원저 Lab Med Online Vol. 1, No. 3: 147-152, July 2011 진단혈액학 소구성저색소성빈혈을보이는성인여성에서만성질환빈혈과철결핍빈혈의감별진단에망상적혈구지수의유용성 Reticulocyte Indices for the Differential Diagnosis of Anemia of Chronic Disease and Iron Deficiency Anemia in Adult Women with Microcytic Hypochromic Anemia 박순호 서일혜 박필환 김경희 송영희 정지훈 안정열 Soon-Ho Park, M.D., Yiel-Hea Seo, M.D., Pil-Hwan Park, M.D., Kyung-Hee Kim, M.D., Young-Hee Song, M.D., Ji-Hun Jung, M.D., Jeong-Yeal Ahn, M.D. 가천의대길병원진단검사의학과 Department of Laboratory Medicine, Gachon University Gil Hospital, Incheon, Korea Background: Iron deficiency anemia (IDA) is the most common anemia followed by anemia of chronic disease (ACD). Reticulocyte indices have been shown to be helpful indicators for detecting IDA. We investigated whether RBC and reticulocyte indices can be used to differentiate ACD from IDA. Methods: A total of 85 women showing microcytic hypochromic anemia (38 IDA and 47 ACD cases) were enrolled. IDA was defined as those with ferritin level of <6 µg/dl and total iron binding capacity (TIBC) of >450 µg/dl. ACD was defined as ferritin level of 6 µg/dl, TIBC of 450 µg/dl, and presence of underlying diseases. We measured complete blood count, TIBC, iron, ferritin, and RBC and reticulocyte indices. The mean values of each item were compared between the two groups and sensitivity and specificity of each item in the differential diagnosis of ACD from IDA were determined by ROC curve analysis. Results: In ACD, most of the RBC and reticulocyte indices were significantly higher than in IDA: mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), cellular hemoglobin concentration mean (CHCM), cellular hemoglobin content (CH), red cell distribution width (RDW), reticulocyte hemoglobin content (CHr), and mature RBC cellular hemoglobin content (CHm). All these indices, except MCV showed significant correlations with ferritin and/or TIBC. CHr level of 24.6 pg could be used to differentiate ACD from IDA with 85.1% sensitivity and 81.6% specificity. Conclusions: The reticulocyte indices, especially CHr, are useful for the differential diagnosis of microcytic hypochromic anemias, ACD and IDA. Key Words: Microcytic hypochromic anemia, Iron deficiency anemia, Anemia of chronic disease, Reticulocyte hemoglobin content (CHr), Reticulocyte indices 서론 철결핍빈혈과만성질환빈혈은가장흔한빈혈이며, 이두질환 Corresponding author: Jeong-Yeal Ahn, M.D. Department of Laboratory Medicine, Gachon University Gil Hospital, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, Korea Tel: +82-32-460-3831, Fax: +82-32-460-3415, E-mail: jyahn@gilhospital.com Received: December 1, 2010 Revision received: April 18, 2011 Accepted: April 29, 2011 This article is available from http://www.labmedonline.org 2011, Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 의감별은체내의철상태를평가하는것이다 [1]. 체내의철상태의평가는골수천자나골수생검검체로철염색을시행하여저장철의정도를측정하는것이표준검사이지만침습적이고, 고가이므로잘이용되지않는다. 대신혈청철, 총철결합능, 페리틴, 트란스페린포화도, 혈청트란스페린수용체 (stfr) 등의여러지표를이용하게된다 [2]. 혈청페리틴은체내의저장철을반영하나, 정상소아에서는감소하고, 염증이있거나, 고령에서증가하므로페리틴만으로철결핍을진단하기에는무리가있다. 혈청트란스페린수용체는조직으로의철공급이감소할때증가하며, 페리틴과달리염증에영향을받지않지만용혈성빈혈같은적혈구조혈이증가하는경우에증가한다. 혈청트란스페린포화도도사용되고있으나혈중철의일내변동이심하고만성감염상태에서감소하므로민감도와특이도면에서제한적이다 [3, 4]. 최근에유세포분석원리를가지는자동혈액분석기가도입되면 eissn 2093-6338 www.labmedonline.org 147
서여러가지적혈구지수와망상적혈구지수를구할수있게되었고, 이를이용하여철결핍성빈혈의진단에유용한지표들이보고되고있다 [5]. 특히망상적혈구지표중망상적혈구혈색소량 (reticulocyte hemoglobin content, CHr) 은적혈구조혈의영향을받아최근생성된망상적혈구내혈색소의양을반영한다. 망상적혈구혈색소량은체내철결핍시혈색소나평균적혈구용적 (MCV, mean cell volume) 와평균적혈구혈색소 (MCH, mean cell hemoglobin) 같은적혈구지수가감소하기전에감소하므로철결핍상태를조기에진단할수있는지표로보고되고있다 [6]. 이에본연구에서는경증의소구성저색소성빈혈을보이는성인여성을대상으로만성질환빈혈군과철결핍빈혈군으로나누어적혈구지수와망상적혈구혈색소량을포함한망상적혈구지수를비교하여만성질환빈혈과철결핍빈혈의감별진단에유용한지표로사용가능한지확인하고자하였다. 대상및방법 1. 대상 2008년 1월부터 2010년 4월까지가천의대길병원을방문한 17세이상의성인여성중전혈구계산 (CBC) 과말초혈액도말검사에서평균적혈구용적 70 fl 이상 80 fl 이하이면서평균적혈구혈색소가 27 pg 이하인소구성저색소성빈혈을보이는환자를후향적으로선별하였다. 환자군은페리틴 6 µg/dl 이상, 총철결합능이 450 µg/ dl 이하이며기저질환을가지고있는경우만성질환빈혈군으로선택하였으며, 동반된기저질환은악성종양 11명, 자가면역질환 10명, 당뇨 7명, 만성심장질환 5명, 만성신부전 2명, 간질환 2명, 내분비질환 1명, 만성염증 ( 결핵, 만성위염등 ) 9명이었다. 반면, 철결핍빈혈군은기저질환에상관없이페리틴 6 µg/dl 미만총철결합능 450 µg/dl초과인경우를기준으로선택하였다. 하지만성인의경우만성질환과철결핍이공존하는경우페리틴과총철결합능의수치가영향을받을수있으므로페리틴 6 µg/dl 이상이며총철결합능이 450 µg/dl 초과인경우나페리틴이 6 µg/ dl 미만이면서총철결합능 450 µg/dl 이하인어느군에도속하지않는환자군은전부배제하여명확한만성질환빈혈과철결핍빈혈만을대상으로비교하고자하였다. 따라서만성질환빈혈군 47명, 철결핍성빈혈군 38명을선별하였다. 2. 방법적혈구지수와망상적혈구지수는 K 3EDTA 시험관에채혈한정맥혈을 ADVIA120과 ADVIA2120 (Bayer Diagnostics, Tarrytown, NY, USA) 으로 8시간이내측정하였다. Advia 자동혈구계산기는적혈구채널과망상적혈구채널을통해 적혈구지수와망상적혈구지수를구할수있다. 적혈구채널에서는적혈구를등용적의구형으로만든후단색광을산란시켜그용적과반사지수로써혈색소를측정한다. 