{"id":1793,"date":"2019-10-28T14:35:33","date_gmt":"2019-10-28T13:35:33","guid":{"rendered":"https:\/\/www.newslab.sk\/2019\/10\/28\/uloha-holotranskobalaminu-v-diferencialnej-diagnostike-nedostatku-b12\/"},"modified":"2019-11-04T14:04:45","modified_gmt":"2019-11-04T13:04:45","slug":"uloha-holotranskobalaminu-v-diferencialnej-diagnostike-nedostatku-b12","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/uloha-holotranskobalaminu-v-diferencialnej-diagnostike-nedostatku-b12\/","title":{"rendered":"Role of holotranscobalamin in differential diagnostics of the deficiency of vitamin B12"},"content":{"rendered":"<p><span style=\"color: #ff0000;\"><strong>*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/p>\n<p>&nbsp;<\/p>\n<h2><strong>\u00davod<\/strong><\/h2>\n<p>Kobalam\u00edn je nevyhnutn\u00fd pre transform\u00e1ciu metyltetrahydrofol\u00e1tu na tetrahydrofol\u00e1t, a t\u00fdm pre spr\u00e1vnu synt\u00e9zu deoxyribonukleovej kyseliny (DNA), tvorbu erytrocytov<br \/>\na spr\u00e1vnu funkciu nervov\u00e9ho syst\u00e9mu (predov\u0161etk\u00fdm tvorbu myel\u00ednov\u00fdch obalov). Nedostatok m\u00f4\u017ee vies\u0165 k \u0161irok\u00e9mu spektru hematologick\u00fdch, neurologick\u00fdch \u010di neuropsychiatrick\u00fdch<br \/>\nzmien, ktor\u00e9 s\u00fa v\u010dasnou diagnostikou a lie\u010dbou reverzibiln\u00e9. Kobalam\u00edn (cobalamin, Cbl) alebo vitam\u00edn B12 je jeden z vitam\u00ednov rozpustn\u00fdch vo vode, obsiahnut\u00fd hlavne v \u017eivo\u010d\u00ed\u0161nych produktoch. Denn\u00fd pr\u00edjem tvor\u00ed pribli\u017ene 3 \u2013 30 \u03bcg a potrebn\u00e9 denn\u00e9 mno\u017estvo 2 \u2013 4 \u03bcg. Zv\u00fd\u0161en\u00e1 spotreba je v obdob\u00ed rastu, tehotenstva, doj\u010denia a pri hojen\u00ed r\u00e1n(1). Kobalam\u00edn je syntetizovan\u00fd iba mikroorganizmami, rastliny a vy\u0161\u0161ie \u017eivo\u010d\u00edchy t\u00fato schopnos\u0165 nemaj\u00fa. Najv\u00e4\u010d\u0161\u00edm zdrojom Cbl s\u00fa bakt\u00e9rie v hrubom \u010dreve \u017eivo\u010d\u00edchov vr\u00e1tane \u010dloveka, kde sa v\u0161ak Cbl u\u017e nevstreb\u00e1va, aj ke\u010f denn\u00e1 produkcia by sta\u010dila na lie\u010dbu klinicky deficientn\u00fdch pacientov, ako to vo svojej \u0161t\u00fadii potvrdila Callenderov\u00e1. Deficit Cbl u veg\u00e1nov s klinick\u00fdmi prejavmi nedostatku vitam\u00ednu B12 nahradila vodn\u00fdm extraktom ich vlastnej stolice. Najviac Cbl obsahuj\u00fa \u017eivo\u010d\u00ed\u0161ne prote\u00edny. M\u00e4so z parench\u00fdmov\u00fdch org\u00e1nov je najbohat\u0161\u00edm zdrojom, \u010falej ryby, mlieko, mlie\u010dne produkty a vaje\u010dn\u00fd \u017e\u013atok. Cbl v potrave je odoln\u00fd proti vareniu pri vysokej teplote, ale \u013eahko konvertuje do inakt\u00edvnych anal\u00f3gov p\u00f4soben\u00edm kyseliny askorbovej. Cbl je v\u00fdnimo\u010dne dobre usklad\u0148ovan\u00fd v koenz\u00fdmovej forme v tkaniv\u00e1ch.