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Epidemiological, clinical and laboratory profile of glucose-6-phosphate dehydrogenase deficiency in the middle and north of Iraq: a comparative study M.D. Al-Mendalawi 1

ABSTRACT This study determined the epidemiological, clinical and laboratory profile of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Baghdad (central Iraq) and compared it with previous data from Mosul (northern Iraq). We reviewed the records of 156 under-5-year-olds with G6PD deficiency admitted to 3 hospitals in Baghdad over a 6-year period. A preponderance of males was noted in both Baghdad and Mosul (1.6:1 and 3.4:1 respectively). Family history of G6PD deficiency was positive in 19.2% of patients in Baghdad and 13.6% in Mosul. A majority of patients in Baghdad (69.2%) and Mosul (76.1%) showed haemolysis within 13 days of exposure to noxious agents. Similarities in the profiles from Baghdad and Mosul suggest that there are similar G6PD variants and similar exposure to precipitating agents.

1Department of Paediatrics, Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq (Correspondence to M.D. Al-Mendalawi: mdalmendalawi@yahoo.com).

Received: 21/01/09; accepted: 19/02/09

: 6-

) ( 6- : 5 156 .) ( . 6 3 6- %19.2 6- .)1:3.4( )1:1.6( )%76.1( )%69.2( . %13.6 . 3-1

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tude comparative du profil pidmiologique, clinique et biologique du dficit en glucose-6-phosphate dshydrognase au nord et au centre de lIraq

RSUM La prsente tude a permis de dterminer le profil pidmiologique, clinique et biologique de la carence en glucose-6-phosphate dshydrognase (G6PD) Bagdad (centre de lIraq) et de le comparer avec des donnes antrieures recueillies Mossoul (nord de lIraq). Nous avons examin les dossiers de 156 enfants gs de moins de 5 ans qui prsentaient une carence en G6PD, hospitaliss dans trois hopitaux de Bagdad sur une priode de six ans. Une prpondrance masculine a t constate aussi bien Bagdad qu Mossoul (1,6 garon pour 1 fille et 3,4 garcons pour 1 fille respectivement). Des antcdents familiaux de cette maladie ont t observs chez 19,2 % des patients Bagdad et 13,6 % de ceux de Mossoul. Dans les deux villes, la majorit des patients prsentaient une hmolyse un trois jours aprs une exposition des agents nocifs (69,2 % Bagdad et 76,1 % Mossoul). Des analogies entre les profils de Bagdad et ceux de Mossoul laissent penser quil existe des variants similaires de la G6PD et une exposition semblable des facteurs dclenchants.

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Introduction

A functional deficiencyof glucose-6-phosphatedehydrogenase(G6PD)which oxidizes glucose-6-phosphateto 6-phosphogluconolactone in thepentosemonophosphate shuntwithformation of reduced nicotinamideadenine dinucleotide phosphate(NADPH)leadstooxidant-inducedred-bloodcelldestruction[1]. It is themost common enzymopathy in theworld and it hasbeenestimated thatmorethan200millionpeoplethrough-outtheworldareG6PDdeficient.Thisgeneticdefect showssex-linked inher-itance and a marked heterogeneity.Morethan300abnormalvariantswithdeficient biochemical characteristicsandabout100diversemutationshavebeen identified [2,3].Themost com-monclinical consequencesofG6PDdeficiency areneonatal jaundice andsporadichaemolytic crises causedbyinfections,certaindrugsor,intheMedi-terraneanvariant,by ingestionof fava beansorinhalationoftheirpollen[1,4].

The studyofG6PDdeficiency inIraqdatesback to1963[5]when thefirstpublishedstudytriggeredacascadeofresearchontheprobleminthecoun-try.Thepresent studyaimed todeter-mine theepidemiological, clinical andlaboratoryprofileofG6PDdeficiencyinBaghdadinthecentreofIraqandcom-pare itwithpreviouslypublisheddatafromMosulinthenorthofthecountry.Unfortunately, similarpublisheddatafromBasra,southofBaghdad,wasuna-vailableforcomparison.

