Paediatrica Indonesiana

VOLUME 49 July ‡ NUMBER 4

Original Article

Impact of iron therapy on Mentzer index and red cell distribution width index in primary school children with iron deficiency

Budi Andri Ferdian, Nelly Rosdiana, Bidasari Lubis

Abstract utritional anemia is commonly found in Background Iron deficiency anemia (IDA) remains a common GHYHORSLQJFRXQWULHVLQWKH\HDU QXWULWLRQDOSUREOHPHVSHFLDOO\LQVFKRRODJHFKLOGUHQ'XHWR RIWKHFXUUHQWZRUOGSRSXODWLRQ the many examinations that are needed to be performed and the VXIIHUHGIURPLURQGHILFLHQF\DQG invasive gold standard procedure, an easy and simple alternative N examination to diagnose IDA is needed. of world population was anemic, with more than Objective To determine the impact of iron therapy on Mentzer half of these people having iron deficiency anemia and red cell distribution width (RDW) indexes of children with (IDA).Iron deficiency may also cause impairments IDA. in a child’s growth and development, as well as Methods A randomized open clinical trial was conducted in primary school aged children in North Aek Nabara, between decreased immunity and a lack of concentration  1RYHPEHUDQG1RYHPEHU,'$ZDVGHWHUPLQHGEDVHG during learning. There is no single test to diagnose on WHO criteria. Subjects with severe anemia were excluded. iron deficiency with or without anemia. The gold Subjects were randomly assigned to groups that received either standard for identifying iron deficiency is bone iron therapy or a placebo. marrow biopsy stained with Prussian blue. However, Results7KUHHKXQGUHGVXEMHFWVIURPDJHGWR\HDUVROG ZHUHUHFUXLWHGDQGVXEMHFWVFRPSOHWHGWKHVWXG\7KHPHDQ the procedure is invasive so that indirect assays RDW index of the iron and placebo groups after three months are generally used. There are two types of test. REVHUYDWLRQZHUH 6' DQG 6'  +HPDWRORJLFWHVWVDUHEDVHGRQUHGEORRGFHOO 5%&  respectively. The mean Mentzer index mean for the iron therapy features, while biochemical tests are based on markers DQGSODFHERJURXSVDIWHUWKUHHPRQWKVREVHUYDWLRQZHUH 6' DQG 6' UHVSHFWLYHO\ Conclusion After therapy, there are no significant differences in either the Mentzer or RDW indexes between the therapy and placebo groups. [Paediatr Indones. 2009;49:195-9]. Presented at the Workshop & Symposia: New Trend in Pediatrics Problem -DQXDU\0HGDQ,QGRQHVLD Keywords: anemia, iron supplementation, RDW, Mentzer )URPWKH'HSDUWPHQWRI&KLOG+HDOWK0HGLFDO6FKRRO8QLYHUVLW\RI North Sumatera, H. Adam Malik Hospital, Medan, Indonesia.

Reprint request to%XGL$QGUL)HUGLDQ0''HSDUWPHQWRI&KLOG Health, Medical School, University of North Sumatera, H. Adam Malik +RVSLWDO-O%XQJD/DXQR0HGDQ,QGRQHVLD7HO )D[(PDLO[email protected].

