foliumis mjavas deficitit gamowveuli anemia

foliumis mjavas deficitit gamowveuli anemia klinikuri praqtikis erovnuli rekomendacia (gaidlaini) 1

klinikuri praqtikis erovnuli rekomendacia (gaidlaini) `foliumis mjavas deficitit gamowveuli anemia~ mirebulia klinikuri praqtikis erovnuli rekomendaciebis (gaidlainebi) da daavadebata martvis saxelmwifo standartebis (protokolebi) SemuSavebis, Sefasebis da danergvis erovnuli sabwos 2008 wlis 5 noembris #1 sxdomaze da damtkicebulia saqartvelos Sromis, janmrtelobisa da socialuri dacvis ministris 2009 wlis 21 ianvris # 39/o brzanebit. 2

1. daavadebis definicia foliumis mjavas deficitit gamowveuli anemia megaloblastur anemiebs miekutvneba. patogenezit is vitamin B 12 -is deficitit ganpirobebul anemiebs hgavs. foliumis mjavas deficiti iwvevs nukleinis mjavebis sintezis darrvevas, rac yvelaze metad azianebs Zvlis tvins, irrveva normaluri eritropoezi da vitardeba megaloblasturi sisxlwarmoqmna (1). sinonimebi da terminologia _ foliumis mjavas deficiti, folat deficiti, vitaminebis deficiti, mikrocitozi, hipersegmentacia, megaloblasturi anemia. 2. epidemiologia daavadebis gamomwvevi mizezi umetes SemTxvevaSi aris arasrulfasovani foliumis mjavit Raribi kveba. foliumis mjavas deficiti xsiria indoetsi, CineTSi, malaiziasi, iq sadac sakvebad TiTqmis ar iyeneben xorcs, bostneuls ki didxans amusaveben Termulad. marali iyo avadoba kanadasi, amerikasi, evropis qveynebsi inglissi, SvedeTSi da a.s. XX saukunis bolodan am qveynebsi fortificirebuli produqtebis gamoyenebis Semdeg mnisvnelovnad Semcirda mosaxleobis avadoba da orsulta da axalsobilta patologiebi (2, 3, 4, 5, 6, 7, 8) [A]. Semcirda aseve gulsisxlzarrvta sistemis daavadebis ricxvic (9). daavadebis risk-jgufebs miekutvnebian bavsvebi ert wlamde, mozardebi, orsulebi, vinaidan mati motxovnileba foliumze ufro didia vidre sxva jgufebis. saqartvelosi daavadeba sakmaod gavrcelebulia, magram epidemiologiuri kvleva ar Catarebula da Sesabamisi monacemebi ar arsebobs. 3. etiopatogenezi foliumis mjava anu pteroilglutaminis mjava wyalsi xsnadi, Termolabiluri vitaminia, romelic aucilebelia sisxlwarmoqmnisa da nervuli sistemisatvis. adamiani mas Rebulobs mxolod sakvebit an mcire raodenobit nawlavis mikrofloris sintezirebis Sedegad. is Sedis rogorc mcenareul ise cxovelur produqtebsi (RviZli, xorci, soko, ispanaxi, mwvane salati, bardisebrta ojaxis mcenareebi, axali xili da bostneuli, safuari, rze). arsanisnavia, rom qalisa da Zroxis rze Seicavs folatebis daaxloebit Tanabar raodenobas (50 ng/g ), xolo Txis rzesi misi raodenoba 8-jer naklebia. foliumis mjava Termolabiluria, ris gamoc kulinariuli damusavebisas folatebis 50% isleba, amitom misi deficitis Tavidan asacilebad aucilebelia umi bostneulisa da xilis mireba. folatebis Sewova xdeba Tormetgoja nawlavisa da wvrili nawlavis proqsimalur nawilsi. I etapze sakvebsi arsebuli folatebi (poliglutamatebis) y-glutamatkarbopepdidazas (Seicavs nerwyvis, nawlavis sekreti, wvrili nawlavis lorwovani) moqmedebit isleba monoglutamatebad. II etapze fermenti dehidro-folatreduqtaza warmoqmnis 5-meTiltetrahidrofolats. am saxit igi xvdeba sisxlsi, sadac ukavsirdeba sxvadasxva cilebs (makroglobulini, albumini, transferini, specialuri cila-gadamtani) da miitaneba RviZlisa da Zvlis tvinis swrafad proliferirebad ujredebsi). folatebis transmembranuli transporti da ujredsi dagroveba xorcieldeba 3

