Clinical Pediatric Hematology-Oncology Volume 22 ㆍ Number 1 ㆍ April 2015 ORIGINAL ARTICLE 소아및청소년에서중증철결핍빈혈환자의특성 권혜원ㆍ권성은ㆍ이지은ㆍ전용훈ㆍ김순기 인하대학교의과대학소아과학교실 The Characteristics of Severe Iron Deficiency Anemia in Children and Adolescents Hye Won Kwon, M.D., Sung Eun Kwon, M.D., Ji Eun Lee, M.D., Ph.D., Yong Hoon Jun, M.D., Ph.D. and Soon Ki Kim, M.D., Ph.D. Department of Pediatrics, Inha University School of Medicine, Incheon, Korea Background: Severe iron deficiency anemia (IDA) can cause developmental and growth problems in children and disease severity is more than cognitive disorder or diabetic neuropathy according to the disability weight (DW). Methods: Severe IDA is defined as serum hemoglobin (Hb) level less than 7.0 g/dl in younger than 4 years of age and less than 8.0 g/dl in older than 5 years, which has been caused by iron deficiency. Among 2,336 patients with IDA, 130 (5.6%) were diagnosed as severe IDA. The exclusion criteria were other hematologic diseases, history of preterm birth or low birth weight and acute blood loss due to trauma. Results: The rate of severe IDA among IDA patients was higher in female than male. Patients from age 1 to 6 and adolescents over the age of 13 outnumbered others, and the majority of adolescent patients were female. Among weight groups, low weight-for-ages (less than 3 rd percentile) was prevail (20%). There were no statistical differences between laboratory results of symptomatic patients and those of asymptomatic ones (25.4%). The common causes of severe IDA were; long-term exclusive breast feeding (13.0%), menorrhagia (10.0%), H. pylori gastritis (9.2%), upper GI bleeding (9.2%) and malnutrition (8.5%). All were treated with oral or intravenous iron replacement therapy and after 3 months, laboratory results were significantly improved. In cases of H. pylori gastritis, iron replacement therapy in conjunction with H. pylori eradication showed better efficacy in treatment. Conclusion: The importance of severe IDA should not be underestimated. Especially with female adolescents, H. pylori gastritis patients, and athletes, it is still more important to make prompt diagnosis and early treatment. Key Words: Iron deficiency anemia, Children, Severe, Disability weight pissn 2233-5250 / eissn 2233-4580 http://dx.doi.org/10.15264/cpho.2015.22.1.54 Clin Pediatr Hematol Oncol 2015;22:54 59 Received on April 4, 