history consistent with poor iron intakeor blood loss and RBC indices consistent with irondeficiency, no additional laboratory work may beneeded. Treatment of the underlying cause of the defi-ciency can begin, and oral iron replacement can beinitiated. An increase in hemoglobin, reticulocytecount, and MCV within 1 to 4 weeks of starting irontherapy is the best test to confirm the diagnosis of irondeficiency.

If the clinical history or laboratory findings are incon-clusive or conflicting, more specific measurements ofiron status may be warranted. Concentrations of serumferritin, an indirect measurement of body iron stores, aredecreased in iron deficiency. However, as an inflamma-tory marker, ferritin values can be elevated during acuteor chronic illness. Total iron-binding capacity (TIBC)may be elevated, and the transferrin saturation�100(serum iron/TIBC) is low. Concentrations of free eryth-rocyte protoporphyrin (FEP), a heme precursor, may beelevated, reflecting the body’s inability to complete hemeproduction without iron. FEP also may be elevated withlead toxicity.

In the presence of a microcytic anemia, a Mentzerindex (MCV/RBC) score above 13 is consistent withiron deficiency, and a value below 13 is consistent withbeta thalassemia trait. The index, however, should beused only as a “screen.”

Figure 1. Schematic of hemoglobin structure.





TreatmentIron deficiency and its underlying cause should be ad-dressed concurrently by decreasing the consumption ofcow milk, increasing the amount of heme-rich foods inthe diet, or stopping bleeding. For parents who havedifficulty limiting their child’s milk consumption, it ishelpful to point out that humans are the only animals todrink routinely the milk of another species.

Assuming a normal functioning gut, iron should bereplaced orally. Intramuscular or intravenous replace-ment of iron is inappropriate for routine nutritional irondeficiency. The usual dose for oral replacement is6 mg/kg per day of elemental iron. The dose may bedivided either three times (tid) or twice (bid) daily,depending on patient preference or on the developmentof adverse effects such as nausea, stomach cramping,constipation, or diarrhea. Vitamin C (ascorbic acid) in-creases the absorption of iron, and supplements ideallyare taken with vitamin C-containing foods or juices.

There does not appear to be any discernible differencein the tolerability of different iron formulations. Ferroussulfate is the least expensive. Patients should return after1 to 2 weeks of therapy to have an increase in hemoglo-bin concentration and reticulocyte count documented;these findings assess compliance with the therapy and can

validate the diagnosis. Children who have severe irondeficiency anemia (eg, hemoglobin �5 to 6 g/dL [50 to50 g/L]) should return earlier to assure that the anemiais not worsening. Iron replacement should continue forat least 2 months after the anemia has been corrected,assuming that the underlying cause has been addressed.

Some children who are breastfed exclusively may ben-efit from supplemental iron, especially if they were bornpreterm, have not started taking iron-fortified cereals, orhave been shown by laboratory tests to have low ironstores.

The most common causes of treatment failure arenoncompliance and failure to treat the cause of the irondeficiency. Disorders of malabsorption, such as celiacsprue, are rarely the cause for lack of response. Thalasse-

mia trait, frequently mistaken for iron deficiency, must beconsidered if there is no response to iron therapy.

ThalassemiasThe thalassemias are a family of disorders that result fromdecreased globin chain production. Either alpha-globin(alpha thalassemias) or beta-globin (beta thalassemias)production may be decreased. The abnormalities resultin quantitative changes in globins, as opposed to hemo-globinopathies, in which globin defects are qualitative orfunctional.

Beta ThalassemiasTwo genes control beta-globin production, one on eachchromosome 11. Depending on the particular mutation,beta-globin production can range from nearly normal toentirely absent.

A one-gene defect results in beta thalassemia trait.This disorder is seen most commonly in African-Americans and people of Mediterranean descent. Chil-dren who have beta thalassemia trait are asymptomaticand have no physical findings.