vitamin B 12 -is daxmarebit (ujredsi metiltetrahidrofolati gardaiqmneba tetrahidrofoliumis mjavad, romelic transformirdeba poliglutamur tetrahidrofolatad). foliumis mjava (5,10 _ metiltetrahidrofoliumis mjavas saxit) monawileobs uridinfosfatidan Timidinfosfatis sintezsi, es ukanaskneli ki dnm-is sintezsi. misi deficitis dros irrveva am nukleinis mjavas sintezi sisxlmbad ujredebsi da vitardeba megaloblasturi anemia. foliumis mjavas ZiraTadi nawili deponirdeba RviZlSi, magram maragi Zalian mcirea da mxolod 4-5 Tves SeiZleba eyos organizms, Warbi xarjvis an arasakmarisi raodenobit mirebis SemTxvevaSi. foliumis mjavaze motxovnileba orive sqesis 19 welze meti asakis mozrdilebsi sasualod Seadgens 200mkg/dReSi. orsulobisas da laqtaciisas motxovnileba izrdeba (cxrili #1). foliumis mjavas moxmarebis sarekomendacio dozebi mkg/dresi cxrili 1. qalebi mamakacebi araorsulebi laqtaciis orsulebi (19+) periodi janmo 170 170 370-470 270 evropa 200 200 400 350 foliumis mjavas utilizacia damokidebulia kvebis xasiatze, mis damusavebaze. sintezuri foliumis mjava uketesad SeiTviseba, vidre sakvebit mirebuli (10). orsulebma unda miiron 600mkg, mezuzurebma 500mkg, danarcenebma 400mkg. sakvebit mirebuli f.m. 1mkg sasualod udris folatis 0,6mkg. mecnieruli gamokvlevebit (11, 12) damtkicda, rom adamianebis umetesoba imaze nakleb foliums moixmars vidre mas esawiroeba [A]. amis gamo me-20 saukunis bolodan bevr qveyanasi mirebul iqna kanoni sakvebi produqtebis aucilebeli fortifikaciis Sesaxeb. foliumis mjavas deficitit gamowveuli anemiis (Harrison) ganvitarebis mizezebi I. sakvebit arasakmarisi raodenobit mireba: arasrulfasovani kveba (qronikuli alkoholizmit daavadebulebi, mozardebi, Cvilebi) II. gazrdili motxovnileba: a) orsuloba; b) Cvilebi; g) avtvisebiani daavadebebi; d) gazlierebuli eritropoezi; e) eqsfoliaturi eritrodermia; 4

III. IV. v) hemodializi. Sewovis darrvea: a) spru b) celiakia g) samkurnalo sasualebebi: fenitoini, barbituratebi. foliumis mjavas metabolizmis darrveva: a) dihidrofolatreduqtazis inhibitorebi: metotreqsati, pirimetamini, pentamidini da sxva. alkoholi dihidrofolatreduqtazis da sxva fermentebis naklovaneba (isviatad). sakvebit arasakmarisi mireba: foliumis mjavas deficitit gamowveuli anemiis xsiri mizezia folatebis arasakmarisi mireba, gamowveuli am vitaminis Semcveli produqtebis (bostneuli, xili, xorci da sxva) sakvebis racionsi SemcirebiT an sakvebis araswori kulinariuli damusaveba; Cvili bavsvis Txis rzit kveba an iseti sakvebi produqtebit, romlebic ar Seicaven, an mcire raodenobit Seicaven folatebs; sakvebi racionidan xili, bostneulis da xorcis amoreba; qronikuli alkoholizmit daavadebulebi (arasrulfasovani kveba). gazrdili motxovnileba (13, 14, 15, 16, 17): orsulebi; Cvilebi, xsiria bavsvebsi gansakutrebit 1 wlamde; mozrdilebsi intensiuri zrdis processi, sqesobrivi momwifebisas. foliumis mjava xmardeba spermatogenezs, qalis sqesobriv momwifebas (57); qronikuli antebiti daavadebebi; qronikuli hemolizuri anemiebi; simsivnuri daavadebebi, mat Soris leikozebi; eqsfoliaturi eritrodermia. Sewovis darrveva (18, 19, 20) _ nawlavebsi foliumis mjavas Sewovis darrveva SeiZleba gamowveuli iyos igive mizezebit, rac vitamin B 12 deficituri anemiis dros: nawlavis rezeqcia, gansakutrebit wvrilis; enzimodeficituri enteropatiebi; 5