2015 Revised on April 15, 2015 Accepted on April 22, 2015 Corresponding Author: Soon Ki Kim Department of Pediatrics, Inha University School of Medicine, 27, Inhang-ro, Jung-gu, Incheon 400-711, Korea Tel: +82-32-890-2843 Fax: +82-32-890-2844 E-mail: pedkim@inha.ac.kr 서 소아및청소년에있어서빈혈의가장흔한원인은철결핍 론 (iron deficiency, ID) 으로, 2007년 WHO 보고에의하면 30-50% 의빈혈이 ID에의해발생한다. Mclean 등에의하면전체빈혈환자의수는 16억명에달하므로철결핍빈혈 (iron deficiency anemia, IDA) 환자의수는전세계적으로수억명 54
Characteristics of Severe IDA in Children 에달할것으로예상할수있다 [1]. 국내의보고에의하면 10세이상성인의빈혈유병률은남자 2.5%, 여자 11.6% 로이는각각약 582,000여명과 2,719,000 여명에이르는수이며, 이들중 IDA 환자의수는각각 20만명과 100만명에이르는것으로추산해볼수있다 [2]. 소아를대상으로한미국의통계에의하면 1세부터 3세의영유아중 9% 에서 ID가발견되고 IDA를진단받은환자도전체의 2-3% 에달하는데 [3,4], IDA의위험요인으로잘알려져있는미숙아혹은저체중출생아, 쌍둥이, 모유단독수유환자등에서는더욱높은유병률을보일것으로예상할수있다 [5,6]. WHO의분류에따르면 IDA 환자중 4세미만에서혈색소 (hemoglobin, Hb) 7.0 g/dl 미만, 5세이상에서 Hb 8.0 g/dl 미만일때중증 (severe) IDA 분류할수있고또한 IDA는장애무게 (disability weights, DW) 에따라분류할수있다. DW는미국, 페루, 탄자니아, 방글라데시및인도네시아 5개국의인구집단 31,000명이상의조사결과, 연구자나의료진의전문의견보다는집단적대중의판단으로부터산출된건강상태의중한정도 (severity) 로이러한기준에따라 IDA를경증 (mild), 중등도 (moderate) 및중증 (severe) 으로나누었다 [7,8]. Paoletti 등의연구에서중증 IDA 환자는 13개월에서 36개월사이에주로발견되며특히 Hb이 5 g/dl 미만인환자는모두 15개월이상인것으로나타났다 [9]. 이는걸음마시기의소아에서철분요구량이증가함에따라 IDA가중증의경과를보이기쉬움을시사하는결과로, 두뇌발달즉, 인지기능발달과정신운동발달을달성해야할 1세에서 3세의소아에서중증 IDA의치료가늦어지는경우정신신경발달에좋지않은영향을줄수있고이러한변화가비가역적일수있다는점에서시사하는바가크다 [9-12]. IDA에대한많은연구에도불구하고중증 IDA 환자에대한연구는아직국내에보고된바가없다. 따라서본연구는특별히철분결핍에의한중증빈혈환자를대상으로하여임상적 특성과치료결과에대해고찰해보고자한다. 대상및방법 1996년 3월부터 2013년 12월까지인하대병원소아청소년과에서 IDA로진단받은 19세미만의환자 2,336명가운데, 중증 IDA로분류된 130명 (5.6%) 을대상으로하였다. IDA는 Table 1에서처럼, 빈혈이있으면서, 혈청페리틴이 10 ng/ml 미만또는트란스페린포화도가 15% 미만인경우로진단하였다 [7,13]. 중증 IDA는위에서언급한 WHO의기준에따라, 4세미만에서 Hb 7.0 g/dl 미만, 5세이상에서 Hb 8.0 g/dl 미만이면서, 혈청페리틴의감소나 TS의감소를동반한경우로정의되었다. 미숙아, 저체중출생아이거나다른혈액학적질환을진단받은환자, 그리고외상으로인한급성출혈환자는제외되었다 [7]. 대상환자의정맥혈채취후, 자동화세포계산기 (Automated Cell Counter, ADVIA 2120) 에의하여 Hb, 적혈구용적 (hematocrit), 평균적혈구용적 (mean corpuscular volume, MCV), 평균적혈구혈색소량 (mean corpuscular hemoglobin, MCH), 적혈구분포폭 (red cell distribution width, RDW), 망상적혈구수치 (reticulocyte count) 를측정하였다. 혈청페리틴은 Cobas 6000에의한 LCIA 법, 총철결합능 (total iron binding capacity, TIBC) 은 Hitachi 7600에의한 photometry method에의하여측정되었고, 트란스페린포화도 (transferrin saturation, TS) 는혈청철 /TIBC 100의공식에의하여계산되었다. 본연구의분석에서통계적방법은 IBM SPSS statistics ver. 9.0를이용하였고, 연속형자료는이표본 t 검정 (Two sample t-test) 을하였다. 