THE$IRON$STATUS$AMONG$A$COHORT$OF$ PEDIATRIC$PATIENTS$WITH$SICKLE$CELL$ DISEASE$

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1 THE$IRON$STATUS$AMONG$A$COHORT$OF$ PEDIATRIC$PATIENTS$WITH$SICKLE$CELL$ DISEASE$ HortenseHUBINONT 18/02/2016

2 Ironstatus:sicklecelldiseasecontext Redcellturnover Transfusions Hepcidindecrease?)! Anaemia! Tissuehypoxia! Erythropoiesis s9mula9on Inadequateironintake Excessiveurinarylossof iron Increasedreleaseof hepcidin?)! Chronicinflamma9on «func9onaldeficiency»! Renalinsufficiency

3 Serummarkersofironburden Inflamma9on " Ferri9n Independently$of$ Iron$stores$ # iron,transferrin andtransferrinsatura9on) Func9onal$deficiency

4 Aimsofthestudy 1) Prevalenceofirondeficiency 2) anditsimpactonanaemia

5 Methods 200pa9entswithSCD 5 18years FollowedatHUDERF Excluded: Z Hematopoie9cstemcell transplanta9on24)$ Z LosttofollowZup6)$ N=170$:Analysisinsteady'state' Demographicdata,clinicaldata, biologicaldata,transcranialdoppler USandMRIresults,treatments)

6 Analyseddataon170SCDpa9ents

7 Descrip9onoftheSCDpopula9onN=170) Demographic,$clinical$and$therapeu9c$ data$$n$=$170)$ Ageyears) Number$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$%$$ Median*''''''''''''''''''''''''''''''''''''''Range)*' 10*'''''''''''''''''''''''''''''''''''''''''''''''''''3'3'17)*' Girls/Boys 90/8053%/47% GenotypeSS/Sβ % G6PDdeficiency % BMIkg/m 2 ) FollowZup9meyears) 16,74*''''''''''''''''''''''''''''''''''''13.2'3'35.3)*' 7*''''''''''''''''''''''''''''''''''''''''''''''''''''1'3'17)*' VOC % ACS % Stroke 105.8% Hydroxyurea % Chronictransfusions %

8 Descrip9onofourSCDpopula9onN=170) Biological$data$N$=$170)$ Median$range)$ $N$pa9ents$%)$ Normal$values$ Hbvaluesg/dL)forage 163anaemicpa9ents96%) g/dL MCVvaluesfL)forage 40microcy9cpa9ents23%) 83normocy9cpa9ents49%) 47macrocy9cpa9ents28%) 77 95fL Plateletsx10 3 /μl) Z1654) x10 3 /μl Whitecellcountx10 3 /μl) Z23.9) 5 13x10 3 /μl Neutrophilsx10 3 /μl) Z19) 2 8x10 3 /μl Re9culocytesx10 3 /μl) Z661) 155regenera9ve91%) x10 9 /L HbF%) 140.2Z44) <1.5%oftotaleHb TotalBilirubinmg/dl) Z8.5) mg/dl LDHUI/L) Z898) UI/L GOTUI/L) 3315Z121) 15Z40UI/L Ferri9nμg/l) 1098Z1980) 15Z300μg/L Ironμg/dl) 8330Z208) μg/dl Transferrinmg/dl) Z365) mg/dL Transferrinsatura9on%) 266Z58) 15 50% );20 55 ) 9

Methods 200pa9entswithSCD 5 18years FollowedatHUDERF Excluded: Z Hematopoie9cstemcell transplanta9on24)$ Z LosttofollowZup6)$ N=170$:Analysisinsteady'state' Demographicdata,clinicaldata,

9 Methods 200pa9entswithSCD 5 18years FollowedatHUDERF Excluded: Z Hematopoie9cstemcell transplanta9on24)$ Z LosttofollowZup6)$ N=170$:Analysisinsteady'state' Demographicdata,clinicaldata, biologicaldata,transcranialdoppler USandMRIresults,treatments) 24«ironZdeficiency» N$=$13$ Iron<50μg/dL<12yr) Iron<50μg/dL >12yr) Iron<65μg/dL >12yr) N$=$12$ Transferrinsatura9on <15% ) <20% ) N$=$2$ Ferri9n<15μg/L N$=$8$ Ferri9n<30μg/L Nelson textbook of pediatrics, 20th edition

10 Which parameter is the most reliable to estimate iron deficiency?

11 Themostreliableparametertodefineirondeficiency Z Z Z Z Z MCV:dependsonHUintakesandonthepresenceofathalassemictrait Serumiron:diurnalvaria9ons Transferrinsatura9on:notspecificenough SerumtransferrinreceptorsandsTfR/logferri9nindex): elevatedstfrlevelsreflectincreasederythropoie9cdriveratherthanirondeficiency inscd Ferri9n:isthemostreliableparametertodefineirondeficiency,butwehaveto adjustthecutzoffvaluetotheinflammatorycontext.