malabsorbciis sindromi, sxvadasxva genezis (enteritis, eqsudaciuri hipoproteinemiuli enteropatia, nawlavis amiloidozi) kronis daavadeba da sxva; wvrili nawlavis simsivneebi. foliumis mjavas metabolizmis darrveva. _ sxvadasxva preparatebis mirebam SeiZleba gamoiwvios foliumis mjavas deficitit gamowveuli anemia. preapratebis moqmedeba gansxvavebulia: foliumis mjavas Sewovisa da gamoyenebis darrveva SeiZleba gamoiwvios cikloserinma (antibiotiki, romelic gamoiyeneba tuberkulozis da sasarde organoebis infeqciebis dros). kruncxvis sawinaarmdego preparatebma (heqsamidini, fenobarbitali da sxva); metforminma (II tipis Saqriani diabetis samkurnalo preparati (21, 22) [A]. ferment dihidrofolatreduqtazas datrgunvas iwvevs pentamidini, kotrimoqsazoli, (antiinfeqciuri preparatebi), metotreqsati (citostatiuri preparatebi), triamtereni (kalium SemanarCunebeli diuretiki) ( 23, 24, 25, 26, 27); pirimidinebis sintezis darrveva arinisneba citostatikit 5- ftoruracili; ferment ribonukleotidreduqtazas datrgunvas iwveven citostatikebi citarabini, hidroqsikarbamidi), romlebic fartod gamoiyeneba hematologiasi. alkoholi xels uslis folatebis Sewovas wvril nawlavsi, amitom qronikuli alkoholizmi SeiZleba gaxdes foliumis mjavas deficitis mizezi (28). dihidrofolatreduqtazas, forminotransferazisa da sxa fermentebis Tandayolili deficiti iwvevs folatebis Sewovisa da metabolizmis darrvevas. 4. klinikuri simptomatika a) simptomebis CamonaTvali foliumis mjavas mwvave deficiti SeiZleba ganvitardes foliumis mjavas antagonistebis mirebis Semdeg. mas axasiatebs madis dakargva, tkivili muclis aresi, gulisreva, diarea, wylulebi piris RruSi, saylapavsi, kanis dazianeba da Tmis cvena. foliumis mjavas qronikuli ukmarisobis gamovlineba aris: zogadi Civilebi _ saerto sisuste, advilad darla, depresia, motentiloba, wylulebi enaze da piris RruSi. kani iqterulia, xsiria kuwis sekrecis daqveiteba. vitamin B 12 deficitisagan gansxvavebit foliumis mjavas deficits ar axasiatebs nevrologiuri simptomatika paresteziebi, kidurebze WianWvelebis cocvis SegrZneba, qvemo kidurebis mgrznobelobis dakargva da sxva (29). orsulebs SeiZleba ganuvitardet gulisreva, Rebineba, anoreqsia. b) gartulebebi: 6

megaloblasturi anemia; leikopenia; Trombocitopenia; angularuli stomatiti; glositi; diarea; gulisreva da Rebineba; temperaturuli reaqcia; naadrevi msobiaroba; nayofis defeqtebi, gansakutrebit nervuli sistemis mxriv; bavsvebis simarlesi zrdis Seferxeba; sqesobrivi momwifebis Seferxeba; depresia. 5. daavadebis diagnozi a) diagnostikuri kriteriumebi _ simptomebi: avadmyofebs arenisnebat araspecifiuri anemiuri sindromistvis damaxasiatebeli Civilebi _ saerto sisuste, Sromis unaris daqveiteba, Tavbrusxveva, diarea, glositi, enaze wylulebi. foliumis MmJavas deficitit gamowveuli anemiis diagnostikuri kriteriumebi: 1. sisxlis saerto analizi: hiperqromuli anemia, eritrocitebis makrocitozi, neitrofilebis hipersegmentacia, retikulocitopenia; 2. leikocitebi _ leikopenia, neitrofilebis hipersegmentacia; 3. mielograma _ megaloblastozi, neitrofilebis hipersegmentacia; 4. glositis da atrofiuli gastritis ararseboba; 5. funikulari mielozis ararseboba; 6. sisxlsi vitamin B 12 normaluri Semcveloba; 7. sisxlis SratSi da eritrocitebsi foliumis mjavas raodenobis Semcireba; 8. Sardis metilmalonis mjavis normaluri sekrecia; 9. SesaZlebelia arapirdapiri bilirubinis raodenobis momateba (eritrocitebis hemolizis Sedegad). b. diferencialuri diagnozi: diferencialuri diagnozi unda gatardes im patologiebtan, romlebic xasiatdebian megaloblasturi sisxlwarmoqmnit: vitamin B 12 deficituri anemia; 7