Paediatr Indones, Vol. 49, No. 4, July 2009‡195 Budi Andri Ferdian et al: Impact of iron therapy on Mentzer index and red cell distribution width index of iron metabolism e.g. zinc protoporphyrin (ZPP), FRQFHQWUDWLRQRIKHPRJORELQRIOHVVWKDQJGOIRU and serum ferritin concentration. Hematologic tests children aged 6 – 14 years. Iron deficiency anemia is are more widely available and less expensive than GLDJQRVHGLIKHPRJORELQFRQFHQWUDWLRQLV JGO biochemical tests.5,6 0&9 I/5':!0HQW]HULQGH[! Another method to diagnose IDA is to start iron DQG5':LQGH[! WKHUDS\WKLVLVHDV\SUDFWLFDOVHQVLWLYHDQGFRVW All subjects were randomly assigned to either HIIHFWLYHHVSHFLDOO\LQKLJKULVNFKLOGUHQZLWK,'$ receive iron therapy or placebo. Iron was given daily Iron preparation is given at a dose of 6 mg/kg body as capsule containing 5 mg elemental salt iron per ZHLJKW$IWHUWRZHHNVDQLQFUHDVHRIPRUHWKDQ kg body weight The placebo, was also given daily in PJGOLQKHPRJORELQOHYHOFRQILUPVWKHGLDJQRVLV the same form as the iron capsule. Both therapy and of IDA.However, the clinician is often confronted placebo were given until the 4th month of the study. with microcytic anemia in populations with a higher Blood examinations were done at three different time prevalence of thalassemia.6 To distinguish between SRLQWVDWWKHVWDUWRIWKHVWXG\ 'HFHPEHU RQ iron deficiency from minor thalassemia, the Mentzer WKHthGD\ 0DUFK DQGLQWKHth month of LQGH[ 0&95%& DQG5':LQGH[ 0&95%& VWXG\ 1RYHPEHU $OOEORRGVSHFLPHQVZHUH x RDW) can be used. Mentzer index of at least analyzed for concentration, , LQGLFDWHV,'$ZKLOHDQLQGH[RIOHVVWKDQLV erythrocyte count, indicative for thalassemia. Similarly, a RDW index of 0&9 PHDQFRUSXVFXODUKHPRJORELQ 0&+  DWOHDVWLVLQGLFDWLYHIRU,'$ZKHUHDVDQLQGH[RI mean corpuscular hemoglobin concentration OHVVWKDQLVLQGLFDWLYHIRUWKDODVVHPLD5,6 Previous 0&+& UHGEORRGFHOOGLVWULEXWLRQZLGWK 5':  studies in Indonesia only examined the relationship Mentzer index, and distribution width between erythrocyte index and RDW index to index (RDW Index). Blood samples were measured confirm the diagnosis of IDA. We investigated the using a photometry procedure using an autoanalyzer use of Mentzer and RDW indexes for the diagnosis $%;Œ0LNURV)UDQFH  of IDA. 7KHVWXG\GDWDZHUHSURFHVVHGXVLQJ6366ŒIRU :LQGRZVY 6366,QF&KLFDJR ,QGHSHQGHQW WWHVRU:LOFR[RQ6LJQUDQNVWHVWZDVXVHGWRDQDO\]H Methods the data. The results were considered to be significant LI3 7KLVVWXG\ZDVDSSURYHGE\WKH(WKLFDO This randomized open trial was conducted over 5HYLHZ&RPPLWWHHRI0HGLFDO)DFXOW\8QLYHUVLW\RI PRQWKVIURP1RYHPEHUWR1RYHPEHU North Sumatra, Medan, Indonesia. 7KHVWXG\SRSXODWLRQZDVFKRVHQIURP local primary school children from the PTPN III Plantations in Aek Nabara, Kecamatan Bilah Results Hulu, Labuhan Batu District, North Sumatera Province, Indonesia. 3UHOLPLQDU\VFUHHQLQJRISULPDU\VFKRROFKLOGUHQ :HLQFOXGHGSULPDU\VFKRRODJHFKLOGUHQ DJH \LHOGHGFKLOGUHQZLWK,'$DQGIXOILOOHGWKH \HDUVROG ZKRVXIIHUHGIURP,'$ZKR agreed eligibility criteria. These subjects were randomized to follow the study until completion, and provided XVLQJEORFNUDQGRPL]DWLRQUHVXOWLQJLQVXEMHFWV written informed consent from their parents. We LQWUHDWPHQWJURXSDQGLQSODFHERJURXS$WWKH excluded children who suffered from severe anemia, beginning of our study, we determined that there severe infection, both with or without malnutrition. were no significant differences between the iron %RG\ZHLJKWDQGKHLJKWZHUHPHDVXUHGZLWK0,&Œ therapy and placebo groups with respect to sex, age, ERG\VFDOH DFFXUDWHWRNJIRUZHLJKWDQGFP body weight, height, and hemoglobin concentration for height). and other blood parameters (Table 1). During the %ORRGVDPSOHVFRQVLVWLQJRIDSSUR[LPDWHO\ study period, two subjects in the iron therapy group ml of peripheral capillary blood was taken from the were lost to follow up, therefore the study was fingers. We used WHO criteria for anemia, i.e. the FRPSOHWHGZLWKVXEMHFWV