If both beta-globin genes are completely nonfunc-tional, beta thalassemia major (Cooley anemia) results.No beta-globin is available as the infant transitions from

the fetal to adult hemo-globin pattern. Thus, chil-dren who have beta thalas-semia major present whenHbA (alpha2beta2) is ex-pected to be the dominanthemoglobin, sometimeduring the second half ofthe first postnatal year.Physical findings may in-clude hepatosplenomeg-

aly, poor growth, and in untreated cases, frontal bossingand maxillary hyperplasia resulting from deformation ofcortical bone due to bone marrow erythroid hyperplasia.

In beta thalassemia intermedia, there is some degreeof beta-globin gene activity between the two genes. Theamount of beta-globin produced may be so minimal as topresent a clinical picture identical to that of beta thalas-semia major or it may be sufficient for transfusions to beavoided. Much depends on how well a patient who hasbeta thalassemia intermedia tolerates anemia and thephysician’s threshold for performing transfusions.

LABORATORY FINDINGS. Children who have betathalassemia trait have a microcytic anemia. However, asopposed to iron deficiency, the concentrations of ferritin,

Iron replacement should continue for at least2 months after the anemia has been corrected,assuming that the underlying cause has beenaddressed.





serum iron, TIBC, and FEP are normal. The Mentzerindex (MCV/RBC) is usually less than 13. Hemoglobinelectrophoresis shows essentially normal amounts ofHbA and increased amounts of HbA2 and HbF. Becausebeta thalassemia trait and iron deficiency are the mostcommon microcytic anemias encountered in children, itis important to distinguish between them (Table 3).

The blood count in beta thalassemia major shows asevere microcytic anemia. Electrophoresis findings areremarkable for the absence of HbA and increasedHbA2 and HbF. Review of a newborn screen reveals thepresence of only HbF. Beta thalassemia intermediashows varying (but low) amounts of HbA on electro-phoresis, depending on its severity. The iron status ofchildren who have thalassemia can range from iron defi-cient (patients who have both iron deficiency and thalas-semia) to normal. In cases of beta thalassemia major, iftransfusion therapy has been initiated, patients may showexcess iron (elevated ferritin and transferrin saturation).

TREATMENT. Children who have beta thalassemia traitrequire no treatment. Parents of children who have betathalassemia trait should consider being tested for the disor-der themselves. If both are carriers of a one-gene mutation(ie, both have beta thalassemia trait), there is a 25% chanceof them having a child afflicted with a major beta thalasse-mia syndrome. After conception, chorionic villous samplingor amniocentesis allows prenatal diagnosis.

Patients who have beta thalassemia major requirechronic RBC transfusions and suffer from the associatedcomplications of iron overload, exposure to multipleRBC antigens, and potential exposure to blood-borne

pathogens. Bone marrow transplant from a matcheddonor is curative.

Depending on the severity of the mutations in thebeta-globin genes, children who have beta thalassemiaintermedia may require infrequent transfusion support ormay have a clinical course indistinguishable from that ofbeta thalassemia major.

Alpha ThalassemiaFour identical genes are responsible for the production ofalpha-globin, two on each copy of chromosome 16.Mutations in these genes often result in stop codons,thus knocking out a gene’s alpha-globin productionentirely (ie, the gene is either normal and “on” or abnor-mal and “off”).

All four alpha-globin genes function in the normalstate (Fig. 2). A one-gene defect results in “alpha thalas-semia silent carrier” status, which is asymptomatic. Twogene defects lead to “alpha thalassemia trait.” The traitmay be the result of one gene deleted on both chromo-somes (“trans” deletions, more common in African-Americans) or two genes deleted on the same chromo-some (“cis” deletions, more common in Asians).Affected children have microcytosis but often only mild(or no) anemia. This disorder should be suspected whenthere is microcytosis but no evidence of iron deficiency orbeta thalassemia trait. Newborn screening programs maydetect Bart hemoglobin (HbB) (heme associated withfour gamma chains). Three gene deletions lead to hemo-globin H (HbH) disease. HbH is composed of hemeassociated with four beta chains, due to the paucity ofalpha chains. This defect results in microcytic anemia,

Table 3. Differences Among Microcytic Anemias

IronDeficiency

BetaThalassemiaTrait

ChronicInflammation

LeadToxicity

MCV Low Low Normal-low Normal-lowRDW High Normal Normal Normal-highRBC number Low Normal-high Normal LowMentzer Index (MCV/RBC) >13 <13 N/A N/APlatelet count Normal-high Normal Normal-high NormalFerritin Low Normal Normal-high Normal-lowTransferrin saturation