혈색소, 적혈구수, 평균적혈구용적, cellular hemoglobin concentration mean (CHCM), red cell distribution width (RDW) 는직접측정하고이로부터 Mean cell hemoglobin concentration (MCHC) 과평균적혈구혈색소량을계산하며 CH는각혈구용적에혈색소농도를곱한값으로구할수있다. 망상적혈구채널에서는적혈구를구형화한다음 oxazine 750으로염색한후함유 RNA량에따라망상적혈구와성숙적혈구를분류한다. 이렇게분류된망상적혈구로망상적혈구수를구하고, 그외에평균망상적혈구혈색소농도와망상적혈구혈색소량을포함한망상적혈구지수를구할수있다 [7]. 적혈구지수에는혈색소, 적혈구용적률, 평균적혈구용적, 평균적혈구혈색소, MCHC, CHCM, CH (cellular hemoglobin content), RDW, HDW (hemoglobin concentration distribution width) 가포함되었으며망상적혈구지수에는망상적혈구혈색소량, CHm (mature RBC cellular hemoglobin content) 이포함되었다. 혈청철, 총철결합능은 serum separate tube (SST) 시험관에정맥혈을채혈하여원심분리후혈청을이용하여 Hitachi7600 (Hitachi, Tokyo, Japan) 으로측정하였고, 페리틴은 Immunoradiometric assay법으로 1470 WIZARD gamma-counter (PerkinElmer, Turku, Finland) 를이용하여측정하였다. 3. 통계분석양군간의적혈구지수, 망상적혈구지수, 총철결합능, 철과페리틴의비교는비모수적방법인 Mann-Whitney 검정을하였고, 만성질환빈혈과철결핍빈혈의감별능력은 ROC 곡선을이용하여 area under the curve (AUC) 와경계치를정하였고지수들간의상관관계는 Pearson의상관분석법을이용하였다. 통계는 SPSS (version 15.0; SPSS Inc., Chicago, IL, USA) 를이용하였으며, P <0.01를통계학적으로유의한차이가있는것으로간주하였다. 결과 만성질환빈혈군은 47명 ( 평균연령 57.4±18.9 세 ), 철결핍빈혈군은 38명 ( 평균연령 43.3±13.6 세 ) 으로만성질환빈혈환자군에서평균연령이높았다. 만성질환빈혈군과철결핍빈혈군을비교한결과는 Table 1에제시하였고, 그중평균적혈구용적, 평균적혈구혈색소, MCHC, CHCM, CH, RDW, 망상적혈구혈색소량, CHm이통계적으로유의한차이를보였다. 철결핍빈혈군과비교하여만성질환빈혈군을진단하는 ROC분 148 www.labmedonline.org
석에서 CHCM, CH, RDW, 망상적혈구혈색소량, CHm 이 AUC 0.70 이상이었으며그중망상적혈구혈색소량이 0.870 로가장높게나 타났으며통계적으로유의하였던모든지수의판정기준치를정하 여민감도와특이도를구하였다 (Table 2). 특히망상적혈구혈색소 Table 1. Comparison of RBC and reticulocyte indices between anemia of chronic disease and iron deficiency anemia ACD (N=47) IDA (N=38) P * Hgb (g/dl) 8.4 (7.3-9.2) 8.9 (7.75-9.45) 0.194 Hct (%) 27.0 (24.1-29.8) 28.6 (26.1-31.3) 0.051 MCV (fl) 76.2 (74.4-78.0) 74.0 (72.8-75.8) <0.01 MCH (pg) 23.8 (22.7-24.4) 22.5 (21.2-23.4) <0.01 MCHC (g/dl) 31.2 (30.4-31.7) 30.5 (29.1-31.2) <0.01 CHCM (g/dl) 31.2 (30.7-32.4) 30.5 (29.0-31.2) <0.01 CH (pg) 23.8 (22.9-25.0) 22.5 (21.0-23.3) <0.01 RDW (%) 17.5 (16.0-19.7) 16.0 (15.5-17.3) <0.01 HDW (g/dl) 3.3 (3.1-3.6) 3.3 (3.1-3.7) 0.961 Reticulocyte (%) 1.96 (1.30-3.10) 1.67 (1.30-1.89) 0.146 CHr (pg) 27.0 (25.1-30.2) 23.1 (22.2-24.3) <0.01 CHm (pg) 24.2 (23.4-25.3) 22.6 (21.4-23.4 <0.01 Data were expressed as medians and interquartile ranges in parentheses. *Mann-Whitney U-test. Abbreviations: ACD, anemia of chronic disease; IDA, iron deficieny anemia; Hgb, hemoglobin; Hct, hemotocrit; MCV, mean