<br \/>\nCelkov\u00e9 mno\u017estvo v tele je pribli\u017ene 2 \u2013 5 mg u dospel\u00fdch, z \u010doho asi 1 mg je v pe\u010deni(1,2). Peror\u00e1lne prijat\u00fd kobalam\u00edn sa vstreb\u00e1va z prijatej potravy ve\u013emi zlo\u017eit\u00fdm a \u013eahko naru\u0161ite\u013en\u00fdm mechanizmom, \u010do m\u00f4\u017ee by\u0165 zdrojom mnoh\u00fdch por\u00fach vstreb\u00e1vania. Kobalam\u00edn je v \u017eivo\u010d\u00ed\u0161nych bielkovin\u00e1ch viazan\u00fd peptidickou v\u00e4zbou, z ktorej je uvo\u013e\u0148ovan\u00fd v kyslom prostred\u00ed \u017eal\u00fadka kyselinou chlorovod\u00edkovou a proteolytick\u00fdmi enz\u00fdmami. Kysl\u00e9 prostredie je nevyhnutn\u00e9 pre tvorbu vn\u00fatorn\u00e9ho faktora (intrinsic factor, IF), bez ktor\u00e9ho doch\u00e1dza k neefekt\u00edvnej proteol\u00fdze,<br \/>\nodkia\u013e poch\u00e1dza deficit vitam\u00ednu B12 pri hypochl\u00f3rhydrii a pravidelnom u\u017e\u00edvan\u00ed inhib\u00edtorov prot\u00f3novej pumpy. Po uvo\u013enen\u00ed Cbl z peptidickej v\u00e4zby s\u00fa pre spr\u00e1vnu reabsorpciu Cbl potrebn\u00e9 v\u00e4zbov\u00e9 prote\u00edny:<br \/>\na) haptokor\u00edny (HC, k\u00f3dovan\u00e9 TCN1 g\u00e9nom), ktor\u00e9 maj\u00fa vysok\u00fa afinitu ku Cbl pri n\u00edzkom pH v \u017eal\u00fadku, okrem \u017eal\u00fado\u010dnej \u0161\u0165avy s\u00fa tie\u017e v slin\u00e1ch a \u010fal\u0161\u00edch telesn\u00fdch tekutin\u00e1ch a ich funkcia okrem v\u00e4zby Cbl je ochrann\u00e1 \u2013 pred denatur\u00e1ciou Cbl v \u017eal\u00fadku;<br \/>\nb) vn\u00fatorn\u00fd faktor \u2013 Cbl via\u017euci glykoprote\u00edn (k\u00f3dovan\u00fd g\u00e9nom GIF), produkovan\u00fd pariet\u00e1lnymi bunkami fundu \u017eal\u00fadka, ktor\u00fd m\u00e1 vysok\u00fa afinitu k Cbl pri vy\u0161\u0161om pH, v alkalickom prostred\u00ed v tenkom \u010dreve a duod\u00e9ne. IF via\u017ee len akt\u00edvnu formu kobalam\u00ednu \u2013 metylkobalam\u00edn, adenosylkobalam\u00edn, kyanokobalam\u00edn, akvakobalam\u00edn(3,4,5). Haptokor\u00edny maj\u00fa siln\u00fa v\u00e4zbov\u00fa afinitu ku kobalam\u00ednu pri n\u00edzkom pH v \u017eal\u00fadku, a preto \u017eal\u00fadok op\u00fa\u0161\u0165a hlavne kobalam\u00edn naviazan\u00fd na HC (HC-Cbl), odtia\u013e postupuje do duod\u00e9na a horn\u00fdch \u010dast\u00ed jejuna. Tu vplyvom alkalick\u00e9ho pH a pankreatick\u00fdch prote\u00e1z doch\u00e1dza k parci\u00e1lnemu uvo\u013eneniu Cbl z HC a m\u00f4\u017ee sa tak vo zv\u00fd\u0161enej miere viaza\u0165 na IF (mo\u017en\u00e1 pr\u00ed\u010dina deficitu B12 pri pankreatickej a \u010drevnej insuficiencii). V z\u00e1saditom<br \/>\nprostred\u00ed duod\u00e9na teda vznik\u00e1 preva\u017ene komplex Cbl-IF(4). Kobalam\u00edn m\u00f4\u017ee by\u0165 absorbovan\u00fd akt\u00edvnym transportom alebo pas\u00edvnou dif\u00faziou. Akt\u00edvnym