mwvave eritromielozi; mielodisplaziuri sindromi. foliumis mjavas deficitit gamowveuli anemiis klinikuri surati isetivea, rogorc vitamin B 12 deficituri anemiis, magram ar axlavs nevrologiuri patologia. amave dros qronikuli alkoholizmit daavadebulebs, rogorc wesi arenisnebat alkoholuri polineiropatia, rac SeiZleba gaxdes mcdari diagnozis mizezi. am ori patologiis diferencialur diagnostikuri kriteriumebi warmodgenilia qvemot (cxrili #2) foliumis mjavas deficitit gamowveuli anemiis da vitamin B 12 deficituri anemiis diferencialur-diagnostikuri kriteriumebi nisnebi vitamin B 12 deficituri anemia gastreqtomia anamnezsi xsiria ara cxrili 2 foliumis mjavas deficitit gamowveuli anemia avadmyofta asaki xsiria moxucebsi xsiria axalgazrdebsi atrofiuli hunteris glositi damaxasiatebelia Aar axasiatebs atrofiuli gastriti aqiliit da kuwsi pepsinis donis SemcirebiT damaxasiatebelia Aar axasiatebs funikularuli mielozi damaxasiatebelia Aar axasiatebs vitamin B 12 zemoqmedeba retikulocitebis raodenobaze foliumis mjavas Semcveloba sisxlis SratSi da eritrocitebsi vitamin B 12 raodenoba sisxlsi metilmalonuri mjavas gamoyofa SardiT mnisvnelovnad zrdis sisxlis SratSi momatebulia, eritrocitebi umnisvnelod daqveitebulia an normaluria mnisvnelovnad daqveitebulia mnisvnelovnad gazrdilia ar moqmedebs daqveitebulia normaluria normaluria diferencialuri diagnozi ZiriTadad unda gatardes foliumis mjavas deficitit gamowveul anemiebsa da vitamin B 12 deficitur anemias Soris. samwuxarod xsir SemTxvevaSi foliumis mjavisa da vitamin B 12 gansazrvra ver xerxdeba. amitom unda gamoviyenot sxva sadiagnostiko nisnebi. 8

klinikur praqtikasi ufro xsiria vitamin B 12 deficituri anemia, vidre foliumis mjavas deficitit gamowveuli anemia. vitamin B 12 -is danisvnidan 1 kvirasi unda ganvitardes retikulocituri krizi, winaarmed SemTxvevaSi unda vifiqrot foliumis mjavas deficitis gamomwvev anemiaze. vitamin B 12 deficituri anemiis dros mxolod foliumis mjavas danisvna iwvevs avadmyofis mdgomareobis gauaresebas. amitom gaurkveveli megaloblasturi anemiis SemTxvevaSi, rodesac ar aris sasualeba Cataredes diagnozis dazustebisatvis sawiro gamokvlevebi, mkurnaloba unda daiwyos vitamin B 12. Tu ar dadasturda vitamin B 12 da foliumis mjavas deficitit gamowveuli anemiis diagnozi unda gamoiricxos mielodisplaziuri sindromi. ukanasknelis diagnostika sawiroebs rtul gamokvlevebs specializirebul hematologiur klinikasi. mat Soris citogenetikur da citoqimiur gamokvlevebs, imunofenotipirebas. 6. gamokvlevis sqema 1. sisxlis saerto analizi: eritrocitebis raodenoba da morfologia, hemoglobini, feradobis macvenebeli, retikulocitebis raodenoba, leikocitebi, Trombocitebi, leikocituri formula, edsi; 2. Zvlis tvinis morfologia; 3. sisxlis bioqimuri analizi: bilirubinis gansazrvra, cila da cilis fraqciebi; 4. sisxlsi vitamin B 12 da foliumis mjavas gansazrvra (Tu SesaZlebelia); 5. Sardis saerto analizi. yvela zemot CamoTvlili gamokvleva unda Catardes pirvelive 24 saatsi. amis Semdeg ki CamoTvlili gamokvlevebi: muclis Rrus organoebis: elentis, kuwqvesa jirkvlis, narvlis bustis, Tirkmlis eqoskopiuri gamokvleva; fibrogastroduodenoskopia; fibrokolonoskopia; ganavlis gamokvleva helmintebze. 