12 2studiesaimtodefineaferri9nleveladjustedtotheSCD contextfordiagnosisofid Autors$ Vichinskyet'al.' 1981 Raoet'al Ferri9n$levels$ µg/l)$ <25 <30 The$way$used$ to$diagnose$ the$id$ Responseto irontherapy Bonemarrow aspira9on N$pa9ents$ presen9ng$id$ 74%) 85%)

13 Inourstudy,wedefinedthe irondeficiencybyferri9n<30 μg/l $Prevalenceofiron deficiency=5% 14

14 Ferri9n μg/l' Characteris9csoftheironZdeficientpa9entsn=8 Iron μg/dl' TfSat %' Hb g/dl'' MCV fl' Re9c. Count X10 3 /μl GenoZ type Treat ment Age Yr.' F=0 G= ,8 HbSS HU,T 14 1 Clinical complica9ons 12VOC,5 ACS,1silent infarct , ,7 HbSS T 15 1 AVC , ,5 HbSC HU VOC,2ACS , ,2 HbSB VOC , HbSS VOC,2ACS ,9 HbSS VOC , ,6 HbSC VOC,1ACS , HbSS The iron-deficient patients are anaemic and most of them are microcytic. 1/3 have low reticulocyte count. No patients between 7 and 12 years old are iron-deficient. The ratio / = of them received chronic transfusions

15 Characteris9csoftheironZdeficientpa9entsn=8 Ferri9n iron TfSat ΔHb Δ MCV Re9c. count GenoZ type Treat ment Age F=0 G= Z4 Z14 191,8 HbSS HU,T 14 1 Clinical complica9ons 12VOC,5 ACS,1silent infarct Z6,4 Z7 85,7 HbSS T 15 1 AVC Z2, ,5 HbSC HU VOC,2ACS Z2,4 Z18 134,2 HbSB VOC Z5,1 Z HbSS VOC,2ACS Z6 Z4 534,9 HbSS VOC Z1,7 Z15 86,6 HbSC VOC,1ACS Z0,8 Z13 62 HbSS The iron-deficient patients are anaemic and most of them are microcytic. 1/3 have low reticulocyte count. No patients between 7 and 12 years old are iron-deficient. The ratio / = of them received chronic transfusions

16 Doestheironstatusvarywith Genotype? Gender? Age? NumberofVOC? 17

17 HbSS/Sβ 0 grouppresentsmoreclinicalcomplica9onsandare moreotenontreatmentintensifica9on GENOTYPE N = 170) HbSS and S 0 groups n = 141) Median range) N %)* Hb S + and SC groups n = 29) Median range) N %)* P-value Demographic data - - > 0,05 Clinical data Treatments VOC/patient ACS/patient Serious infection Stroke Silent infarct Hydroxyurea Chronic transfusions ) ) 0 0-4) 10 7%)* 45 33%)* %)* 24 17%)* 1 0-5) 0 0-4) 0 0-1) 0 0%)* 3 11%)* 6 21%)* 0 0%)* < 0,001 0,03 0,325 0,214 0,021 < 0,001 0,016

18 HbSS/Sβ 0 pa9entsaremoreanaemic,serumferri9nlevelarehigher, andhemolysisismorepronouncedthaninhbsβ + /SCpa9ents GENOTYPE N = 170) HbSS/S 0 group n = 141) Median range) N %)* Hb S +/SC group n = 29) Median range) N %)* P-value Biological data Ferritin μg/l) iron μg/dl) Transferrin mg/dl) Transferrin saturation %) Hb g/dl) MCV fl) HbF %) Reticulocytes x10 3 /μl) Bilirubin mg/dl) LDH UI/L) ) ) ) ) 8, ) ) ) ) 1, ) ) ) ) ) ) 11, ) ) 6,7 1-38) ) 0, ) ) <0,001 0,023 0,035 0,03 <0,001 <0,001 0,01 <0,001 <0,001 <0,001