평균 ± 표준편차 (standard deviation) 로표기하였고, P<0.05일때의미있다고판정하였다. Table 1. Hemoglobin levels to diagnose anemia at sea level (g/dl) Population Non Anemia Anemia Mild Moderate Severe Children 6-59 months of age 11 or higher 10-10.9 7-9.9 lower than 7 Children 5-11 years of age 11.5 or higher 11-11.4 8-10.9 lower than 8 Children 12-14 years of age 12 or higher 11-11.9 8-10.9 lower than 8 Non-pregnant women 12 or higher 11-11.9 8-10.9 lower than 8 Pregnant women 11 or higher 10-10.9 7-9.9 lower than 7 Men 13 or higher 11-12.9 8-10.9 lower than 8 Disability weights 0.0030-0.0062 0.0453-0.0727 0.1327-0.2019 Clin Pediatr Hematol Oncol 55
Hye Won Kwon, et al Table 2. Laboratory results at diagnosis and follow-up visits (mean±sd) Laboratory items Values at diagnosis Values after treatment Hb (g/dl) 6.26±0.9 11.69±1.5 MCV (fl) 64.5±11.8 75.23±9.3 MCH (pg) 18.5±5.4 24.25±3.4 RDW (%) 18.6±3.0 18.70±5.1 Reticulocyte 2.43±1.7 1.94±1.5 count (%) Iron ( g/dl) 19.02±18.0 92.78±67.1 TIBC ( g/dl) 427.10±89.3 348.14±97.9 TS (%) 4.95±5.2 24.83±23.4 Ferritin (ng/ml) 6.53±7.4 27.85±43.2 Platelet ( 10 3 /mm 3 ) 406±170 329±123 Hb, hemoglobin; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RDW, red cell distribution width; TIBC, total iron binding capacity; TS, transferrin saturation. 결 중증 IDA 환자 130명의평균연령은 6.7세 (0-19세), 중간연령은 4.5세였으며남아와여아의비율이 1:1.7로 19세미만일반인구의남녀성비 1:0.89와는차이가있었다. 성별에따라서는, 2,336명의 IDA 환자중중증환자의비율은남아가 4.0%, 여아가 8.4% 였다. 또한연령에따른중증 IDA의비율은 1세미만에서 23명으로 17.7%, 1세이상 6세미만에서 45명으로 34.6%, 6세이상 13세미만에서 23명으로 17.7% 로나타났으며 13세이상에서도 39명으로 30.0% 의높은비율을보이는것으로나타났다. 대상환자들의체중분포를살펴보면, 진단시연령대비체중이 3 퍼센타일미만인환자가 20.0% 에달했으며 3-5 퍼센타일에속하는환자와 90 퍼센타일이상의환자는각각 6.6% 를차지하고, 97 퍼센타일이상의환자는 3.3% 였다. 이들이처음병원에내원한증상은창백, 어지러움, 경구섭취감소등이가장많았지만 (5명, 38.5%) 빈혈에관련된증상이아닌다른증상으로내원하여발견된빈혈도 27명 (25.4%) 이었다. 이들은기침, 콧물등의호흡기감염증상이나발열, 위장관출혈을동반하지않은장염, 기흉, 골절등다양한다른이유로병원을찾아시행한혈액검사에서빈혈이확인되어관련검사후비로소 IDA로진단된환자들이었으며별증상을호소하지않은 27명환자의평균 Hb 수치는 6.7 g/dl로, 빈혈증상이있었던나머지 103명환자의평균 Hb 수치인 6.2 g/dl와의미있는차이가없었다 (P=0.19). 한편진단당시대상환자들의혈액검사수치의평균을살 과 Table 3. Main causes of severe IDA Causes N % Prolonged BMF feeding 17 13.1 Menorrhagia 13 10.0 GI bleeding d/t ulcer, gastritis 12 9.2 H. pylori gastritis 12 9.2 Malnutrition 11 8.5 Meckel's diverticulum 2 1.5 Blood loss other than GI tract 2 1.5 Other diseases a) 6 4.6 Unknown 55 42.3 Total 130 100 a) Idiopathic pulmonary hemosiderosis (1), portal vein thrombosis (1), SLE (1), duplication of intestine (1), splenectomy (1), infratemporal retiform hemangioendothelioma (1). 