(serum iron/TIBC)�100Low Normal Low Normal-low

Hemoglobinelectrophoresis

Normal Increased HbA2; �/�increased HbF

Normal Normal

Response to iron Improves No change No change No changeOther Elevated ESR or CRP Elevated lead concentration

MCV�mean cell volume, RDW�red cell distribution width, RBC�red blood cell, TIBC�total iron-binding capacity, ESR�erythrocyte sedimentation rate,CRP�C-reactive protein, HbA2�hemoglobin A2, HbF�fetal hemoglobin





chronic hemolysis, and splenomegaly. HbB is detectedon a newborn screen. Finally, when all four alpha genesare defective, no normal hemoglobin can be made, evenin utero. Hydrops fetalis (severe anemia with high-output cardiac failure and anasarca) results and almostalways is fatal.

LABORATORY FINDINGS. Alpha thalassemia silent car-rier state is associated with no abnormalities on a bloodcount. Alpha thalassemia trait is diagnosed most com-monly when evaluation of a microcytic anemia shows noevidence of iron deficiency or of beta thalassemia trait.The hemoglobin electrophoresis pattern in patients hav-ing alpha thalassemia trait is normal. HbB, if present on anewborn screen, is helpful evidence of the disorder, butits absence does not rule out the condition.

Children who have HbH disease have significant mi-crocytic anemia and demonstrate HbH on electrophore-sis. Molecular studies of the ratio of beta chains to alphachains are available (mean beta/alpha�1 in unaffectedindividuals, mean beta/alpha�1.3 for alpha thalassemiatrait, mean beta/alpha�2.6 for HbH disease) but usu-ally are unnecessary to make a diagnosis or providecounseling. Similarly, molecular testing for defective orabsent alpha genes can be performed but usually is re-served for when results of the blood count and hemoglo-bin electrophoresis are inconclusive or when more exten-sive genetic counseling is needed.

TREATMENT. Silent carrier statusand alpha thalassemia trait requireno treatment. Because patients ofAsian descent who have alphathalassemia trait tend to have twogenes affected on the same chro-mosome, they should be counseledon the potential risk of having chil-dren with a partner of similar eth-nicity because the chance of havinga baby who has a four-alpha genedeletion (hydrops fetalis) is in-creased. Children who have HbHdisease may require folate supple-ments, periodic transfusions, orperhaps splenectomy; these pa-tients should be followed by a pedi-atric hematologist. Infants whohave hydrops fetalis/Bart hemo-globinopathy may be kept alivewith lifelong transfusion therapy.A bone marrow transplant is cura-

tive and is the treatment of choice.

Hemoglobinopathies With and WithoutThalassemiaHemoglobinopathies represent qualitative or functionaldefects of globins. Dozens of mutations in the genes foralpha- and beta-globin that lead to structural globinabnormalities have been described. Some mutationscause no significant microcytosis unless there is a con-comitant defect in the amount of globin produced (ie, athalassemia). The two primary severe hemoglobinopathysyndromes seen in the United States are homozygous SSdisease and SC disease, both usually referred to as sicklecell disease. In homozygous SS disease, both beta-globingenes have a mutation that causes a substitution of valinefor glutamate at amino acid position six on the beta-globin chain. In SC disease, one beta-globin chain hasthe S mutation and the other a C mutation (lysinesubstituted for glutamate at amino acid six). These twogroups of patients have anemia but usually only mildmicrocytosis, if any. The diseases are associated withlifelong complications, including pain crises, overwhelm-ing bacteremia, splenic sequestering of blood, gallstones,retinopathy, avascular necrosis of bones, acute chest syn-drome, and stroke. SS and SC disease are suspected whena newborn screen reports the presence of HbS or HbC inthe absence of HbA or there is a family history of sicklecell disease or sickle trait. When homozygous CC disease

Figure 2. Gene deletions in alpha thalassemia syndromes.





occurs, it is associated with a mild microcytic anemia anda relatively benign clinical course.