Methods

Thestudywasconductedon156under5-year-oldswithdocumentedG6PDdeficiencybyG6PDenzymeessay.Datawerecollectedover theperiod1 Janu-ary2000 to31December2006 fromtherecordsofpatientsadmittedwithahaemolyticepisodetooneofthe3hos-pitals inBaghdadcity(Al-Khadimyiah

paediatrichospital,Al-KaramateachinghospitaldepartmentofpaediatricsandAl-Noor teachinghospitaldepartmentofpaediatrics).

Throughareviewofmedicalrecords,dataconcerningage,sex,clinicalpresen-tation,onsetofhaemolysis,pasthistoryofneonatal jaundice, familyhistoryofG6PD deficiency, laboratory resultsandfinaloutcomewereobtained.Theabovedatawerecomparedwith thosereportedpreviouslyinMosulcity[6].

Results

Outof 156patients recruited to thestudy,97(62.2%)weremales and59(37.8%)werefemales,amaletofemaleratio of 1.6:1.Themean agewas 2.8(standarddeviation1.2) years.Morethanhalf thepatients(58.3%)were intheagegroup14years.

The characteristics of the study patientsareshowninTable1.Pasthis-toryofneonatal jaundicewasrecordedin11.5%andapositivefamilyhistoryofG6PDdeficiency in19.2%.Recurrentepisodesofhaemolysis werereportedby10.9%ofpatients.Amajorityofpatients(69.2%)hadexperiencedhaemolyticepisodeswithin13daysofexposureto precipitating agents (usually fava beansandtoa lesserextentdrugssuchas trimethoprime-sulfamethoxazoleornalidixicacid.Clinically,symptomsandsignsofdarkcoloururineandpallorwereuniversalpresentingsymptoms(100%),whereasjaundicewasreportedin82.7%andhepatosplenomegaly in56.4%ofpatients.Half thepatients(52.6%)hadmoderateanaemia(57g/dL).

Reticulocyte count and totalwhite blood cell counts ranged from4.5% to19.6%and4.9 to25109/L respectively.The rangeof total serumbilirubin (mainly indirect type)was2.613.8mg/dL.Bloodureaandserumcreatininerangedfrom35to47mg/dLand0.7to1.1mg/dLrespectively.

All patients receivedblood trans-fusions in various amounts andwere

dischargedwithin24daysofhospitali-zation.Nodeathswererecorded.

Discussion

Iraq is situated within a region of ahigh frequency of G6PD deficiencygenotype,withacarrierfrequencyinthepopulationof6.3% [7]. Studying the pattern of G6PD deficiency in thepopulation isessential foranumberofreasons: the increasingcostsofhealthcareassociatedwithfrequenthospitali-zations[8];thesubstantialmorbidityintermsofpsychosocialburdenanddis-turbed familyenvironment forparentscopingwithchildrenwithchronic ill-ness [9]; and forplanningpreventivestrategies[10].

Apreponderanceofmaleswasnot-edinboththepresentstudyinBaghdadandthepreviousstudyinMosul(1.6:1and3.4:1respectively).Thepreponder-anceoffemalesnotedinsomestudiesinothercountriesintheEasternMediter-raneanRegionmaybeduetohighratesof consanguinity, leading to increasednumbers of homozygous females inadditiontoahighfrequencyofinactiva-tionof thenormalXchromosome infemaleheterozygotes,which leads todisturbances in theHardyWeinbergequilibrium.Moreover, thepresenceofan enhancedgene thatmakes theexpressionofG6PDdeficiencymorelikelyhasbeensuggested[11,12].

Apasthistoryofneonatal jaundicewasfoundinsimilarproportionsofchil-dren in this study inBaghdad(11.5%)and the previous study in Mosul(14.8%)[6].Severeneonatal jaundice,particularlywhen it requiresexchangetransfusion, shouldalertpaediatriciansto thepossibilityofG6PDdeficiency.Currently,mosthospitalsroutinelytestforG6PDwhen screening neonatesbeforetheyaredischargedfromhospi-tal[13].

Apositive familyhistoryofG6PDdeficiencywasreportedatahigherrateintheBaghdad(19.2%)thaninMosul

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(13.6%).Thismaybeduetotheobser-vation thatmanypatients are asymp-tomatic andunaware they areG6PDdeficientunlesstheyareinvestigatedorexposedtoanoxidizingagent.