transportom je absorbovan\u00e1 v\u00e4\u010d\u0161ina Cbl. Komplex Cbl-IF je vychyt\u00e1van\u00fd \u0161pecifick\u00fdmi kubil\u00ednov\u00fdmi receptormi na povrchu buniek tenk\u00e9ho \u010dreva za pr\u00edtomnosti Ca2+ a neutr\u00e1lneho pH. Kubil\u00ednov\u00fd receptor (k\u00f3dovan\u00fd CUBN g\u00e9nom) via\u017ee iba komplex Cbl-IF; vo\u013en\u00fd Cbl, ani IF nie s\u00fa schopn\u00e9 v\u00e4zby na tento receptor. Kubil\u00edn tvoria \u03b1-podjednotky a hydrof\u00f3bne \u03b2-podjednotky a na to, aby Cbl pre\u0161iel do bunky, mus\u00ed vytvori\u0165 funk\u010dn\u00fd komplex s amnionless prote\u00ednom, ktor\u00fd umo\u017en\u00ed prechod ligandu do bunky. Pre spr\u00e1vnu funkciu a prenos ligandu do bunky je potrebn\u00fd aj \u010fal\u0161\u00ed receptor \u2013 megal\u00ednov\u00fd. Kubil\u00edn a megal\u00edn s\u00fa pr\u00edtomn\u00e9 v tenkom \u010dreve, v obli\u010dk\u00e1ch a v \u017e\u013atkovom vaku okolo vyv\u00edjaj\u00faceho sa embrya. Kubil\u00edn bez megal\u00ednu nie je schopn\u00fd reabsorbova\u0165 prote\u00edny, i ke\u010f megal\u00edn m\u00e1 t\u00fato schopnos\u0165(<br \/>\n4,6,7). Pas\u00edvnou dif\u00faziou prech\u00e1dza len okolo 1 \u2013 3 % prijat\u00e9ho Cbl a uplat\u0148uje sa hlavne pri vy\u0161\u0161\u00edch d\u00e1vkach Cbl (nad desiatky a\u017e stovky mikrogramov). T\u00fdmto sp\u00f4sobom absorbovan\u00fd vitam\u00edn sa objavuje v krvi za nieko\u013eko min\u00fat a je to mechanizmus vyu\u017e\u00edvan\u00fd hlavne u pacientov s pernici\u00f3znou an\u00e9miou(4,5). Transport kobalam\u00ednu v plazme riadia R prote\u00edny (transkobalam\u00edny),<br \/>\nv literat\u00fare tie\u017e ozna\u010dovan\u00e9 R binders, \u201eR viaza\u010de\u201c, aby sa odl\u00ed\u0161ili od R prote\u00ednov, ktor\u00e9 via\u017eu kobalam\u00edn v \u017eal\u00fadku(3). Pred naviazan\u00edm kobalam\u00ednu na transkobalam\u00edn doch\u00e1dza k jeho premene na metylov\u00e9 a adenosylov\u00e9 formy. Metylov\u00e1 forma tvor\u00ed 60 \u2013 80 % celkov\u00e9ho kobalam\u00ednu v plazme a adenosylov\u00e1 forma do 20 %. V malom mno\u017estve s\u00fa zast\u00fapen\u00e9 aj in\u00e9 formy kobalam\u00ednu, kyanokobalam\u00edn a hydroxykobalam\u00edn(8). Hlavn\u00fdm transportn\u00fdm prote\u00ednom akt\u00edvnej formy Cbl v plazme je transkobalam\u00edn II. Transkobalam\u00edn II je tvoren\u00fd r\u00f4znymi tkanivami, hlavne endotelov\u00fdmi bunkami, m\u00e1 biologick\u00fd pol\u010das 90 min\u00fat a via\u017ee len funk\u010dn\u00e9 anal\u00f3gy kobalam\u00ednu.