cell volume; MCH, mean cell hemoglobin; MCHC, mean cell hemoglobin concentration; CHCM, cellular hemoglobin concentration mean; CH, cellular hemoglobin content; RDW, red cell distribution width; HDW, hemoglobin concentration distribution width; CHr, reticulocyte hemoglobin content; CHm, mature RBC cellular hemoglobin content. Table 2. Areas under the ROC curves of RBC and reticulocyte indices for differential diagnosis of anemia of chronic disease from iron deficiency anemia AUC (95% CI) Cut-off value Sensitivity Specificity MCV 0.681 (0.565-0.797) >75.0 68.1 57.9 MCH 0.729 (0.620-0.839) >23.1 70.2 65.8 MCHC 0.677 (0.563-0.791) >30.8 72.3 57.9 CHCM 0.708 (0.598-0.818) >30.8 70.2 63.2 CH 0.764 (0.662-0.867) >23.3 72.3 76.3 RDW 0.703 (0.592-0.815) >16.6 70.2 65.8 CHr 0.870 (0.789-0.951) >24.6 85.1 81.6 CHm 0.770 (0.667-0.873) >23.6 72.3 78.9 량은 24.6 pg 을판정기준치로하였을때, 민감도 85.1%, 특이도가 81.6% 로높게나타났으며, 28.0 pg 을판정기준치로정하였을때특 이도가 100% 로나타났다 (Table 3, Fig. 1). 페리틴은통계학적으로유의하였던지표중에망상적혈구혈색 소량과강한상관관계를보였고 (r = 0.568, P <0.01), 다른지표들과 도양의상관관계를보였다 (Table 4). 고찰 철결핍빈혈은가장흔한빈혈의형태로모든빈혈의 50% 정도를 차지하고있다 [1]. 남성보다여성에서흔하며, 특히가임기여성이 나임신부에서호발한다. 철의섭취감소나흡수장애, 장내출혈, 질 출혈등지속적인철분결핍이있거나임신이나성장기에철분요구 Table 4. Correlation coefficients between RBC and reticulocyte indices and ferritin and TIBC Sensitivity 1.0 0.8 0.6 0.4 Ferritin TIBC CHr.402* -.392* MCH.334* -.290* MCHC.236 -.084 CHCM.287* -.250 CH.381* -.399* RDW.209 -.306* CHm.362* -.382* *P <0.01; P <0.05 by Pearson correlation. Abbreviations: TIBC, total iron binding capacity; others, See Table 1. Abbreviations: AUC, area under the curve; CI, confidence interval; others, See Table 1. Table 3. Cut-off CHr level for differential diagnosis of anemia of chronic disease from iron deficiency anemia 0.2 CH CHr Cut-off Sensitivity Specificity 23.0 91.5 44.7 24.0 89.4 65.8 25.0 76.6 86.8 26.0 66.0 94.7 27.0 48.9 97.4 29.0 34.0 100 Abbreviation: CHr, reticulocyte hemoglobin content. 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity Fig. 1. Comparison of receiver operating characteristic curves for differential diagnosis of anemia of chronic disease from iron deficiency anemia. Abbreviations: CH, cellular hemoglobin content; CHr, reticulocyte hemoglobin content. www.labmedonline.org 149