196‡Paediatr Indones, Vol. 49, No. 4, July 2009 Budi Andri Ferdian et al: Impact of iron therapy on Mentzer index and red cell distribution width index

$IWHUGD\VRIWKHUDS\WKHKHPRJORELQ Discussion FRQFHQWUDWLRQKHPDWRFULW0&+DQG0&+&LQ the iron therapy group increased, and there was 2XWRIVXEMHFWVZKRZHUHLQLWLDOO\UHYLHZHG also a slight decrease in the value of RDW index.   ZHUHIRXQGWRKDYH,'$DQGZHUH A similar trend also occurred in the placebo group UHFUXLWHG2IWKHVHVXEMHFWVFRPSOHWHGWKLV (Table 2). study. This study used simple techniques to confirm ,URQWKHUDS\ZDVFRQWLQXHGXQWLOGD\V6HYHQ the diagnosis of IDA i.e. hemoglobin concentration, months after the end of therapy, the hematological 0&95':0HQW]HULQGH[DQG5':LQGH[7KH values of the subjects were measured again. The hemoglobin concentration and the hematocrit test KHPRJORELQFRQFHQWUDWLRQKHPDWRFULW0&+DQG were not the examination of choice due to poor 0&+&KDGDOOGHFUHDVHGZKLOHRWKHUYDULDEOHVVXFK sensitivity in detecting IDA. However, as hemoglobin as RDW, Mentzer and RDW indexes had increased. concentration and the hematocrit test are easy This trend was seen in both the iron therapy and the and accessible, they may be used as part of the placebo groups (Table 2). iron deficiency screening tests and can also help to determine the severity of the anemia.5,6 These tests are not specific for the diagnosis of IDA because the etiology of anemia is very broad.5,6,11 The best diagnosis, based on sensitivity and Table 1. Subject characteristics specificity, for IDA may be based on microcytic Characteristic Iron therapy Placebo K\SRFKURPLF5%&LQSHULSKHUDOEORRGVPHDULQ Age, mean (SD) mo 121.18 (17.88) 121.21 (15.49) FRQMXQFWLRQZLWKDIHUULWLQVHUXPYDOXHRI  Sex mcg/l. However, these are not a common test for IDA Male 22 27 as these are relatively expensive.5,15 Female 29 26 0&9FDQEH Body weight, mean (SD) kg 27.89 (6.11) 25.47 (5.49) used to determine whether the anemia is microcytic, Height, mean (SD) cm 130.0 (8.39) 127.0 (8.19) normocytic, or macrocytic. As RDW has a lower Hemoglobin, mean (SD) g/dl 10.32 (1.22) 10.09 (1.42) specificity, it can not be used as part of screening Hematocrit, mean (SD) % 32.26 (5.05) 31.41 (5.05) Erythrocyte, mean (SD) 106/μl 5.01 (3.80) 4.37 (0.7) WHVW\HWLWLVXVHGZLWK0&9WRGHWHUPLQHWKHW\SHRI /%8OGCP 5& ƀ 72.66 (2.77) 72.58 (4.10) DQHPLDIRUH[DPSOHLQFUHDVHG5':DQGGHFUHDVHG MCH, mean (SD) pg 23.40 (2.59) 23.29 (2.50) RI0&9LQGLFDWHVLURQGHILFLHQF\ MCHC, mean (SD) g/dl 31.93 (3.13) 32.32 (3.16) RDW, mean (SD) % 15.81 (2.11) 15.79 (2.12) Iron preparation therapy can be given through Mentzer index, mean (SD) 16.50 (3.02) 17.26 (4.63) either oral or parenteral route, although oral iron RDW index, mean (SD) 261.11 (64.06) 279.98 (121.13) preparations are easier to administer. The side effects