펴보면, Hb 6.3 g/dl, 적혈구용적 22.5%, MCV 64.5 fl, MCH 18.5 pg, RDW 18.5%, 망상적혈구 2.43%, 혈청철 19.0 g/dl, TIBC 427.1 g/dl, TS 4.9%, 페리틴 6.5 ng/ml이었다 (Table 2). 대상환자들가운데 IDA의원인이밝혀진환자는모두 75 명으로장기간의모유단독수유가원인인경우가 17명 (13.0%) 으로가장많았으며월경과다로인한경우가 13명으로 10.0% 를차지했다 (Table 3). 또 H. pylori 위염이확진된경우가 12 명 (9.2%) 이었으며 H. pylori 감염은아니지만위염과궤양으로인해상부위장관출혈이있었던경우도 12명 (9.2%) 으로나타났다. 또한뇌성마비, 만성경련성질환등으로누워지내는 (bed-ridden) 상태의환자들에서영양결핍으로인한 IDA 가나타난경우가 11명 (8.5%) 이었다. Meckel 게실에의한출혈이있었던환자가 2명 (1.5%), 단순장염으로일시적인혈변증상이있은후 IDA가발생한경우도 2명 (1.5%) 이었다. 또 idiopathic pulmonary hemosiderosis, portal vein thrombosis, SLE 등의기저질환이동반된환자는 6명 (4.6%) 였다. 130명중두명의환자는중장거리육상선수로서, 이중한명의환자는 H. pylori 위염이동반되었으나다른한명은원인이밝혀지지않았다. 치료는경구철분제 (ferrous sulfate) 를체중 kg 당하루 4-6 mg 투약하였고 4주간투약후반응이없을경우정맥주사 (iron sucrose) 를투여하였다. 수혈이필요한경우는없었다. 치료시작후추적검사는평균 3개월뒤에시행하였다. 이들의치료기간은 3개월이상시행했으며 4주후치료에반응하지않아정맥주사를처방받은 3명의환자를제외하고는모두경구철분제제를복용하였다. 진단을받은뒤병원에내원하지않아추적관찰이중단된 34명을제외한 96명환자의 56 Vol. 22, No. 1, April 2015
Characteristics of Severe IDA in Children 치료후혈액검사는평균 3.2개월후시행하였고, 그결과 Hb 11.7 g/dl, MCV 75.2 fl, MCH 24.3 Pg, RDW 18.7%, 망상적혈구 1.94%, 혈청철 92.8 g/dl, TIBC 348.1 g/dl, 트란스페린포화도 24.8%, 페리틴 27.8 ng/ml로모든수치가호전된것을확인할수있었다 (Table 2). 이러한치료전과치료후의 Hb와 MCV는각연령군에서통계적으로유의하게개선되었다 (P<0.01). 위에서밝힌바와같이, 130명중 12명의환자에서는 H. pylori 감염이확인되었다. 이들의진단시 Hb은평균 7.5 g/dl 였으며철분제제를복용한후확인된 Hb은평균 9.1 g/dl, 철분제복용과 H. pylori에대한치료를병행한뒤확인된 Hb 은평균 12.7 g/dl로나타나철분섭취만으로는통계적으로의미있는치료성적을거두지못했으나 (P=0.0712) 제균요법을병행한경우통계적으로도의미있는치료효과를보였다 (P<0.0001). 고찰본연구에서는 19세미만의소아청소년연령에서특히중증에속하는 IDA 환자의특성에대해고찰해보고자하였다. IDA는전세계어디에서나볼수있으며영유아, 소아및청소년에가장흔하게발생하는영양학적문제이다. IDA는빈혈에의한영향뿐만아니라철분을이용하는효소활성도의감소로인하여신경학적발달이지연되고, 이장애가지속될경우 IDA가치료된이후에도비가역적인두뇌손상을유발한다. 따라서 IDA의예방과치료는소아청소년과에서특히중요하다고할수있겠다. 그러나실제로는빈혈, 특히철분부족에의한 IDA의심각성이제대로인식되지못하고있다. 많은경우에발견이늦고발견되더라도치료가불충분한경우가많았다. 이는의료진의책임역시크다고볼수있는데, 본연구는이러한심각성에대하여 DW 점수가높은중증 IDA 환자를선별하여분석하였다. DW는 220개의건강상태를등급화한것으로, 가장경한것을 0 (perfect health), 사망에해당하는것은 1 (death) 로하여, 경도 (mild) 는 DW 0.005로서, 먼거리를못본다든지오래전치료한골절보다약간심한정도이다. 중등도 (moderate) 는 DW 0.058로서, 귀울림을동반한중등도의청력감퇴와유사하고, 중증 (severe) 은 DW 0.164로서, 장기간한쪽다리의절단과유사한정도이다. 이러한분류에의하면 IDA는경증이 0.0, 중등도가 0.011, 중증이 0.09에해당하는데중증 IDA는 DW 0.024의인지기능장애나 0.072의당뇨신경병증을넘어서는수치로그질환의중대함이큰것을알수있다 [14]. 본연구결과를살펴보면, 그간의연구에서성별에따른 IDA 유병률이남녀가거의유사하지만남아에서다소높게나타났던것과는달리 IDA 환자중중증 IDA의비율은여아에서더높았다 [3]. 연령별로는 1세에서 6세미만, 13세이상의연령군에서가장높은비율을보여 6개월에서 3세사이와청소년기에각각높은 IDA 유병률을보인이전의연구들과유사한현상을보였다 [3,4]. 