<\/p>\n<p>Komplex Cbl-IF prech\u00e1dza endocyt\u00f3zou do cytoplazmy enterocytu, kde je vplyvom lyzoz\u00f3mov vn\u00fatorn\u00fd faktor degradovan\u00fd a Cbl sa via\u017ee na transkobalam\u00edn, \u010d\u00edm vznik\u00e1 akt\u00edvna forma vitam\u00ednu B12 \u2013 holotranskobalam\u00edn (holoTC). HoloTC op\u00fa\u0161\u0165a enterocyt cez bazolater\u00e1lnu membr\u00e1nu a vstupuje do port\u00e1lnej krvi. Absorpcia akt\u00edvnym transportom prebieha v termin\u00e1lnej \u010dasti ilea a trv\u00e1 okolo 3-4 hod\u00edn. HoloTC tvor\u00ed len 10 \u2013 30 % celkov\u00e9ho vitam\u00ednu B12, je to v\u0161ak akt\u00edvna, biologicky dostupn\u00e1 forma vitam\u00ednu B12. HoloTC m\u00e1 biologick\u00fd pol\u010das 5-6 min\u00fat(5,8). Druh\u00fdm transportn\u00fdm prote\u00ednom je haptokor\u00edn (HC), transkobalam\u00edn I. HC je \u03b1-glykoprote\u00edn tvoren\u00fd v \u0161pecifick\u00fdch granul\u00e1ch granulocytov. Vo ve\u013ekom mno\u017estve je pr\u00edtomn\u00fd v slin\u00e1ch, materskom mlieku a slz\u00e1ch. Biologick\u00fd pol\u010das m\u00e1 9-10 dn\u00ed. HC naviazan\u00edm Cbl tvor\u00ed holohaptokor\u00edn (holoHC), ktor\u00fd tvor\u00ed 70 \u2013 90 % cirkuluj\u00faceho Cbl, odtia\u013e vysok\u00e9 hodnoty vy\u0161etrovan\u00e9ho B12 v s\u00e9re. HC via\u017ee v\u0161etky formy Cbl, aj nefunk\u010dn\u00e9, av\u0161ak komplex holoHC nedok\u00e1\u017ee prestupova\u0165 do buniek, preto\u017ee na bunke nie s\u00fa \u0161pecifick\u00e9 receptory, ktor\u00e9 by rozpoznali tento komplex. HoloHC m\u00f4\u017ee<br \/>\nvstupova\u0165 do buniek v\u010faka ne\u0161pecifick\u00fdm receptorom (asialoglykoprote\u00ednom) v pe\u010deni po desialyz\u00e1cii molekuly haptokor\u00ednu(3,9). Holohaptokor\u00edn predstavuje tzv. z\u00e1sobn\u00fa formu, ktorej funkcia nie je presne zn\u00e1ma, av\u0161ak Cbl v tejto forme je viazan\u00fd ve\u013emi pevne, uvo\u013e\u0148uje sa pomaly a m\u00f4\u017ee trva\u0165 aj nieko\u013eko rokov, k\u00fdm absorpcia v \u010dreve ustane a za\u010dne sa manifestn\u00fd deficit akt\u00edvnej formy kobalam\u00ednu. M\u00f4\u017ee trva\u0165 3 \u2013 6 rokov, k\u00fdm sa mno\u017estvo holoHC (celkov\u00e9ho B12) zn\u00ed\u017ei pod 200 pmol\/l. Len holoTC, ktor\u00fd je r\u00fdchlo vychyt\u00e1van\u00fd bunkami, predstavuje aktu\u00e1lne hladiny akt\u00edvnej formy B12 s poklesom hne\u010f po zhor\u0161en\u00ed intestin\u00e1lnej absorpcie. Hodnoty vitam\u00ednu B12 v s\u00e9re 150 \u2013 300 pmol\/l pova\u017eujeme za siv\u00fa z\u00f3nu, ke\u010f je diagnosticky v\u00fdhodnej\u0161ie stanovenie akt\u00edvnej formy vitam\u00ednu B12 \u2013 holoTC(4,5,8). Receptory pre holotranskobalam\u00edn s\u00fa pr\u00edtomn\u00e9 na v\u0161etk\u00fdch bunk\u00e1ch, aj ke\u010f prednostne je holoTC vychyt\u00e1van\u00fd hlavne v pe\u010deni, kostnej dreni a \u010fal\u0161\u00edch tkaniv\u00e1ch. T\u00fdm sa kobalam\u00edn st\u00e1va dostupn\u00fdm pre v\u0161etky bunky v tele, ktor\u00e9 syntetizuj\u00fa DNA alebo ribonukleov\u00fa kyselinu (RNA). HoloTC prech\u00e1dza do buniek endocyt\u00f3zou.