Table 2. Hematological variables between iron treatment and placebo groups at 90 days and 8 months after discontinuation of iron therapy After 90 days After the treatment stopped of treatment (8 months later) Variables Iron therapy Placebo Iron therapy Placebo P P n = 51 n = 53 n = 51 n = 53 Hb, mean (SD) g/dl 15.09 (7.03) 12.13 (1.18) 0.04 9.88 (1.76) 9.30 (1.90) 0.13 Ht, mean (SD) % 33.41 (2.93) 32.89 (3.23) 0.52 30.47 (5.05) 28.96 (4.99) 0.09 RBC, mean (SD) 106/ml 4.60 (0.40) 4.53 (0.48) 0.62 4.05 (0.67) 3.78 (0.74) 0.06 /%8OGCP 5& ƀ 73.35 (4.39) 72.64 (4.35) 0.71 76.03 (2.31) 77.39 (4.49) 0.06 MCH, mean (SD) pg 26.98 (1.64) 26.86 (2.26) 0.92 26.02 (3.32) 26.47 (4.62) 0.66 MCHC, mean (SD) g/dl 36.99 (1.48) 36.92 (1.68) 0.87 32.11 (2.28) 31.99 (2.95) 0.93 RDW, mean (SD) (%) 16.54 (2.32) 17.52 (2.75) 0.01 21.92 (1.24) 22.01 (1.43) 0.053 RDW index, mean (SD) 239.96 (39.25) 235.17 (31.77) 0.72 428.39 (108.52) 471.89 (119.81) 0.08 Mentzer index, mean (SD) 16.08 (1.98) 16.20 (2.27) 0.72 19.39 (3.97) 21.46 (5.66) 0.06

Paediatr Indones, Vol. 49, No. 4, July 2009‡197 Budi Andri Ferdian et al: Impact of iron therapy on Mentzer index and red cell distribution width index of oral iron preparation occur more in adults than diagnosis, it is recommended to check iron status and in children and those include nausea, abdominal KHPRJORELQHOHFWURSKRUHVLVH[DPLQDWLRQ%H\DQ et discomfort and diarrhea. Therefore, it is recommended alLQVKRZHGWKDWLQDGXOWVZLWKK\SRFKURPH to divide the administration into twice or three times microcytic anemia, it is recommended to continue daily.The oral iron preparation therapy is better the examination of iron status (e.g. ferritin serum, to be preserved in ferro form because it is easier iron serum, transferrin saturation), and hemoglobin to be absorbed and causes fewer side effects in the electrophoresis. gastrointestinal tract. The decrease in results of routine blood In our study, we provided capsules of ferrous examination at the end of observation must be sulfate for all subjects to make the administration noticed, and considered that IDA in Indonesia is easier and more attractive for the subjects and their related to poverty, malnutrition, and infection.15 parents. During the first three months, the iron In this study, the mean local community salary was preparation was given to the treatment group in ORZDWDERXW,'5SHUPRQWK GDWDZDV order to examine the recovery response. During that not published) and the malnutrition rate was still period, both iron therapy and placebo group had higher. improved results in hematologic profile, however, There are some limitations in our study. We did based on hemoglobin concentration and RDW, the not complete some important examinations such as iron therapy group showed more improvement than reticulocyte count, levels of ferritin and transferrin. the placebo group. The hemoglobin concentration in We also should have supervised the subjects’ WKHLURQWKHUDS\JURXSDQGSODFHERJURXSZDV compliance, and not leaving this to be carried out DQGUHVSHFWLYHO\DQGWKH5':UHVXOWZDV by parents and teachers. Furthermore, we did not DQGUHVSHFWLYHO\ Table 2). evaluate the factors that could inhibit iron absorption We did not find significant differences between such as parasite infection and consumption of food the Mentzer and RDW indexes of the iron therapy that affects iron levels. With those limitations and placebo groups. There are several possible in mind we conclude that iron therapy given to explanations for this including low compliance of \HDUROGFKLOGUHQZLWKLURQGHILFLHQF\DQHPLD subjects, parasite infection, lack of consumption of does not change Mentzer and RDW indexes when YLWDPLQ& ZKLFKFDQKHOSLURQDEVRUSWLRQ DQGWKH compared with placebo treated children with iron lack of consumption of animal protein. In addition, deficiency anemia. some foods that prevent iron absorption were probably still being consumed during this study (e.g. tea, coffee, egg yolk).11 This study did not find any side effects of Acknowledgments oral iron preparation. After eight months of observation, the blood This study was supported by PT. Perkebunan Nusantara III parameters returned to values similar to those at the (PTPN III). Our deepest gratitudes to PTPN III directors and Dr. start of the study. For example, in the iron therapy Hendi Suhendro, MSc (Manager of Aek Nabara Hospital). We JURXSWKHKHPRJORELQFRQFHQWUDWLRQZDV 6' also would like to thank the Head Office of Dinas Pendidikan &  JGODWWKHEHJLQQLQJRIWKHVWXG\DQG 6' Pengajaran Aek Nabara, school headmasters, teachers, parents,  JGODWWKHHQG6LPLODUO\LQWKHSODFHERJURXS and all children who participated in our study. WKHKHPRJORELQFRQFHQWUDWLRQZDV 6'  JGODWWKHEHJLQQLQJRIWKHVWXG\DQG 6'  g/dl at the end. References Demir et al,16LQFRQFOXGHGWKDWWKHUH LVQRKHPDWRORJ\H[DPLQDWLRQWKDWKDV  6WROW]IXV5-'HILQLQJLURQGHILFLHQF\DQHPLDLQSXEOLFKHDOWK VHQVLWLYLW\DQGVSHFLILFLW\EXWRIFRUUHFWHG WHUPVDWLPHIRU5HIOHFWLRQ-1XWU6 5%&FRXQWZLWK5': LQGH[LVWKHPRVWUHOLDEOH  'DOOPDQ351XWULWLRQDODQHPLD,Q5XGROSK$0+RIIPDQ examination to differentiate EWKDODVVHPLDIURP -,(5XGROSK&'HGLWRUV5XGROSK3HGLDWULFVWKHG iron anemia deficiency. However, for more accurate &RQQHFWLFXW$SSOHWRQ /DQJHS