Amajorityofpatients inBaghdad(69.2%)andMosul (76.1%) showedhaemolysiswithin13daysofexposuretoprecipitatingagents.Thisissimilartowhathasbeenreportedelsewhere[1416]. Recurrent haemolytic episodes

were recorded ina slightly lowerper-centageofchildreninBaghdad(10.9%)andMosul (9.1%).Preventionof fur-therattacksneedsawarenessofpatientsand their families to theneed toavoidexposuretooxidativestress.

Darkcoloururine,pallor, jaundiceandhepatosplenomegalywerethelead-ingclinicalpresentationsinbothareasofIraq.Thisobservationisconsistentwithprevious studies [1416].When liver

function isnormal, jaundice typicallydoesnotoccuruntilmorethan50%oferythrocytes have been haemolysed[17].Thesizeofthespleenandliverinbothstudiesvariedfromjustpalpableto34cmbelowthecostalmargin.

Feverwasdocumentedin37.8%ofthepatientsintheBaghdadstudycom-paredwith44.3% in theMosul study.Many individuals develop fever aftertheonsetof infectionssuchasurinary

Table 1 Epidemiological, clinical and laboratory variables of the studied children with glucose-6-phosphate dehydrogenase (G6PD) deficiency in Baghdad and Mosul

Variable Baghdad studya (n = 156) Mosul studyb (n = 88)

No. % No. %

Sex

Male 97 62.2 68 77.3

Female 59 37.8 20 22.7

Male:female (ratio ) 1.6:1 3.4:1

Clinical history

Positive past history of neonatal jaundice 18 11.5 13 14.8

Positive family history of G6PD deficiency 30 19.2 12 13.6

Recurrent attacks of haemolysis 17 10.9 8 9.1

Onset of haemolysis

Few hours 10 6.4 4 4.5

13 days 108 69.2 67 76.1

47 days 38 24.4 17 19.3

Clinical presentation

Dark colour urine 156 100.0 88 100.0

Pallor 156 100.0 88 100.0

Jaundice 129 82.7 69 78.4

Hepatosplenomegaly 88 56.4 55 62.5

Fever 59 37.8 39 44.3

Abdominal pain 33 21.1 14 15.9

Haematological tests

Haemoglobin (g/dL)

< 5 42 26.9 29 32.9

57 82 52.6 39 44.3

79 32 20.5 20 22.7

Reticulocyte count (%) 4.519.6 3.025.0

White blood cell count (/L) 4.925.0 109 3.940.0 109

Biochemical tests

Total serum bilirubin (mainly indirect) (mg/ dL) 2.613.8 1.228.2

Blood urea (mg/dL) 3547 Normal

Serum creatinine (mg/dL) 0.71.1 Normal

Outcome

Recovery (days) 24 23

Mortality rate (%) 0 0

Sources: aPresent study; b[6].

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tract infection, enteric feverandchestinfections. The mechanism linkinginfection andhaemolysis is complexandpoorlyunderstood.Howeverithasbeen suggested thatduringphagocy-tosis leukocytesdamageerythrocytesin theirvicinitybydischargingreactiveoxygenspecies.Moreover,certaininfec-tiousorganisms, such asPlasmodium,Clostridium,Babesia and Bartonellaspp.,aredirectlytoxictoredbloodcells[18].Recently,itwasnotedthatamilddegreeofG6PDdeficiency(comparabletothehuman class IIIG6PDdeficiencies)worsenserythrocytedysfunctionduringsepsis.Increasederythrocyterigidityandatendencyforhaemolysis,togetherwithalterations in the interactionbetweenerythrocyteband3proteinandspectrin,maycontributetotheimmunomodula-toryeffectofG6PDdeficiencyobservedaftermajortraumaandinfectioninhu-mans [19] .Unfortunately, screeningfor infectiousdiseaseswasnotdone ineitheroftheIraqistudies.