Sickle Cell with Beta ThalassemiaIn patients who have sickle-beta-thalassemia (Sbeta0),one beta-globin gene has the S mutation and the other isnonfunctioning. Sbeta0 results in more significant micro-cytosis than homozygous SS disease, but the two disor-ders are identical clinically.

If a patient has one beta-globin gene with the Smutation and the other with a normal beta-globin genethat has decreased production, that individual is diag-nosed as having Sbeta� thalassemia. The amount ofnormal beta-globin produced by the thalassemic genedetermines disease severity. All affected patients have amicrocytic anemia to some degree. If a significantamount of normal beta-globin is made, HbA(alpha2beta2) concentrations may be greater than 25%.Although somewhat protected by the presence of HbA,patients still are at risk for complications of sickle celldisease and should be followed by a hematologist. Simi-larly, a beta-globin gene that has the C mutation can becoupled with a beta-globin gene that has no activity(Cbeta0) or partial activity (Cbeta�). These disorders areclinically mild but do cause microcytic anemia.

LABORATORY FINDINGS AND TREATMENT. Sickle syn-dromes are diagnosed and defined best with hemoglobinelectrophoresis, which determines the type and amount ofhemoglobin present. Severe sickle/sickle-thalassemia syn-dromes (SS, SC, Sbeta0, Sbeta�) are diagnosed most often

by a newborn screen (Table 4). Hemoglobin electrophore-sis should be repeated after 6 months of age to quantify theexact distribution of hemoglobin types and to define thepatient’s genotype better. It often is helpful to obtain he-moglobin electrophoreses on both parents, when possible.

Overwhelming infection with encapsulated organismsis the major cause of morbidity and mortality in childrenwho have severe sickle disorders. Thus, even the sugges-tion of a severe sickle syndrome on a newborn screen (ie,HbS or HbS and HbC in the absence of HgbA) should leadto the immediate initiation of penicillin prophylaxis (peni-cillin G 125 mg by mouth tid) with referral to a hematolo-gist (Table 3). Children who have a severe sickle/sickle-thalassemia syndrome require care from practitioners whoare knowledgeable about the natural history, complications(some life-threatening), and unique health supervisionneeds associated with these diseases.

Milder sickle syndromes (CC, Cbeta0, Cbeta�) causemicrocytic anemia, but do not require prompt initiationof penicillin prophylaxis. They do, however, warrantreferral to a hematologist.

Hemoglobin EHemoglobin E results from yet another mutation in thebeta-globin gene. The condition is interesting in that theresulting globin chain has an abnormal structure (a glo-binopathy) and is produced in less-than-normal amounts(a thalassemia). The gene defect is most prevalent insoutheast Asia, China, and the Indian subcontinent.

In the heterozygote state (Hb E-trait) (one normalbeta-globin gene and one beta-globin gene with the E

Table 4. Newborn Hemoglobin Electrophoresis Results*

HgbPattern Possible Diagnosis

StartPenicillinProphylaxis† Further testing and referral

FA Normal No NoFAS Sickle Trait No Family testing and counselingFAC C Trait No Family testing and counselingFC HbCC disease OR Cbeta0 No Family testing and counseling, refer to hematologyFS HbSS disease OR Sbeta0 Yes Family testing and counseling, refer to hematologyFSC HbSC disease Yes Family testing and counseling, refer to hematologyFSA HbSbeta� thalassemia Yes Family testing and counseling, refer to hematologyFSV or

FSD/GSickle with indeterminate hemoglobin

patternYes Family testing and counseling, refer to hematology

Some beta-globin chain variants incombination with HbS can be assevere as HbSS

*By convention, hemoglobins are reported in order of decreasing concentration (eg, “FA” denotes more HbF than HbA)†Penicillin 125 mg twice a day, 62.5 mg twice a day for infants less than 3 kgAdapted with permission from New England Pediatric Sickle Cell Consortium, 2002.





mutation), there is microcytosis but only mild (or no)anemia. Because the normal beta-globin is made prefer-entially, HbA accounts for most of the hemoglobinproduced. Affected patients are asymptomatic and re-quire no treatment.