또 13세이상의연령군에서전체 IDA 환자중중증환자의비율이 30% 에달한다는사실도눈여겨볼만하다. 이들의성별을살펴보면남아가 9명, 여아가 32명으로여아의수가훨씬많은것을알수있고이것은여아의초경연령과무관하지않을것으로생각된다. IDA의원인중, 월경과다는전체의 10% 를차지하는데 (Table 3), 이는원인이밝혀진환자들가운데 17.3% 를차지하는높은비율이다. 뿐만아니라병원진료를받을정도의월경과다가있었던환자를제외하더라도, 13세이상여아에서의중증 IDA 유병률이높다는사실에서정상적인월경만으로도초경이후나이에실혈로인한 IDA의위험이높음을알수있었다 [15-17]. 더구나 Elwood 등에따르면성인여성에서, Hb 수치와월경으로인한철분소실이음의상관관계가있다는결과도보고된바있어특히가임기여성이나청소년에서적정 Hb 수치를유지하는것이더욱중요할것으로생각된다 [17]. 한편, H. pylori 위염 (12명) 과다른위염이나위궤양 (12명), Meckel 게실 (2명) 등, 다양한위장관출혈로인한 IDA 환자는 26명으로 20% 를차지했다. 따라서중증 IDA 환자에서위장관증상에대한면밀한검사와병력조사가필요함을알수있었고위염이확인되었으나 H. pylori에대한검사가이루어지지않은환자도있었다. 현재모든 IDA 환자에서 H. pylori에대한검사가권장되지는않으나, 위염을시사하는증상이있을경우또상부위장관내시경검사의적응증이된다면이에대한검사도고려해볼필요성이있다 [18-21]. 또한 H. pylori 위염을진단받은환자의경우철분제재의투약뿐아니라 H. pylori 제균치료가병행되지않으면 IDA 치료가불충분하거나재발하기쉬우므로 H. pylori 위염의진단이중요함을알수있었다. 현재까지의연구결과에의하면빈혈을진단받은환자에서 H. pylori 감염의유병률이의미있게높다는결론은없었지만빈혈환자중 H. pylori 감염군에서비감염군에비해 Hb과혈청페리틴수치가의미있게낮았다는보고가있는만큼중증 IDA 환자에서는 H. pylori 감염자체가질병을중증의경과로이행하게하는데어떤역할을할가능성이있다고하겠다 [18]. Clin Pediatr Hematol Oncol 57
Hye Won Kwon, et al 대상환자의체중분포분석에서는출생체중이 3 퍼센타일미만인환자를연구대상에서제외하였음에도불구하고진단당시에연령대비저체중을보인환자의비율이높은것으로나타났다. 이러한사실은 IDA와체중증가폭사이의음의상관관계를추정할수있게한다. 그러나이들의상관관계를밝히기위해서는저신장의가족력등자세한병력과혈청비타민 D 수치등철분영양상태에영향을줄수있는관련요인에대한연구가보충되어야할것이다 [22]. 또대상환자중두명의환자는중장거리육상선수인청소년여아였는데, 강도높은운동을하는경우달리기후위장관출혈이증가하고, 달리는도중적혈구의파괴가일어나혈뇨가발생하며또적혈구의전환 (turnover) 이운동선수에서증가한다는보고도있다 [23]. 이는특히여성에서 20% 가량더빠르고하는데이와같이일반인보다철분요구량이더많음에도불구하고합숙이나단체식사를하는과정에서영양적인불균형이오기쉬워 IDA가발생하고재발이잦은경우였다. 이번연구의대상에는포함되지않았지만운동선수이면서중등도 IDA를진단받은환자들도다수발견되어청소년운동선수에대하여철분공급과함께적극적으로영양학적개입이필수적임을알수있었다. 치료후의검사결과를보면, 중증 IDA 환자에서평균약 3개월의치료기간이지난뒤 Hb을비롯한모든객관적지표가호전되는양상을확인할수있었다. 본연구의대상환자 130명중경구철분제재에반응하지않아정맥철분제제를투약한 2명의환자와신생아기에장폐색으로장절제술을시행받아위장관을통한철분의흡수가저하된한명의환자를제외하고는모두경구철분제제로써유의한치료효과를얻었다. 정맥철분제재를사용한 3명의환자의경우평균 5일간의 iron sucrose (Venoferrum) 투약으로검사결과의호전이있었다. 이전의연구에서위장관흡수장애가있는경우정맥치료가효과적일수있음이알려져있으므로경구제재로의치료에실패한경우라면정맥치료가좋은대안이될수있을것이다 [24-26]. 또한빈혈에관련된증상이아닌다른이유로병원을찾아중증 IDA를진단받은환자와어지러움이나창백등빈혈을시사하는증상이있었던환자들사이에평균 Hb 수치의차이가없었다는점을주목해야할필요가있을것이다. 이러한사실은중증 IDA의진단이늦어지거나치료가지연되는환자가많은이유를짐작할수있게하며적극적인검사의필요성을시사한다. 더구나중증 IDA의치료는성별, 연령과무관하게철분제의투약으로그성적이좋으므로무엇보다도환자를조기발견하는일이중요하게생각된다. 특히식이, 출혈등의 주요위험요인과더불어 H. pylori 감염, 월경등 IDA의위험요인이될수있는원인요소를가진소아청소년에서더욱적극적인검사와진단, 나아가서는예방의필요성역시매우강조된다하겠다 [27]. 본연구에서는후향적인데이터분석의방법을사용함에따라, 대상환자들의식이력이나사회경제적상태등철분을비롯한영양상태에영향을줄수있는요인들에대한분석이이루어지지않았다 [28-30]. 또한질병의특성상증상이호전되면더이상병원에내원하지않는환자의비율이많아추적관찰이중단된환자의비율이높아짐에따라 IDA의원인과장기적인합병증등에대한분석이어려웠기에이러한부분은연구의한계로생각된다. 