19 BoyspresentmorestrokeandG6PDdeficiency GENDER SS/SBO population, N = 141) Girls n = 73) Median range) N %)* Boys n = 68) Median range) N %)* P-value Demographic data Age, BMI,f ollow-up time G6PD deficiency %) %) > 0,05 < 0,001 Clinical data VOC/patient ACS/patient Serious infection Stroke Silent infarct ) 1 0-7) 0 0-1) 2 2.7%)* 25 35%)* ) ) 0 0-4) %)* 20 31%)* 0,438 0,164 0,148 0,049 0,716 Treatments Hydroxyurea Chronic transfusions 56 77%)* 8 11%)* 50 74%)* 16 24%)* 0,7 0,071

20 Ironmarkersdonotvarywithgenderexceptserum iron GENDER SS/SBO population) N = 141 Girls n = 73) Median range) N %)* Boys n = 68) Median range) N %)* P-value Biological data Ferritin μg/l) iron μg/dl) Transferrin mg/dl) Transferrin saturation %) Hb g/dl) MCV fl) HbF %) Reticulocytes x10 3 /μl) Bilirubin mg/dl) LDH UI/L) ) ) ) ) 8, ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) 0,114 0,003 0,495 0,153 0,566 0,324 0,062 0,24 0,309 0,176

21 Ironmarkersdonotvarywithage AGE SS/SBO population) N = 141 Demographic data Clinical data 5 10 years n = 67) Median range) N %)* years n = 74) Median range) N %)* P-value Sex, G6PD deficiency - - > 0,05 VOC/patient ACS/patient Stroke Silent infarct ) 0 0-4) %)* %)* ) ) 3 4.1%)* %)* 0,001 <0,001 0,192 0,151 Treatments Hydroxyurea Chronic transfusions 45 67%)* 8 12%)* 61 82%)* 16 22%)* 0,0504 0,178 Biological data Hemoglobin and hemolysis markers Ferritin μg/l) iron μg/dl) Transferrin mg/dl) Transferrin saturation %) ) ) ) ) ) ) ) ) > 0,05

22 The«VOC>1»grouppresentsahigherserumironlevelbut theotherironparametersarecomparable VOC SS/SBO population) N = 141 Demographic data Clinical data Treatments Biological data 0 or 1 VOC n = 54) Median range) N %)* VOC > 1 n = 87) Median range) N %)* P-value Age, follow-up time ), ) ), ) < 0,05 Serious infection Stroke Silent infarct Hydroxyurea Chronic transfusions Ferritin μg/l) iron μg/dl) Transferrin mg/dl) Transferrin saturation %) Hb g/dl) MCV fl) 0 0-1) %)* 12 23%)* 33 61%)* %)* ) ) ) ) ) ) 0 0-4) 2 2.3%)* 33 39%)* 73 84%)* %)* ) ) ) ) ) ) 0,013 0,007 0,061 0,003 0,818 0,228 0,029 0,6 0,178 0,013 0,009

23 Irondeficiency:prevalenceintheliverature Worldwideprevalenceofirondeficiencyforchildrenaged between5and14yearsoldoms,2008):25,4% PrevalenceofirondeficiencyforSCD$pa9ents<li]erature): 0à25% OurprevalenceofirondeficiencyforSCDis5%

24 PrevalenceofirondeficiencyinSCD:widevariability Americancountries USA N=104 Stevleretal.2001 USA N=51 Lullaetal.2010 Brazil N=135 Rodriguesetal.2011 Jamaica Kingetal.2005 *Dependingonage' Genotype Age$ years) Biological$criteria$of$iron$ deficiency HbSS 0,5Z18 MCV<70Z78fl* Iron<50mcg/dL Tfsatura9on<20% Ferri9n<4 12ng/ml HbSS, HbSβ0,HbSC 1Z6 Ferri9n<25ng/mlor, Tfsatura9on<16%or, MCV<70 73fl* HbSS,HbSC 0Z2 MCV<70florMCH<23pg +ferri9n<10ng/mlor Tfsatura9on<12% HbSS,HbSC 1Z5 Tfsatura9on<16% Iron<10,7micromole/L andmcv$ Prevalence$of$iron$ deficiency 11% 10% 12% 0% 21% 17,8% 8,5%