Patients who have two E mutations (homozygous HbE)produce almost all HbE along with some HbF and have asignificant microcytosis with mild-to-moderate anemia.

When a child has one beta-globin gene with the Emutation and one beta-globin gene with a beta thalasse-mia mutation (HbE-beta thalassemia [Ebeta�]), thecondition is more severe than if either were presentalone. Affected patients can be clinically similar to thosehaving beta thalassemia intermedia, with potentially sig-nificant microcytic anemia, depending on the amount ofnormal beta-globin that is produced.

LABORATORY FINDINGS AND TREATMENT. Hemoglo-bin electrophoresis distinguishes the different subtypesof HbE disease. HbE trait and HbEE require no treat-ment other than genetic counseling. Patients who haveHbEbeta� likely need chronic transfusion support andiron chelation therapy; they also benefit from a hematol-ogist’s involvement.

Lead PoisoningLead paint and leaded gasoline for cars were phased outof production in the 1970s, 1980s, and 1990s. However,many older homes contain residual lead paint. In addi-tion, lead from auto emissions stays in soil for years, thusproviding sources for lead poisoning. Also, certain hob-bies, such as collecting leaden toy figures or using ce-ramic glazes that contain lead, may expose children tothe metal. Lead can cause a microcytic anemia throughtwo mechanisms. First, as a divalent metal, it interfereswith iron absorption and utilization in normal iron path-ways such as heme production (indeed, the microcytosisseen in lead poisoning is often due to iron deficiency).Second, lead can inhibit enzymes required for hemesynthesis directly. Children who have lead poisoning mayhave pica either as a cause or symptom of lead poisoning.

Laboratory Findings and TreatmentBlood lead levels are easily measured. The Centers forDisease Control and Prevention and the American Acad-emy of Pediatrics have published recommendations fortesting, follow-up, and treatment that are posted athttp://aappolicy.aappublications.org/.

Anemia of InflammationAny inflammatory state, acute or chronic, can produceeither normocytic or microcytic anemia, sometimes

called anemia of chronic disease. Cytokines such as inter-leukins-1 and -6; tumor necrosis factor-alpha; andinterferon-alpha, -beta, and -gamma are produced ininflammatory states, including cancer, acute or chronicinfection, and autoimmune disorders (eg, inflammatorybowel disease, juvenile idiopathic arthritis, connectivetissue disease). These cytokines alter iron homeostasis,promoting accumulation of iron in storage sites (macro-phages in the marrow and reticuloendothelial system)and inhibiting marrow RBC proliferation and differenti-ation. The result can be either micro- or normocyticanemia. The cause of inflammation is usually apparent inchildren who have this type of anemia. When there are noclinical signs of inflammation but laboratory findingssuggest anemia of inflammation, checking for serologicmarkers of inflammation may be helpful.

Laboratory Findings and TreatmentIn addition to microcytic anemia, inflammation typicallyproduces an elevated ferritin level, elevated erythrocytesedimentation rate, and increased C-reactive proteinconcentrations, but decreased serum iron concentrationsand transferrin saturation. The underlying cause of in-flammation should be addressed. Because children whohave inflammation also may be iron deficient, iron statusshould be evaluated and iron replaced as needed. Severeanemia may require transfusions. The use of recombinanterythropoietin may be beneficial in some children whohave chronic inflammation.

Sideroblastic AnemiaThe sideroblastic anemias are a rare group of disorders,some inherited and some acquired, that result fromabnormal mitochondrial metabolism. This abnormalityleads to ineffective heme synthesis and erythropoiesis. Un-used iron is deposited in bone marrow erythroblasts andappears as rings around the nucleus (“ringed sideroblast”).Some of the sideroblastic anemias cause microcytic anemia.A sideroblastic anemia is diagnosed best with a bone mar-row biopsy and warrants consultation with a hematologist.