<\/p>\n<p>Metabolick\u00fd obrat komplexu s akt\u00edvnym Cbl dosahuje maxim\u00e1lne 6 nmol\/de\u0148, holohaptokor\u00ednu 0,1 nmol\/de\u0148. Receptor pre holotranskobalam\u00edn v obli\u010dk\u00e1ch vyu\u017e\u00edva na absorpciu vitam\u00ednu megal\u00edn, v in\u00fdch tkaniv\u00e1ch nie je megal\u00edn s\u00fa\u010das\u0165ou receptora pre holoTC. V obli\u010dk\u00e1ch je holoTC reabsorbovan\u00fd z glomerulov\u00e9ho filtr\u00e1tu a nepatrn\u00e9 mno\u017estvo je cez baz\u00e1lnu membr\u00e1nu tubul\u00e1rnych buniek vyl\u00fa\u010den\u00e9 do mo\u010du(8,10). \u00daloha transkobalam\u00ednu III zatia\u013e nie je \u00faplne zn\u00e1ma, pravdepodobne pln\u00ed transportn\u00fa funkciu pre Cbl z perif\u00e9rnych tkan\u00edv sp\u00e4\u0165 do pe\u010dene. Podobne ako transkobalam\u00edn I via\u017ee v\u0161etky formy vitam\u00ednu aj nefunk\u010dn\u00e9 anal\u00f3gy(8). Pribli\u017ene 60 \u2013 70 % kobalam\u00ednu prijat\u00e9ho z potravy je vylu\u010dovan\u00e9 z organizmu \u017el\u010dou a mo\u010dom, v podobe vo\u013en\u00e9ho vitam\u00ednu, akt\u00edvne formy si telo nech\u00e1va. U pacientov s naru\u0161enou absorpciou vitam\u00ednu s\u00fa tieto straty a\u017e 100 %, v z\u00e1vislosti od mno\u017estva funk\u010dn\u00e9ho IF. V pe\u010deni je Cbl naviazan\u00fd na HC, prech\u00e1dza do \u017el\u010de, n\u00e1sledne do \u010dreva a tu je spracovan\u00fd ako Cbl prijat\u00fd z potravy. Ve\u013ek\u00e1 \u010das\u0165 Cbl je vylu\u010dovan\u00e1 \u017el\u010dou, 0,5 \u2013 5 \u03bcg Cbl za de\u0148 je zo \u017el\u010de vylu\u010dovan\u00e9 do \u010dreva, no okolo troch \u0161tvrt\u00edn sa sp\u00e4tne reabsorbuje prostredn\u00edctvom enterohepat\u00e1lneho cyklu, \u010do prispieva k udr\u017eiavaniu vysok\u00fdch telesn\u00fdch z\u00e1sob vitam\u00ednu. Zvy\u0161n\u00e1 \u0161tvrtina je vyl\u00fa\u010den\u00e1 stolicou. Glomerulovou filtr\u00e1ciou vyl\u00fa\u010den\u00e9 mno\u017estvo Cbl nie je a\u017e tak\u00e9 v\u00fdrazn\u00e9 (&lt; 0,25 \u03bcg\/de\u0148), predsa je niekedy pova\u017eovan\u00e1 za hlavn\u00fa cestu exkr\u00e9cie vitam\u00ednu. V obli\u010dk\u00e1ch s\u00fa receptory pre komplex holoTC, ktor\u00e9 br\u00e1nia nadmern\u00e9mu \u00faniku vitam\u00ednu mo\u010dom. Stopov\u00e9 mno\u017estvo Cbl je vylu\u010dovan\u00e9 ko\u017eou(6,8,11). Holotranskobalam\u00edn \u2013 akt\u00edvna forma vitam\u00ednu B12 prech\u00e1dza do buniek perif\u00e9rnych tkan\u00edv endocyt\u00f3zou sprostredkovanou<br \/>\nreceptormi. Kobalam\u00edn v metabolick\u00fdch procesoch \u013eudsk\u00e9ho organizmu pln\u00ed funkciu koenz\u00fdmov v t\u00fdchto form\u00e1ch: metylkobalam\u00edn a adenosylkobalam\u00edn. Cbl je koenz\u00fdmom<br \/>\npre tieto enz\u00fdmy: metion\u00ednsynt\u00e1zu a L-metylmalonyl-koenz\u00fdm A (CoA) mut\u00e1zu. Metylkobalam\u00edn je kofaktorom pre metion\u00ednsynt\u00e1zu (alebo tie\u017e homocyste\u00ednmetyltransfer\u00e1zu), katalyzuje premenu homocyste\u00ednu (Hcy) na metion\u00edn prostredn\u00edctvom cyklov metyl\u00e1cie a demetyl\u00e1cie Cbl.