결론적으로, IDA의유병률은감소하는추세이지만소아청소년의성장과발달에매우중대한문제를가져올수있는중증 IDA는그중요성이간과되고있는것이현실이다. 걸음마시기의어린영아에서뿐아니라특히청소년기여아들에대한관심의필요성이강조되며, 중증의검사결과를보임에도별다른증상이없는경우도많은만큼, 철저한원인조사, 중재및추적관찰이필요할것으로사료된다. 또한앞으로중증 IDA에관한전국적인연구나전체 IDA 환자와의비교연구등이이루어진다면이를통해중증 IDA 환자의특성에대해더욱잘이해할수있을것으로생각된다. 감사의글 This work was supported by INHA UNIVERSITY Research Grant (51212-01). References 1. McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutr 2009;12:444-54. 2. Ministry of Health and Welfare. Korea Health Statistics 2013 : Korea National Health and Nutrition Examination Survey (KNHANES VI-1). Seoul: Ministry of Health and Welfare, 2014. 3. Brotanek JM, Gosz J, Weitzman M, Flores G. Secular trends in the prevalence of iron deficiency among US toddlers, 1976-2002. Arch Pediatr Adolesc Med 2008;162:374-81. 4.Baker RD, Greer FR; Committee on Nutrition American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young chil- 58 Vol. 22, No. 1, April 2015
Characteristics of Severe IDA in Children dren (0-3 years of age). Pediatrics 2010;126:1040-50. 5. Collard KJ. Iron homeostasis in the neonate. Pediatrics 2009;123:1208-16. 6. Park SH, Kim JS, Jun YH, Kim SK. Weaning food practice in low birth weight infants with iron deficiency anemia. Clin Pediatr Hematol Oncol 2014;21:52-8. 7. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Geneva: World Health Organization, 2011. 8. Salomon JA, Vos T, Hogan DR, et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 2012;380:2129-43. 9. Paoletti G, Bogen DL, Ritchey AK. Severe iron-deficiency anemia still an issue in toddlers. Clin Pediatr (Phila) 2014;53: 1352-8. 10. Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med 1991;325: 687-94. 11. Congdon EL, Westerlund A, Algarin CR, et al. Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years. J Pediatr 2012;160:1027-33. 12. Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol 2006;13:158-65. 13. Dallman PR, Siimes MA. Percentile curves for hemoglobin and red cell volume in infancy and childhood. J Pediatr 1979; 94:26-31. 14. World Health Organization. Global burden of disease 2004 update: disability weights for diseases and conditions. Geneva: World Health Organization, 2004. 15. Igarashi T, Itoh Y, Maeda M, Igarashi T, Fukunaga Y. et al. Mean hemoglobin levels in venous blood samples and prevalence of anemia in Japanese elementary and junior high school students. J Nippon Med Sch 2012;79:232-5. 