SummaryMicrocytic anemia is the anemia encountered most com-monly in pediatrics. Nutrional iron deficiency and betathalassemia trait are the primary causes in pediatrics, andexcessive cow milk consumption is a major cause of irondeficiency. The best method of diagnosing iron defi-ciency is to observe improvement in anemia and micro-cytosis with iron therapy. Beta thalassemia and sicklesyndromes may not be clinically apparent until after 6month of age. Families/patients who have thalassemia





(trait or major) should receive genetic counseling tounderstand their risks for having children who havesevere forms of the disorder. Newborns found to haveHbS or HbC on newborn screening should be started onpenicillin immediately and referred to a hematologist.

Suggested ReadingAndrew NC. Medical progress: disorder of iron metabolism. N Engl

J Med. 1999;341:1986–1995Bergeron J, Weng X, Robin L, Olney HJ, Soulieres D. Prevalence of

alpha-globin gene deletions among patients with unexplained mi-crocytosis in a North-American population. Hemoglobin. 2005;29:51–60

Coyer SM. Anemia: diagnosis and management. J Pediatr HealthCare. 2005;19:380–385

Fleming RE, Bacon B. Orchestration of iron homeostasis. N EnglJ Med. 2005;352:1741–1744

Lo L, Singer ST. Thalassemia: current approach to an old disease.Pediatr Clin North Am. 2002;49:1165–1191

Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Poorerbehavioral and developmental outcome more than 10 years aftertreatment for iron deficiency in infancy. Pediatrics. 2000;105:e51. Available at: http://pediatrics.aappublications.org/cgi/content/full/105/4/e51

Rund D, Rachmilewitz E. Medical progress: beta-thalassemia.N Engl J Med. 2005;353:1135–1146

Tyagi S, Pati HP, Choudhry VP, Saxena R. Clinico-haematologicalprofile of HbE syndrome in adults and children. Hematology.2004;9:57–60

Weiss G, Goodnough LT. Medical progress: anemia of chronicdisease. N Engl J Med. 2005;352:1011–1023

PIR QuizQuiz also available online at www.pedsinreview.org.

1. A 14-month-old boy is brought to your office because a visiting relative noted that he appeared pale. Hedrinks 40 to 50 oz of cow milk daily. He looks well except for pallor. A complete blood count demonstratesa white blood cell count of 6.9�103/mcL (6.9�109/L), hemoglobin of 5.9 g/dL (59 g/L), mean cell volumeof 57 fL, and platelet count of 775�103/mcL (775�109/L). The most appropriate next step is to:

A. Give a blood transfusion.B. Give a single dose of intravenous iron.C. Initiate a trial of oral ferrous sulfate.D. Obtain hemoglobin electrophoresis.E. Obtain serum ferritin, iron, and total iron-binding capacity measurements.

2. A 12-month-old girl is found to have a hemoglobin of 9.7 g/dL (97 g/L) during a health supervision visit.Other findings on the complete blood count are mean cell volume of 63 fL, red cell distribution width(RDW) of 15.1%, and red blood cell count of 5.3�103/mcL 5.3�109/L. She is given a trial of oral ironsulfate, and after 3 weeks, the hemoglobin measures 9.6 g/dL (96 g/L). The most likely explanation for thefailure of the hemoglobin to increase is:

A. Administration of the oral iron with meals.B. Failure to take oral iron.C. Incorrect diagnosis.D. Malabsorption of iron.E. Ongoing blood loss.

3. An 18-month-old girl who was born in Cambodia and recently emigrated to the United States with herparents is brought to you because of pallor and abdominal distention. On physical examination, the girl ispale and quiet. Her spleen is palpable 8 cm below the left costal margin, and her liver is palpable 3 cmbelow the right costal margin. Among the laboratory findings are hemoglobin 4.1 g/dL (41 g/L), mean cellvolume 58 fL, white blood cell count 19.5�103/mcL (19.5�109/L), and platelet count 795�103/mcL(795�109/L). The most likely diagnosis is:

A. E-beta thalassemia.B. Hemoglobin H disease.C. Iron deficiency.D. Malaria.E. Sickle-beta thalassemia.

(continued on page 14)





4. A 17-year-old girl of African descent had a complete blood count obtained in an emergency departmentbecause of high fever. She was told to follow-up with your office because of the findings on the test,which included hemoglobin 10.9 g/dL (109 g/L), mean cell volume 69 fL, white blood cell count 9.5�103/mcL (9.5�109/L) with 24% polymorphonuclear neutrophils, 70% lymphocytes, 6% monocytes, RDW14.5%, and platelets 395�103/mcL (395�109/L). Hemoglobin electrophoresis demonstrates hemoglobinA 97%, hemoglobin A2 2.8%, and hemoglobin F 0.2%. The most likely cause of the anemia is:

A. Alpha thalassemia silent carrier.B. Alpha thalassemia trait.C. Beta thalassemia intermedia.D. Beta thalassemia trait.E. Hemoglobin H disease.