<\/p>\n<p>Pre spr\u00e1vny priebeh metyl\u00e1cie je nevyhnutn\u00e1 spolupr\u00e1ca vitam\u00ednu B12 a kyseliny listovej. Deficit jedn\u00e9ho vitam\u00ednu tak m\u00f4\u017ee maskova\u0165 deficit druh\u00e9ho(8). Vzniknut\u00fd metion\u00edn je esenci\u00e1lnou<br \/>\naminokyselinou pre metyl\u00e1ciu prote\u00ednov, DNA a RNA; \u010falej je donorom metylovej skupiny pri synt\u00e9ze kreat\u00ednu, fosfolipidov a acetylchol\u00ednu. Deficit Cbl vedie k zablokovaniu aktivity enz\u00fdmu, zn\u00ed\u017eenej tvorbe aminokyseliny metion\u00ednu a hromadeniu homocyste\u00ednu. Adenosylkobalam\u00edn je kofaktorom pre L-metylmalonyl-CoA mut\u00e1zu v mitochondri\u00e1ch.<\/p>\n<p>Podie\u013ea sa hlavne na metabolizme mastn\u00fdch kysel\u00edn s nep\u00e1rnym po\u010dtom uhl\u00edkov d\u00f4le\u017eit\u00fdch pre spr\u00e1vnu synt\u00e9zu myel\u00ednov\u00fdch obalov nervovej bunky. Pri deficite Cbl doch\u00e1dza k hromadeniu metylmalon\u00e1tu CoA a metylmal\u00f3novej kyseliny. Typick\u00fdm znakom je metylmal\u00f3nov\u00e1 acid\u00faria, hlavne po zv\u00fd\u0161enom pr\u00edjme mastn\u00fdch kysel\u00edn s nep\u00e1rnym po\u010dtom uhl\u00edkov.<br \/>\nHromadenie metylmal\u00f3novej kyseliny sa negat\u00edvne odraz\u00ed v metabolizme gluk\u00f3zy, glut\u00e1movej kyseliny a inhib\u00edcii cyklu dikarboxylov\u00fdch kysel\u00edn. Zv\u00fd\u0161en\u00e1 tvorba metylmalonylu CoA nar\u00fa\u0161a tvorbu mastn\u00fdch kysel\u00edn, \u010doho n\u00e1sledkom vznikaj\u00fa vetven\u00e9 mastn\u00e9 kyseliny. Nedostatok adenozylkobalam\u00ednu prispieva k tvorbe patologick\u00e9ho myel\u00ednu, ktor\u00fd svojou fragilitou priamo podmie\u0148uje demyeliniz\u00e1ciu nervov\u00fdch vl\u00e1ken(4,5,11).<br \/>\nPr\u00ed\u010dinou vzniku a rozvoja klinick\u00fdch prejavov a laborat\u00f3rnych zn\u00e1mok deficitu Cbl je poru\u0161en\u00e1 funkcia enz\u00fdmov, ktor\u00fdch funkcia je z\u00e1visl\u00e1 od Cbl. Ako bolo spomenut\u00e9, je to metion\u00ednsynt\u00e1za a metylmalonyl-CoA mut\u00e1za. Hlavn\u00fdm znakom je naru\u0161en\u00e9 delenie buniek, pre chybn\u00fa synt\u00e9zu DNA, aj ke\u010f reakcie, pre ktor\u00e9 je Cbl nevyhnutn\u00fd, priamo neovplyv\u0148uj\u00fa synt\u00e9zu DNA. Tento patomechanizmus objasnila a\u017e po rokoch hypot\u00e9za fol\u00e1tovej pasce. Princ\u00edp fol\u00e1tovej pasce spo\u010d\u00edva v tom, \u017ee pri nedostatku Cbl sa hromad\u00ed nevyu\u017eit\u00fd N5-metyltetrahydrofol\u00e1t, ktor\u00fd sa nepremie\u0148a na akt\u00edvnu formu. Nedostatok tetrahydrofol\u00e1tu naru\u0161\u00ed synt\u00e9zu pur\u00ednov\u00fdch b\u00e1z, t\u00fdm tvorbu DNA, a teda aj z\u00e1kladn\u00fa funkciu bunky \u2013 delenie. Zmeny v koncentr\u00e1cii fol\u00e1tu s\u00favisia pravdepodobne s