Variablegradesofanaemia, reticu-locytosisand leukocytosiswerenotedinbothstudies.Ahigher rateofmod-erate anaemia (57g/dL)was foundin Baghdad (52.6%) than inMosul(44.3%).Theoxidizedanddenaturatedhaemoglobinformscross-linksandpre-cipitatesintracellularly,formingred-cellinclusionbodies that are identifiedasHeinzbodiesonsupravital stainingofperipheralblood smears.These inclu-sionbodiesare removed in thespleen,leavingerythrocyteswithamissingsec-tionofcytoplasm.Thesebitecellscanbeseenintheroutinebloodsmear[1].

Althoughhyperbilirubinaemia,par-ticularlyof theunconjugated type, isthemaincriterion for thediagnosisofhaemolyticanaemia, it ismildandself-limitingwhen liver function isnormal[1].IntheBaghdadandMosulstudies,variablegradesofhyperbilirubinaemiaparticularly the indirect typewereseen(2.613.8mg/dLand1.228.2mg/dL respectively).Thehigher rangeofserumbilirubinintheMosulstudymaybeattributed to thepreponderanceofcasesofsevereneonataljaundiceneces-sitatingultimatelyphototherapyand/orexchangetransfusion.

Renal function was preserved inpatients in the Baghdad andMosulstudies,asmanifestedbynearlynormalbloodureaandserumcreatininelevels.Azotaemiacancomplicatesevereintra-vascularhaemolysisandoliguria.There-fore,therapymustfocusonmaintainingahighurineoutput.

Allpatients inbothstudiesshoweduneventfulrecoverywithin24daysofhospitalizationafter receivingvariousdegreesofbloodtransfusion.Nodeathswere reported ineither study.Deathsreportedduringacutehaemolyticepi-sodesareattributed tosevereanaemiacausingcongestiveheartfailure,oliguricrenal shutdown,malaria andhepaticencephalopathy[2023].

The epidemiological , c l inicaland laboratory picture ofG6PDde-ficiency was very similar in patientsfromBaghdadandMosulcities. Ithasbeenobservedthatinareaswithahighoccurrence of red blood cell genetic

abnormalities, suchas sickle-cellgene,G6PDand-and-thalassaemias,vari-ousgenesfrequentlycoexistinthesamepopulation.Coinheritanceof2ormoreabnormalgenes in thesame individualis frequentlyencountered,particularlyincertain closed tribes inwhichcon-sanguineousmarriages are thenorm.Suchgenetic interactionsmodify theclinicalpresentationofthediseasestate[24,25].

Inconclusion,thesimilarepidemio-logical, clinical and laboratoryprofileofG6PDdeficiency in themiddleandnorthofIraqsuggestgeneticsimilaritiesin theG6PDvariants and similar ex-posure toprecipitatingagents.Studiesin theotherpartsof the countrypar-ticularly the southwould further elu-cidate thepictureofG6PDdeficiencyinIraq,andanationalsurveyisneededto address theexactbiochemical andepidemiologicalvariantsofG6PDde-ficiency.Furtherstudieswouldalsobeuseful todeterminepossible interac-tions between various abnormal redblood cell genotypesnotablyG6PD,thalassaemiaandsicklecellhaplotypes.EducationalprogrammesareneededtoincreasepublicawarenessaboutG6PDdeficiency.

Acknowledgements

Greatthanksareduetotheadministra-torsoftheaforementionedhospitalsinBaghdad for theirkindhelp inaccom-plishingthestudy.

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Genomic Resource Centre

TheWorldHealthOrganization(WHO)isoneofseveralinternationalorganizationswhichhaveexpressedconcernabout

thewideningknowledgeandtechnologygapbetweenthemoredevelopedandlessdevelopedcountries,whichcouldlead

totheneglectofthehealthneedsoflow-incomenations.WHOisthereforeworkingtobuildinternationalnetworksthat

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TheHumanGeneticsProgrammehascreatedacomprehensiveInternet-basedresourceongenomics.TheGRCsprimary

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isthefirstwebsiteofitskinddedicatedtoprovidingreliableinformationongenomicsandhealthtodevelopingcountries.

ThemissionoftheGRCistoenhancethetransferofgenomicinformation,toencourageglobalnetworks,tofoster

informeddialogue,andtoimprovehealthservicesingenetics,especiallyinlowtomiddleincomecountries.

Furtherinformationonthisresourceisavailableat:http://www.who.int/genomics/en/

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