량이증가할때발생한다 [8]. 대개소구성저색소성빈혈형태로나타나지중해빈혈, 철적혈모세포빈혈, 만성질환빈혈, 납중독과감별이필요하다 [9]. 만성질환빈혈은 2번째로흔한빈혈이며, 고령이나입원환자에서주로발생한다 [10]. 만성감염, 악성종양, 자가면역질환이나만성신부전이원인이되며, 경증이나중등도일경우정구성정색소성빈혈의형태로대부분소구성저색소성빈혈을보이는철결핍빈혈과구분되나좀더진행하는경우경증의소구성저색소성빈혈로나타나철결핍성빈혈과의감별이필요하다 [11]. 대부분만성질환빈혈의경우도철결핍빈혈과마찬가지로경구를통한철흡수가감소하기때문에경정맥으로철분을보충해주는것은효과적이다. 하지만만성염증이나악성종양에의해발생된만성질환빈혈인경우철분보충은악성종양세포나미생물의증식을증가시키고, 철이침착된단핵구나대식구는면역기능이저하되어악성종양의증식이나만성감염에더욱취약하게된다 [12]. 그러므로같은소구성저색소성빈혈이더라도만성질환빈혈과철결핍성빈혈을초기에감별하는것은임상경과와치료에중요한역할을한다. 본연구에서는철결핍빈혈군과만성질환빈혈군을평균적혈구용적 70 fl 이상 80 fl 이하의경증의소구성빈혈을대상으로선별하였다. 평균적혈구용적이 70 fl 미만인대상군에서본연구에서만성질환빈혈의진단기준인페리틴 6 µg/dl 이상, 총철결합능 450 µg/dl 이하인경우가대상군의수가너무적어평균적혈구용적 70 이하를넣어비교하는것은의미가적으며, 이는적혈구가좀더소구성을가질수록단순만성질환빈혈보다는철결핍이동반된빈혈로생각할수있겠다. 평균적혈구용적 70 fl 이상의경증의소구성저색소성빈혈을보이는군을분류하여분석한결과만성질환빈혈군은철결핍빈혈군에비해연령이높았고, 적혈구지수중평균적혈구용적, 평균적혈구혈색소, MCHC, CHCM, CH가더높게나와같은소구성저색소성빈혈이라하더라도철결핍빈혈환자가만성질환빈혈환자에비해좀더소구성저색소성적혈구를보였지만적혈구지수중평균적혈구용적은연령이증가함에따라값이커지므로그에따른연구가필요하겠다. 적혈구지수중 CH가 ROC 그래프에서가장큰 AUC값을가져높은민감도와특이도를보였으며, 진단기준인페리틴과총철결합능과높은연관성을보였다. 특히 Shin 등 [4] 은채혈이힘든 12개월이하의유아에서철결핍성빈혈을감별진단하는데 CH값이망상적혈구혈색소량보다 AUC값이크며상대적으로높은민감도와특이도를보이며, 이를통해다른검사에사용되는검체채취량과비용부담을줄일수있다고하였다. 적혈구는 120일의긴수명기간을가지고있어최근의적혈구생성능을반영하지못하는반면망상적혈구는골수에서 3일, 말초혈액에서단 1일간만나타나므로최근의적혈구생성능을반영한다. 자동혈구계산기를이용한망상적혈구의측정은수기법보다비교적짧은시간에많은검체를분석할수있고, 예민도와민감도가높고간편하다. 또한망상적혈구의크기와혈색소함량을광선산란법에의해같이측정하여망상적혈구혈색소량, MCVr, CHCMr, RDWr, HDWr, HDWr, CHDWr 등의다양한망상적혈구지수도구할수있다 [7]. 본연구에서비교한망상적혈구지수는망상적혈구수, 망상적혈구혈색소량, CHm이었다. 그중망상적혈구수는통계적의의가적었으나, 망상적혈구혈색소량, CHm은통계적차이를보였다. 망상적혈구혈색소량은철결핍상태를평가하는가장민감하고특이한지표로서, 철결핍상태를진단을위한가장적절한기준값으로알려져있다 [13-15]. 임상적으로도평균적혈구용적, MCHC가정상범위인초기철결핍빈혈에서망상적혈구혈색소량이먼저감소하므로망상적혈구혈색소량측정을통해철겹핍상태를조기에진단하고치료하여철결핍빈혈의예방에도움이된다. 또한망상적혈구혈색소량은연령이나염증, 만성질환등에의하여영향을받지않으므로철결핍빈혈을진단하는데고전적으로사용되는페리틴이나혈중철농도측정보다정확하다 [16-18]. 또한만성질환빈혈을갖고있는환자에서망상적혈구혈색소량의감소는만성질환빈혈과더불어철분결핍이있음을시사해적혈구생성인자 (erythropoietin) 와더불어철분보충의필요성을시사한다. 본연구에서도망상적혈구혈색소량은만성질환빈혈과철결핍빈혈을감별할수있는가장높은민감도와특이도를보이는지표이며, 페리틴과총철결합능과연관성도가장강하게나타나이전의연구와일치하였다. 이처럼자동혈구분석기로쉽게구할수있는망상적혈구지수는여러가지임상상에서적혈구조혈기능판정에유용하게쓰일수있다. 하지만아직까지일부기종에국한되어있고, 아직많은검사실에서망상적혈구지수를같이보고하고있지않다. 또한, 여러보고에서망상적혈구혈색소량이장비마다차이를보이고있기때문에각검사실에맞는참고치를설정해야한다 [19, 20]. 단순철결핍성빈혈과만성질환빈혈을구분하는것은쉽지않다. 특히철결핍이동반되는만성질환빈혈이나기저질환을가지고있는고령에서의경증의소구성저색소성빈혈을보이는경우원인이기저질환인지철분결핍인지알기가어렵다. 일반적인검사실에서두빈혈을구별하기위해쓰이는검사는혈청철, 페리틴, 총철결합능이다. 하지만앞에서언급했듯이이 3가지지표는여러조건하에서값이변할수있어문제가되고있다. Weiss 등 [11] 은철결핍빈혈과만성질환빈혈, 그리고철결핍이동반된만성질환빈혈을구별하기위해트란스페린포화도와페리틴그리고혈청트란스페린수용체를이용하여철결핍성빈혈, 철결핍이동반된만성질환빈혈, 그리고만성질환빈혈 3가지로분류하였다. 하지만검사실마다페리틴과총철결합능에정상범위가다르고혈청트란스페린수용체검사 150 www.labmedonline.org