5. A 4-year-old boy presents with a 4-week history of malaise and occasional low-grade fever. Results oflaboratory studies include hemoglobin 9.5 g/dL (95 g/L), mean cell volume 68 fL, white blood cell count21.5�103/mcL (21.5�109/L) with 65% polymorphonuclear neutrophils, 16% bands, 15% lymphocytes, and4% monocytes, RDW 16.95%, and platelet count 695�103/mcL (695�109/L). Additional findings includeserum iron 15 mcg/dL (2.7 mcmol/L), total iron-binding capacity 210 mcg/dL (37.6 mcmol/L), and serumferritin 160 ng/mL (160 mcg/L). The most likely diagnosis is:

A. Anemia of chronic disease.B. Hemoglobin H disease.C. Iron deficiency.D. Lead poisoning.E. Thalassemia trait.





DOI: 10.1542/pir.28-1-52007;28;5Pediatrics in Review

Matthew RichardsonMicrocytic Anemia

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Suggested ReadingBader-Meunier B, Armengaud JB, Haddad E, et al. Initial presen-

tation of childhood-onset systemic lupus erythematosus: aFrench multicenter study. J Pediatr. 2005;146:648–653

Brasington RD Jr. Immunologic rheumatologic disorders: dys-temic lupus erythematosus. J Allergy Clin Immunol. 2002;111(2 suppl):S593–S601

Hsu S, Le EH, Khoshovis MR. Differential diagnosis of annularlesions. Am Fam Physician. 2001;64:289–296

Klein-Gitilman M. Systemic lupus erythematosus in childhood.Rheum Dis Clin North Am. 2002;28:561–577

Mikdashi J, Krumholz A, Handwerger B. Factors at diagnosispredict subsequent occurrence of seizures in systemic lupuserythematosus. Neurology. 2005;64:2102–2107

Stichweh D, Arce E, Pascual V. Update on pediatric systemic lupuserythematosus. Curr Opin Rheumatol. 2004;16:577–587

Taylor ML, Gill JM. Lupus and related connective tissue diseases.Clin Family Pract. 2005;7:209–224

ClarificationIn reference to the article on abnormalities in head size (Pediatr Rev. 2006;12:473–476),a reader has pointed out that offspring of mothers who have phenylketonuria can havefeatures virtually identical to infants who have fetal alcohol syndrome, including micro-cephaly and classic facial dysmorphology. All mothers who have phenylketonuria are notsignificantly handicapped in their cognitive functions, making it more difficult to diagnosethis disorder.

In the article on microcytic anemia (Pediatr Rev. 2007;28:5), the dose for prophylacticpenicillin V in children younger than 5 years of age is given as 125 mg BID in a table and125 mg TID in the text. The correct dose is 125 mg BID.

visual diagnosis

Pediatrics in Review Vol.28 No.4 April 2007 151



pelvis should be performed to searchfor an occult neoplasm. At least insome situations, early resection andimmunosuppression may slow thedevelopment of bronchiolitis obliter-

ans, the leading cause of death inchildren afflicted with paraneoplasticpemphigus. (Su-Ting T. Li, MD,MPH, University of CaliforniaDavis, Sacramento, Calif.; Matthew

C. Hollander, MD, Wright-PattersonAir Force Base, Ohio)

To view Suggested Reading listsfor these cases, visit pedsinreview.organd click on Index of Suspicion

ClarificationIn the January 2007 article entitled Microcytic Anemia (PIR. 2007;28:5–14), themean hemoglobin value for a newborn is listed in Table 2 as 16.5 g/dL (165 g/L).In the same issue, the In Brief entitled Anemia and Polycythemia in the Newborn(pp 33–34) lists a value of 19.3 g/dL (193 g/L) as the normal newborn value. Thediscrepancy is due to the lower value applying to cord blood but the higher valuerepresenting the finding of a sample obtained from the baby after birth.