7. mkurnalobis sqema foliumis mjava inisneba foliumis mjavas deficitit gamowveuli anemiis dros 5-15 mg dozit eritrocitebis raodenobis normalizaciamde. vitamin B 12 deficituri anemiis dros mxolod foliumis mjavas danisvnam SeiZleba gamoiwvios avadmyofis mdgomareobis gauareseba. im SemTxvevaSi, rodesac ar aris dazustebuli diagnozi, rastan gvaqvs saqme vitamin B 12 deficitur anemiastan Tu foliumis mjavas deficitit gamowveul anemiastan, unda dainisnos, rogorc foliumis mjava 15mg, aseve vitamin B 12, eritrocitebis raodenobis normalizaciamde. eritrocituli masis gadasxma unda Catardes mxolod sasicocxlo CvenebiT. 9

gansakutrebuli yuradreba unda mieqces orsulobisa da laqtaciis periodsi foliumis mjavas gamoyenebas. foliumis mjavas profilaqtikurma gamoyenebam orsulobis periodsi mnisvnelovnad Seamcira axalsobilta Soris spinabifida-s ricxvi. Amaze miutitebs 2007w. CDC-is monacemebi (30, 31, 32, 33, 34) [A]. dadgenilia, rom orsulebsi foliumis mjavas profilaqtikuri kursis gamoyeneba amcirebs bavsvebsi aseve mwvave limfoblasturi leikemiebis ganvitarebis risks (35, 36) [B]. foliumis mjavas didi roli eniweba simsivnuri daavadebebis profilaqtikasi. amaze miutitebs mravalricxovani gamokvlevebi. orsulobisa da laqtaciis periodsi mkurnaloba da profilaqtika reproduqciuli asakis qalebma unda miiron foliumis mjavit mdidari produqtebi; yvela qalma, romelic gegmavs orsulobas unda miiros foliumis mjava 0,4mg dresi, orsulobis 12 kviramde; qalebma, romlebmac wina orsulobidan gaacines bavsvebi nervuli sistemis patologiit, unda miiron foliumis mjava 4mg dresi, orsulobis 12 kviramde (37) [A]; foliumis preparatebs upiratesoba eniwebat polivitaminebtan SedarebiT. 8. reabilitacia da metvalyureoba riskis jgufebi, romlebic sawiroeben metvalyureobas da profilaqtikur kursebs: alimenturi deficitis mqone pirebi; moxucebi arasrulfasovani kvebit (38) [B]; kuw-nawlavis patologiis mqone pirebi _ atrofiuli gastritis, malabsorbciis sindromi, kronis daavadeba, kibo, leikemiebi; kanis daavadebebit, eqsfoliaciuri dermatitit daavadebulni; orsulebi, mezuzurebi; avadmyofebi, romlebic didi xnis ganmavlobasi Rebuloben kibos, antebis, epilefsiis sawinaarmdego preparatebs (antibiotikebi, tuberkulozis, diabetis, kruncxvis, Casaxvis sawinaarmdego sasualebebi, sulfanilamidebi, citostatiuri preparatebi da a.s.); avadmyofebs, gansakutrebit zemocamotvlili mizezebit unda miecet rceva foliumis mjavit mdidari produqtebis da mati swori kulinariuli damusavebis Sesaxeb: produqtebi, romlebic didi raodenobit Seicaven foliumis mjavas: Tirkmelebi, zogierti bostneuli (kombosto, yvavilovani kombosto, 10

salatis fotlebi), Txili, kvercxi, banani, fortoxali, safuari, foliumit fortificirebuli puri, burruleuli; foliumis mjava 95% durilis dros isleba; fotlovan produqtebsi otaxis temperaturaze 3 dris ganmavlobasi Senaxvis Sedegad isleba foliumis mjavis 70%. foliumis mjavit purisa da sxva produqtebis fortificirebam mnisvnelovnad Seamcira foliumis mjavis deficitit gamowveuli anemiis ricxvi, orsulobisa da msobiarobis gartulebebi, nervuli sistemis patologiebi axalsobilebsi. aseti Sedegebi mirebulia XX saukunis meore naxevridan. ass-si, kanadasi, inglissi (39, 40, 41, 42) [A] fortifikaciam kargi Sedegi gamoiro gulis koronaluri patologiis SemcirebaSi. 