neschopnos\u0165ou udr\u017ea\u0165 si fol\u00e1t, preto\u017ee bunky nie s\u00fa schopn\u00e9 udr\u017ea\u0165 N5-metyltetrahydrofol\u00e1t, ktor\u00fd sa nepremenil na akt\u00edvnu formu \u2013 tetrahydrofol\u00e1t(5). Fol\u00e1tov\u00e1 pasca je probl\u00e9mom pri diferenci\u00e1lnej diagnostike megaloblastovej an\u00e9mie, preto\u017ee pr\u00ed\u010dinou tejto an\u00e9mie m\u00f4\u017ee by\u0165 deficit aj Cbl, aj kyseliny listovej. Kontroverzn\u00e1 preto bola fortifik\u00e1cia potrav\u00edn, preto\u017ee kyselina listov\u00e1 zlep\u0161uje megaloblastov\u00fa an\u00e9miu (cez obnovu synt\u00e9zy DNA a delenie buniek), no m\u00f4\u017ee maskova\u0165 deficit Cbl. Fol\u00e1tov\u00e1 pasca je teda tie\u017e d\u00f4vodom, pre\u010do sa ned\u00e1 spolieha\u0165 len na zmenen\u00e9 hematologick\u00e9 parametre v r\u00e1mci diagnostiky pr\u00ed\u010diny makrocytovej an\u00e9mie. Obraz megaloblastovej an\u00e9mie sa d\u00e1 vysvetli\u0165 fol\u00e1tovou pascou a hoci za pr\u00ed\u010dinu neurologick\u00fdch \u0165a\u017ekost\u00ed sa pova\u017euje kobalam\u00ednov\u00fd deficit, patomechanizmus vzniku t\u00fdchto \u0165a\u017ekost\u00ed zatia\u013e nie je \u00faplne objasnen\u00fd(5,10).<br \/>\nPoruchy metabolizmu Cbl m\u00f4\u017eeme rozdeli\u0165 do dvoch ve\u013ek\u00fdch skup\u00edn, a to: 1. deficit Cbl v organizme a 2. deficit enz\u00fdmov, ktor\u00e9 sa podie\u013eaj\u00fa na intracelul\u00e1rnom metabolizme Cbl. Deficit Cbl v organizme vznik\u00e1 v d\u00f4sledku: nedostato\u010dn\u00e9ho pr\u00edjmu Cbl v potrave, poru\u0161en\u00fdm vstreb\u00e1van\u00edm alebo transportom Cbl. Zdrojmi vitam\u00ednu B12 v strave s\u00fa prim\u00e1rne m\u00e4sov\u00e9 a mlie\u010dne v\u00fdrobky. V typickej strave z\u00e1padn\u00e9ho typu je jeho denn\u00fd pr\u00edjem obvykle vy\u0161\u0161\u00ed ne\u017e odpor\u00fa\u010dan\u00fd denn\u00fd pr\u00edsun. Nedostatkom Cbl s\u00fa ohrozen\u00ed hlavne star\u0161\u00ed \u013eudia s jednostrannou stravou aj chronick\u00ed alkoholici a striktn\u00ed veg\u00e1ni(11). Absorpciu Cbl negat\u00edvne ovplyv\u0148uje nedostato\u010dn\u00e1 sekr\u00e9cia pankreatickej \u0161\u0165avy, Zollingerov-Ellisonov syndr\u00f3m, Immerslundov- Gr\u00e4sbeckov syndr\u00f3m, z\u00e1palov\u00e9 ochorenia \u017eal\u00fado\u010dnej alebo \u010drevnej sliznice, parazit\u00e1rne a bakteri\u00e1lne ochorenia gastrointestin\u00e1lneho traktu, chirurgick\u00e9 z\u00e1sahy v oblasti \u017eal\u00fadka a \u010dreva, dlhodob\u00e9 u\u017e\u00edvanie antac\u00edd, autoimunitn\u00e9 ochorenia s tvorbou protil\u00e1tok proti IF alebo proti komplexu IF-Cbl a \u010fal\u0161ie. V poru\u0161enom transporte Cbl v organizme zohr\u00e1vaj\u00fa \u00falohu mut\u00e1cie g\u00e9nu pre holoTC, vroden\u00fd deficit transkobalam\u00ednu, po\u0161kodenie \u0161trukt\u00fary holoTC \u010di vroden\u00e9 poruchy funkcie lyzoz\u00f3mov, ktor\u00e9 ved\u00fa k nadmern\u00e9mu hromadeniu Cbl v lyzoz\u00f3moch(1,3). Klinick\u00e9 prejavy nedostatku \u010di poru\u0161en\u00e9ho metabolizmu<br \/>\nkobalam\u00ednu z\u00e1visia od pr\u00ed\u010diny, d\u013a\u017eky trvania a veku pacienta, kedy porucha vznikne.