가널리진단에사용되고있지않아한계가있다. 본검사실에서시행한혈청철, 총철결합능, 페리틴이철결핍빈혈을진단하는데주로사용되는검사이며혈청트란스페린수용체는검사하지않아 Weiss의진단기준으로구분할수는없었다. 하지만페리틴과총철결합능을이용하여본검사실의기준에따라나누었고, 둘중의하나만만족하는경우는다배제하여만성질환빈혈과철결핍빈혈이겹치는경우를최대한제거하였다. 또한다른연구에서도총철결합능과페리틴또는트란스페린포화도와페리틴을진단기준으로철결핍성빈혈과비철결성빈혈군을나누고있어큰문제는되지않을것이라생각된다 [4, 14, 15, 17]. 결론적으로경증의소구성저색소성빈혈을보이는철결핍성빈혈군과만성질환빈혈군을비교한본연구에서철결핍성빈혈은만성질환빈혈에비해좀더저색소성을보이는반면, 만성질환빈혈군은저색소성을보인다해도경증으로나타났다. 또한망상적혈구지수중망상적혈구혈색소량은두질환을감별하는데높은민감도와특이도를보이므로이를통하여철결핍의유무를보다빠르게진단할수있어초기진단과치료에도움이될것이다. 아직많은검사실에서자동혈구계산기로검사가가능함에도망상적혈구지수에대한보고가이루어지지않고있다. 하지만많은연구에서망상적혈구지수에대한유용성이보고되고있으므로, 망상적혈구지수에대한참고치를설정하여결과보고하는것이환자의빠른진단과치료에도움이되겠다. 요약 배경 : 철결핍성빈혈은가장흔한빈혈이며만성질환빈혈은철결핍성빈혈다음으로흔하다. 망상적혈구혈색소량이포함된망상적혈구지수는철결핍성빈혈을진단하는데유용한지표로사용된다. 우리는소구성저색소성빈혈을가지는환자를두군으로나누어적혈구와망상적혈구지수를측정하여 IDA와 ACD의감별진단에사용할수있는지를보았다. 방법 : 소구성저색소성빈혈환자 85명을선택하였다. 그중 38명은철결핍성빈혈군, 47명은만성질환빈혈군이었다. 철결핍성빈혈군은페리틴 6 μg/dl 이하, 총철결합능 450 μg/dl 이상인반면, 만성질환빈혈군은기저질환을가지면서 6 μg/dl 이상, 총철결합능 450 μg/ dl 이하로정의하였다. 우리는 CBC, 총철결합능, 혈청철, 적혈구지수와망상적혈구지수를측정하였다. 각각의환자군을비교하여평균값을구하였고, 철결핍성빈혈과만성질환빈혈을감별할수있는민감도와특이도를 ROC 곡선에따라구하였다. 결과 : 만성질환빈혈군에서적혈구와망상적혈구지수중평균적혈구용적, 평균적혈구혈색소, MCHC, CHCM, CH, RDW, 망상적혈구혈색소량, CHm이의미있게증가하였고, 이지표들은페리틴과총 철결합능에높은상관관계를보였다. 망상적혈구혈색소량을 24.6 pg 이상으로할때철결핍성빈혈로부터만성질환빈혈의진단율은 85.1% 의민감도와 81.6% 의특이도를보였다. 결론 : 망상적혈구지수는소구성저색소성빈혈의감별진단에유용하다. 망상적혈구지수중망상적혈구혈색소량과적혈구지수중 CH는높은민감도와특이도를보였다. 참고문헌 1. De Benoist B, McLean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993 2005, WHO global database on anemia. Geneva: World Health Organization 2008;21. 2. Worwood M. The laboratory assessment of iron status--an update. Clin Chim Acta 1997;259:3-23. 3. Thomas C and Thomas L. Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem 2002;48: 1066-76. 4. Shin S, Chang JY, Kim JS, Roh EY, Yoon JH. Iron deficiency and hemoglobin content of RBC in infants. Korean J Lab Med 2005;25:14-9. 5. Brugnara C, Zelmanovic D, Sorette M, Ballas SK, Platt O. Reticulocyte hemoglobin: an integrated parameter for evaluation of erythropoietic activity. Am J Clin Pathol 1997;108:133-42. 6. Mast AE, Blinder MA, Dietzen DJ. Reticulocyte hemoglobin content. Am J Hematol 2008;83:307-10. 