9. gaidlainis gadasinjvisa da ganxilvis vada 2 weli 10. gaidlainis mirebis xerxi/wyaro gaidlainis SemuSavebis metodologia: mocemuli gaidlainis Seqmnis processi samusao jgufis mier moziebul da Sefasebul iqna ukve arsebuli praqtikuli rekomedaciebi. SemuSavda arsebuli rekomendaciebis adaptirebuli varianti, romelic ertis mxriv pasuxobs saertasoriso motxovnebs, xolo meores mxriv itvaliswinebs saqartvelos samedicino dawesebulebata, rogorc adamianur, ise materialur-teqnikur resursebs. klinikuri rekomendaciebis diagnostikisa da mkurnalobis Tanamedrove metodebi, epidemiologiuri monacemebi moziebul iqna eleqtronul bibliografiul bazasi (Medline), (EMBASE). agretve Google, Yahoo, Ramblet, Doctor Guide, Yandex saziebo operatorebis mesveobit da kohreinis bibliotekis bazasi (The Cohrane Library 2006). mocemuli gaidlainis SemuSavebisas gamoyenebul iqna mxolod mtkicebulebiti medicines monacemebi, mtkicebulebis donis gatvaliswinebit. avtorta jgufis mier moziebul iqna 700-mde statia, referati da gaidlaini, romelta analizis Sedegad gamoyofil iqna wyaro. arnisnuli wyaroebi safuzvlad daedo klinikuri rekomendaciis Seqmnas. M 11

mtkicebulebis done da rekomendaciebis xarisxi done mtkicebulebis sizlieris done xarisxi rekomendaciebis xarisxi (Muir Gray) (Cook et al) eyrdnoba I donis mtkicebulebas da Sesabamisad mtkiced rekomendebulia I. Zlieri mtkicebuleba, eyrdnoba minimum ert mimoxilvas, romelic efuzneba swori dizainis mqone randomizebul kontrolirebad kvlevas A II Zlieri mtkicebuleba, eyrdnoba minimum erti swori dizainis mqone randomizebul kontrolirebad kvlevas B eyrdnoba I donis mtkicebulebas da Sesabamisad rekomendebulia III klinikuri kvleva randomizaciis garese, kohortuli da SemTxveva-kontrolis kvlevebi C eyrdnoba III donis mtkicebulebas. SeiZleba CaiTvalos Sesabamisad 11. alternatiuli gaidlaini ar arsebobs 12. gamoyenebuli literatura 1. Zittoun J. Anemias due to disorder of folate, vitamin B 12 and transcobalamin metabolism, La Revue du praticien 1993 43 (II): 1358-63; 2. Pietrzik RF, Thorand B. Folate economy in prednancy Nutrition 1997 13 (11-12):975-7; 3. Lumley J, Watson L, Vatson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neurol tube defects (Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford Update Soft ware; 4. FSA. Board recommends mandatory fortification 17 May 2007; 5. Backing for folic acid in bread Retrieved on 2007-05-18; 6. BBC Experts back folic acid in flour 11 May 2007; 7. Daly S. Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Wier DG, Scott JM. Minimum effective dose of folic acid food fortification to prevent neural-tube defects Lanced 1997, 350 (9092): 1666-9; 8. Crandell BF. Corson VL, Evans MI, Coldberd JD, Knight G, Salafsky IS. American College of Medical Genetics statement on folic acid fortification and supplementation. American Journal of Medical Genetics 1998 74(4):381; 9. Malinow MR, Duell PB, Hess DL et al, Reduction of plasma homocysteine levels by breakfast cereal fortified with folic acid in patients with coronary feart desease New England Journal of Medicine 1998, 338 (15): 1009-15; 10. Suitor CW. Bailey LB. Dietary folate equivalents: interpretation and application. Journal of the American Dietic Association 100(1): 88-94, 2000; 11. Raiten DS. Fisher KD Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III 1988-1984) The Jurnal of Nutrition 1995 125(5): 1371S 1398 S; 12. Mahan LK, Escott S. Stump, eds krause s Food. Nutrition and Diet Therapy 2004 11 th ed, pp. 366-67; 12