25 PrevalenceofirondeficiencyinSCD:widevariability Africancountries Nigeria$ N=97 Akoduetal.2013 Yemen$ N=102 Saqladietal.2012 Senegal$ N=40 LopezZSalletal.2004 *'Depending'on'age'' Genotype Age years) Biologicalcriteriaofiron deficiency HbSS 0Z5 Hb$<11g/dl MCV<70fl Tf$satura9on$<16% Ferri9n<25ng/ml Model1=Hb+MCV+ferri9n Model2=Hb+MCV+Tfsat Model3=Hb+Tfsat+ferri9n HbSS 0Z16 Ferri9n<30ng/mlifCRP<10mg/l Ferri9n<70ng/mlifCRP>10mg/l HbSS 3Z18 MCV<73Z77fl* MCH<24Z27pg* Rs`Tf$>3,4mcg/l IndexRsZTf>2 Prevalenceof irondeficiency 0% 3,1% 0% 25% 20%

26 PrevalenceofirondeficiencyinSCD:widevariability Africancountries Nigeria$ N=103 Akinbamietal.2013 Yemen$ N=75 Kassimetal.2012 Genotype HbSS Age years) Mean 23Z25 Biologicalcriteriaofiron deficiency Ferri9n<15ng/ml 7,76% HbSS 1Z30 Iron,$Tf$satura9on,$transferrin,$ MCV Prevalenceof irondeficiency 13,3%

27 Couldirondeficiencyworsenthe anaemiaofscdpa9ents?

28 IDpa9entsvscontrolgroup IronZdeficientpopula9on Controlpopula9on Ferri9n$$ Δ$Hb$1)$ Δ$MCV$ Ferri9n$ Δ$Hb$2)$ Δ$MCV$ Hb2$ $Hb1$ μg/l g/dl fl μg/l g/dl fl g/dl 24 Z4 Z14 32 Z5 Z19 Z1 8 Z6.4 Z7 38 Z6.3 Z Z Z2.3 Z Z2.4 Z18 59 Z2.3 Z Z5.1 Z10 41 Z4.3 Z Z6 Z4 53 Z5.9 Z Z1.7 Z15 49 Z2.2 Z16 Z Z0.8 Z13 Nodata MeanofΔHb=Z0.1g/dL Inthissmallcohort,noimpactofirondeficiencyon anaemiacouldbedemonstrated $Addi9onnalstudyusingironsupplementa9on Mean=Z0.1

29 ImpactofIDonanaemiainSCD:liverature Americanstudy:Lullaetal.,Pediatr'Blood'Cancer, SCDpa9entsbetween15monthsand6yearsofage Pa9entstreatedbychronictransfusionswereexcluded CriteriaofID:ferri9n<25ng/mlorTS<16%orMCV< yr);<732Z6yr)$11pa9entshadanID21%) IDpa9entsreceivedferrous$sulfate6mg/kg/day)for6weeks Allpa9entshadasignificantincreaseinTSbutno$significant$ increase$in$hb$andnosignificantincreaseinferri9n LullaRR,ThompsonAA,LiemRI.Elevatedsolubletransferrinreceptorlevelsreflectincreasederythropoie9cdriveratherthan irondeficiencyinpediatricsicklecelldisease.pediatr'blood'cancer.2010jul15;551):141 4.

30 Irondeficiency:disadvantagesversusbenefits Irondeple9onbenefits: Reduc9onofMCHmightreducethechanceofHbSpolymerisa9on diminishing'the'stechiometric'concentralon'of'hbs)' Mightimprovetherheologybecauseofareducedsizeoftheredcells Giordano'PC,'Huisman'W,'Harteveld'CL.'Iron'DepleLon:'An'AmelioraLng'Factor'for'Sickle'Cell'Disease?' ISRN'Hematol.'2011'Jul'5;2011:e ' Irondeple9ondisadvantages Mighthavenega9velongZtermconsequencesonneurocogni9ve developmentandgrowth Akodu'SO,'Kehinde'OA,'Diaku3Akinwumi'IN,'Njokanma'OF.'Iron'Deficiency'Anaemia'among'Pre3School' Children'with'Sickle'Cell'Anaemia:'SLll'a'Rare'Diagnosis?'Mediterr'J'Hematol'Infect'Dis'[Internet].'2013' Nov'7'[cited'2015'May'5];51).''

31 Conclusions Irondeficiencyisbeveres9matedbyferri9nleveladjustedfor theinflammatorycontext Inouroccidentalcontext,irondeficiencyinSCDpa9entsis uncommon5%) Themul9factorialoriginofanaemiainSCDpa9entsis probablynotaggravatedbyirondeficiency Anaddi9onalstudyusingironsupplementa9onwouldbe beneficialtoes9matetheimpactofirondeficiencyon anaemia

32 Thankyouforyouraven9on

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