7. Riley RS, Ben-Ezra JM, Tidwell A, Romagnoli G. Reticulocyte analysis by flow cytometry and other techniques. Hematol Oncol Clin North Am 2002;16:373-420. 8. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician 2007;75:671-8. 9. Zuckerman K. Approach to the anemias. In: Cecil RL, Goldman L, Ausiello DA. Cecil textbook of medicine. 22nd ed. Philadelphia, Pa: Saunders, 2004:969. 10. Cavill I, Auerbach M, Bailie GR, Barrett-Lee P, Beguin Y, Kaltwasser P, et al. Iron and the anaemia of chronic disease: a review and strategic recommendations. Curr Med Res Opin 2006;22:731-7. 11. Weiss G and Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011-23. 12. Weiss G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev 2002;16:87-96. 13. Mast AE, Blinder MA, Lu Q, Flax S, Dietzen DJ. Clinical utility of the reticulocyte hemoglobin content in the diagnosis of iron deficiency. Blood 2002;99:1489-91. www.labmedonline.org 151
14. Ceylan C, Miskioğlu M, Colak H, Kiliççioğlu B, Ozdemir E. Evaluation of reticulocyte parameters in iron deficiency, vitamin B(12) deficiency and β-thalassemia minor patients. Int J Lab Hematol 2007;29:327-34. 15. Luo D, Chen Y, Wu W, Zhang F, Xu J, Cui W, et al. Reticulocyte hemoglobin content in the diagnosis of iron deficiency in Chinese pre-menopausal women. Chin Med J 2007;120:1010-2. 16. Bakr AF and Sarette G. Measurement of reticulocyte hemoglobin content to diagnose iron deficiency in Saudi children. Eur J Pediatr 2006; 165:442-5. 17. Kim JM, Ihm CH, Kim HJ. Evaluation of reticulocyte haemoglobin content as marker of iron deficiency and predictor of response to intravenous iron in haemodialysis patients. Int J Lab Hematol 2008;30: 46-52. 18. Seo Y, Jung HL, Shim JW, Kim DS, Shim JY, Park MS. Clinical significance of immature reticulocyte fraction and reticulocyte cellular indices in pediatric anemia patients. Korean J Pediatr 2005;48:284-91. 19. Shin S, Kim JE, Yoon JH. Reference intervals of reticulocyte parameters using ADVIA 120. Korean J Lab Med 2003;23:6-11. 20. d Onofrio G, Chirillo R, Zini G, Caenaro G, Tommasi M, Micciulli G. Simultaneous measurement of reticulocyte and red blood cell indices in healthy subjects and patients with microcytic and macrocytic anemia. Blood 1995;85:818-23. 152 www.labmedonline.org