In “Index of Suspicion” Case 3 in the April 2007 issue (2007;28:139–145), thestatement is made that hypercalcemia will cause a prolonged QT interval. A readerpoints out that although hypercalcemia may present infrequently with prolongation ofthe QT interval, it is more likely to manifest as a shortening of the QT interval. Theauthors agree.

index of suspicion

Pediatrics in Review Vol.28 No.7 July 2007 275



CORRECTIONS AND CLARIFICATIONS IN RESPONSE TO READERCOMMENTS, 2007

Readers who send in their answers to the quiz questions using the paper answer sheetoften add comments. Because those sheets sometimes are submitted long after thearticles are published, publication of responses by authors can be delayed considerably.We present corrections and clarifications here that pertain to articles published in 2007(volume 28).

JANUARY. In the article by Richardson on microcytic anemia (pages 5–14), question#2 presents a patient believed to have iron deficiency who does not respond to oraliron. The correct answer is given as C. Incorrect diagnosis. A reader questions whetheranswer B. Failure to take oral iron would be correct. Dr. Richardson replies, “Al-though B is a possibility, the Mentzer index suggests thalassemia trait (90% sensitivefor beta thalassemia trait for values �13). The red blood cell distribution width may bemildly elevated in beta thalassemia and alpha thalassemia trait.” (Eldibany MM.Usefulness of certain red blood cell indices in diagnosing and differentiating thalas-semia trait from iron-deficiency anemia. Am J Clin Pathol. 1999;111:676–682)

Question #4 gives the correct answer as B. Alpha thalassemia trait. A readerquestions why the correct answer is not D. Beta thalassemia trait. Dr. Richardsonreplies, “Alpha thalassemia trait is more common in African American people thanbeta thalassemia trait and a nonelevated hemoglobin A2 value rules out beta thalas-semia trait as the most common type. An unusual ‘delta-beta’ thalassemia or ‘silentcarrier’ beta thalassemia hypothetically could be the answer, but the best answer isalpha thalassemia trait.”

FEBRUARY. In the article by Lewis on pediatric migraine (pages 43–53), 12 keydiagnostic questions are listed; but questions #3 and #5 are identical. Dr. Lewis offersa new key question that can aid in distinguishing migraine from other primaryheadaches:

Are you having any other medical problems or are you being treated with anymedications (for the headache or other purposes)?

NOVEMBER. In the article on seizures by Major and Thiele (pages 405–414), thereis a discrepancy between the caption and the diagram in Figure 1, which shows scalpelectrode placement in electroencephalography. The even-numbered electrodesshould be placed over the right hemisphere, as indicated in the caption.

NOVEMBER. In the In Brief on hyponatremia by Farrell and Del Rio (pages426–428), in Table 2, the third item in the left column should read, “Hypervolemic,increased intravascular volume4.”

OCTOBER, 2008. In the In Brief: Selecting Developmental Surveillance and Screen-ing Tools (pages e52–e58), Table 2 lists screening instruments. One of the authors ofthe Modified Checklist for Autism in Toddlers (M-CHAT) provided a different URLfor reviewing the most up-to-date information about the instrument, which ishttp://www2.gsu.edu/�psydlr.

Find it in May NeoReviews™The American Academy of Pediatrics online neonatology journal at http://neoreviews.aappublications.org

Historical Perspectives: Perinatal Profile: Jim Farquhar and Infants ofDiabetic Mothers—PhilipNeonatal Abstinence Syndrome—Burgos/BurkeFetal Alcohol Spectrum Disorder—Dannaway/MulvihillParallel Circulations: Managing Single-ventricle Physiology—Mastropietro,TournerIndex of Suspicion in the Nursery—West/Shulman/CadichonStrip of the Month: May 2009—Druzin/Arafeh

Pediatrics in Review Vol.30 No.5 May 2009 181



anemia microcitica

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