16. Blanco-Rojo R, Toxqui L, López-Parra AM, et al. Influence of diet, menstruation and genetic factors on iron status: a cross-sectional study in Spanish women of childbearing age. Int J Mol Sci 2014;15:4077-87. 17. Elwood PC, Rees G, Thomas JD. Community study of menstrual iron loss and its association with iron deficiency anaemia. Br J Prev Soc Med 1968;22:127-31. 18. Queiroz DM, Harris PR, Sanderson IR, et al. Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study. PLoS One 2013;8:e68833. 19. Cardenas VM, Mulla ZD, Ortiz M, Graham DY. Iron deficiency and Helicobacter pylori infection in the United States. Am J Epidemiol 2006;163:127-34. 20. Huang X, Qu X, Yan W, et al. Iron deficiency anaemia can be improved after eradication of Helicobacter pylori. Postgrad Med J 2010;86:272-8. 21. Monzón H, Forné M, Esteve M, et al. Helicobacter pylori infection as a cause of iron deficiency anaemia of unknown origin. World J Gastroenterol 2013;19:4166-71. 22. Lee JA, Hwang JS, Hwang IT, Kim DH, Seo JH, Lim JS. Low vitamin D levels are associated with both iron deficiency and anemia in children and adolescents. Pediatr Hematol Oncol 2015;32:99-108. 23. Ehn L, Carlmark B, Höglund S. Iron status in athletes involved in intense physical activity. Med Sci Sports Exerc 1980;12: 61-4. 24. Pinsk V, Levy J, Moser A, Yerushalmi B, Kapelushnik J. Efficacy and safety of intravenous iron sucrose therapy in a group of children with iron deficiency anemia. Isr Med Assoc J 2008;10:335-8. 25. Crary SE, Hall K, Buchanan GR. Intravenous iron sucrose for children with iron deficiency failing to respond to oral iron therapy. Pediatr Blood Cancer 2011;56:615-9. 26. Santiago P. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview. Scientific- WorldJournal 2012;2012:846824. 27. Lim JY. Iron deficiency anemia in infants and young children. Clin Pediatr Hematol Oncol 2014;21:47-51. 28. Kim HJ, Kim DH, Lee JE, et al. Is it possible to predict the iron status from an infant's diet history? Pediatr Gastroenterol Hepatol Nutr 2013;16:95-103. 29. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician 2007;75:671-8. 30. Lukens J. Iron metabolism and iron deficiency. In: Miller DR, Baehner RL, Miller LP, editors, Blood diseases of infancy and childhood. St. Louis: Mosby-Year Book, 1995;193-220. Clin Pediatr Hematol Oncol 59