13. Stolzenberg R. Possible folate deficiency with postsurgical infection Nutrition in Clinical Practice 1994 9(6):247-50; 14. Kelly GS. Folates: Supplemental forms and therapeutic applications Altern med 1998 3(3):208-20; 15. Oakley GP, Adams MJ, Dickinson CM More Folic acid for everyone, now. Journal of Nutrition 1996 126 (3): 751 S 755 S; 16. McNulty H Folate requirements for health in different population groups, British Journal of Biomedical Science 1995 52(2): 110-9; 17. Swedish Nutrition Recommendations 2005; 18. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DS, Fuchs C, Rosner BA, Speizer EE, Willett WC. Multivitamin use, folate and colon cancer in women in the Nurses Health Study Annals of International Medicine 1998 (7): 517-524; 19. Christersen B. Folate deficiency, cancer and congenital abnormalities is there a connection? Tidsskrift for den Norske Laegeforening 1996 116(2):250-4; 20. Freudenheim JL. Grahm S, Marshall JR, Haughey BP, Cholewinski S, Wilkinson G. Folate intake and carcinogenesis of the colon and rectum International Journal of Epidemiology 1991 20 (2): 368-378; 21. Bazzano La, He J, Ogden LG et al. Dictary intake of folate and risk of stroke in US men and women. NHANES Epidemiological Follon-up Study. National Health and Nutrition Examination Survey. Stoke 2002; 33(5): 1183-1188; 22. Sato Y. Honda Y. Iwamoto J. et al. Effect of folate and metcobalamin on hip fractures in patients with stroke: a randomized controlled trial. Jama 2005. 293(9):1082-1088; 23. Shiroky JB The use of folates concomitantly with low-dose pulse methotrexate. Rheumatic Disease Clinics of North America 1997 23 (4): 969-80; 24. Kepka L. De Lassence A, Ribray V, Gachot B, Blot F. Theodore C, Bonnay M, Korenbaum C, Nitenberg G, Successful rescue in a patient with high dose methotrexate _ induced nephrotoxicity and acute Fenal Failure. Leukemia and Lymphoma 1998 29 (1-2); 205-9; 25. Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS. Effect of glutamine on methotrexate efficacy and taxicity. Annals of Surgery 1998 227 (5):772-8; 26. Keshava C, Keshava N, Whong WZ, Nath J. Ong TM Inhibition of methotrexsate- induced chromosomal damaje by folinic acid in 79 cells. Mutation Research 1998 397 (2):221-8; 27. Kamen B: Folate and antifolate pharmacology Seminars in oncology 1997, 24 ( 5 Suppl 18): S 18-30-S 18-39; 28. Mayo Clinic news release Folate Intake Counteracts Breast Cancer Risk Associated with Alcohol Consumption 2001-01-26; 29. Haslarm N. Probert C. An audit of the investigation and treatment of folic acid deficiency. Journal of the Royal Society of Medicine 1998, 91 (2): 72-3; 30. Centers for Disease Control and Prevention (CDC) (2004). Spina bifida and anencephaly before and after folic acid mandate _ United States, 1995-1996 and 1999-2000 Morbedity and Mortality Report 2004 53 (17) : 362-5; 31. Milunsky A, Jick H, Jisk SS, Bruell CL, Maclaughlin D, Rothmam KS, Willett W. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects Journal of the American Medical Association 1989 262 (20):2847-2852; 32. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurence of neural tube defects. Journal of the American Medical Associotion 1988 260 (21-3141-45); 33. Lewis CJ. Crane NT, Wibson DB, Yetley EA Estimated folate in takes: data updated to reflect food fortification, in creased bioavailability, and dietary supplement USE. The American Journal of Clinical Nutrition 1999 70 (2): 198-207; 34. Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA Periconceptional vitamin use, dietaryfolate, and the occurrence of neural tube defects. Epidemiology 1995 6(3):219-226; 13

35. Thomson JR, et al. Matemal folate Supplementation in pregnancy and protection against acute lymphoblastic Leukemia in childhood: a case control study. The Lancet, vol 358. Dec. 8, 2001, pp 1935-40; 36. Jennigs E Folic acid as a can cer preventing agent Medical Hypothesis 1995 45(3):297-303; 37. Goh Yi, Bollano E, Einarson Tr. G. Prenatal multivitamin supplementation and rates of congenital anomalies. A Meta-Analysis J. Obstet Ginecology Canada 2006; 28(8): 680-689; 38. CLarke R. Refsum H. Birks J. et al Screeneng for vitamin B 12 and folate deficiency in older persons Am. J. Clin Nutr 2003:1241-1247; 39. Kenneth F Trofatter, Jr Faleing Folic Acid Levels Portend Problems. Pregnancy and childbirth Nov. 1, 2007; 40. Raiten DJ, Fisher KD (1995). Assesement of folate methodology usid in the third National Health and Nutrition Ezamination Su rvey (NHANES III, 1988-1994). The Journal of Nutrition 125 (5): 13715-13985; 41. Mills JL. Von Kohorn I, Conley MR, Zeller JA, Coxc, Williamson RE, Dufour DR. Low vitamin B 12 concentrations in patients without anemia: tthe effect of folic acid fortification of graiu. Am. J. Clin Nutr 2003 6 (77):1474-7; 42. Ray J. G. Folic acid food fortification in Canada. Nutrition Reviews 2004; 62(6):S35-S39. 13. avtorta jgufi saqartevlos hematologta da transfuziologta asocialcia nino lolasvili _ s.s hematologiisa da transfuziologiis samecniero kvleviti institutis wamyvani mecnier musaki, medicinis mecnierebata doqtori, sdasu sruli profesori; genadi iosava _ s.s hematologiisa da transfuziologiis samecniero kvleviti institutes sametvalyureo sabwos wevri, transfuziologiuri samsaxuris xelmzrvaneli. saqartvelos transfuziologta da hematologta asociaciis prezidenti, medicinis mecnierebata doqtori, Tssu sruli profesori; mamia zodelava _ saxelmwifo samedicino universitetis onkohematologiuri departamentis direqtori, sruli profesori; marina bogvelisvili _ s.s hematologiisa da transfuziologiis samecniero kvleviti institutis wamyvani mecnier musaki, medicinis mecnierebata doqtori, sruli profesori. eqspertebi: saojaxo medicinis profesionalta kavsiri _ irina qarosanize; saojaxo medicinis eqspertta jgufi, romelic aertianebs Tbilissa da sxva regionebsi moqmedi saojaxo medicinis saswavlo centris warmomadgenlebs m.s. praqtikos ojaxis eqimebs. saqartvelos hematologta da transfuziologta asociaciis 2007 wlis 5 noembris sxdomis daskvna; lela woworia _ saqartvelos Sromis, janmrtelobisa da socialuri dacvis saministros jandacvis departamenti; Tea TavidaSvili _ saqartvelos Sromis, janmrtelobisa da socialuri dacvis saministros jandacvis departamenti. 14