198‡Paediatr Indones, Vol. 49, No. 4, July 2009 Budi Andri Ferdian et al: Impact of iron therapy on Mentzer index and red cell distribution width index

 5DVSDWL+5HQLDUWL/6XVDQDK6$QHPLDGHILVLHQVLEHVL  6FKZDUW](,URQGHILFLHQF\DQHPLD,Q%HKUPDQ5( In: Permono B, Sutaryo, Ugrasena IDG, Windiastuti E, Kligman RM, Arvin AM, editors. Nelson textbook of Abdulsalam M, editors. Buku ajar hematologi onkologi anak. SHGLDWULFVWKHG3KLODGHOSKLD6DXQGHUVS -DNDUWD%3,'$,S 16.  0F*UHJRU6*$QL&$UHYLHZRIVWXGLHVRQWKHHIIHFWRI 11. Dallman PR, Yip R, Oski FA. Iron deficiency and related iron deficiency on cognitive development in children. J Nutr. nutritional . In: Nathan DG, Oski FA, editors. 6² of infancy and childhood. 4th ed. Philadelphia:  :X$&/HVSHUDQFH/%HUQVWHLQ+6FUHHQLQJIRULURQ 6DXQGHUVS GHILFLHQF\3HG5HY  ,UZLQ--.LUFKQHU-7$QHPLDLQFKLOGUHQ$P)DP3K\VLFLDQ  6DQGRYDO&-D\DERVH6(GHQ$17UHQGVLQGLDJQRVLVDQG  management of iron deficiency during infancy and early  :LOO$0,URQPHWDEROLVPVLGHUREODVWLFDQHPLDDQGLURQ FKLOGKRRG+HPDWRO2QFRO&OLQ1$P overload. In: Lilleyman JS, Hann IM, Blanchette VS, editors.  $VLK58JUDVHQD,'*3HUPRQR%6RHSDUWR3.HJXQDDQ 3HGLDWULFKHPDWRORJ\QGHG/RQGRQ&KXUFKLOO/LYLQJVWRQH indeks eritrosit untuk diagnosis anemia defisiensi besi. In: S Abstract of Pertemuan Ilmiah Tahunan Ilmu Kesehatan 14. Iron Deficiency Anaemia. Assessment, Prevention and $QDN,,,NDWDQ'RNWHU$QDN,QGRQHVLD 3,7,.$,,,'$,  &RQWURO$JXLGHIRUSURJUDPPHPDQDJHUV1HZ

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