<\/p>\n<p>V detskom veku sa neurologick\u00e9 prejavy manifestuj\u00fa v\u00e4\u010d\u0161inou pred hematologick\u00fdmi, \u010do plat\u00ed aj u star\u0161\u00edch pacientov, u ktor\u00fdch \u010dasto a\u017e psychiatrick\u00e9 pr\u00edznaky m\u00f4\u017eu predbehn\u00fa\u0165 zmeny v krvnom obraze. U dospel\u00fdch pacientov s poruchou vstreb\u00e1vania Cbl b\u00fdva \u010dasto prv\u00fdm rozpoznan\u00fdm pr\u00edznakom makrocytov\u00e1 an\u00e9mia(12,13). Pri poruch\u00e1ch metabolizmu kobalam\u00ednu na intracelul\u00e1rnej \u00farovni v enz\u00fdmoch CblA, CblB a \u010diasto\u010dne aj CblD k rozvoju makrocytovej an\u00e9mie nedoch\u00e1dza z d\u00f4vodu nepr\u00edtomnosti deficitu metylkobalam\u00ednu. Uv\u00e1dza sa, \u017ee a\u017e 40 % pacientov m\u00e1 pr\u00edtomn\u00e9 neurologick\u00e9 prejavy nedostatku vitam\u00ednu B12 sk\u00f4r ako zmeny v hematologick\u00fdch parametroch. Tzv. neuroanemick\u00fd syndr\u00f3m okrem obrazu an\u00e9mie dotv\u00e1raj\u00fa r\u00f4zne neurologick\u00e9 prejavy, ako parest\u00e9zie, poruchy hlbokej citlivosti, zn\u00ed\u017eenie reflexov, z\u00e1vraty. U star\u0161\u00edch pacientov s\u00fa \u010dastej\u0161ie psychiatrick\u00e9 prejavy: apatia, spavos\u0165, emo\u010dn\u00e1 nest\u00e1los\u0165, dezorient\u00e1cia, zm\u00e4tenos\u0165, demencia a v niektor\u00fdch pr\u00edpadoch a\u017e depres\u00edvna psych\u00f3za. U pediatrick\u00fdch pacientov sa naj\u010dastej\u0161ie vyskytuj\u00fa zmeny svalov\u00e9ho tonusu \u2013 hypotonick\u00fd syndr\u00f3m, zaost\u00e1vanie v psychomotorickom v\u00fdvine, extrapyram\u00eddov\u00e9 pr\u00edznaky, myoklonick\u00e9 k\u0155\u010de \u010di atrofia zrakov\u00e9ho nervu. U \u010dasti pacientov sa m\u00f4\u017eu objavi\u0165 aj gastrointestin\u00e1lne \u0165a\u017ekosti: nechutenstvo, nauzea, vracanie, hna\u010dka a typick\u00e9 zmeny na jazyku \u2013 tzv. Hunterov jazyk (vyhladenie pap\u00edl jazyka s p\u00e1len\u00edm na hrote a na okrajoch). Nedostatok kobalam\u00ednu m\u00f4\u017ee by\u0165 pr\u00ed\u010dinou infertility a hypotyreoidizmu(13,14). Hematologick\u00e9 zmeny, ktor\u00e9 n\u00e1s upozornia na mo\u017en\u00fd nedostatok kobalam\u00ednu s\u00fa: makrocytov\u00e1 an\u00e9mia, leukop\u00e9nia, hypersegment\u00e1cia neutrofilov a trombocytop\u00e9nia. Z biochemick\u00fdch markerov: zn\u00ed\u017een\u00e1 alebo norm\u00e1lna koncentr\u00e1cia celkov\u00e9ho vitam\u00ednu B12, pokles holotranskobalam\u00ednu, zv\u00fd\u0161en\u00e1 kyselina metylmal\u00f3nov\u00e1 v mo\u010di, zv\u00fd\u0161en\u00fd homocyste\u00edn, zv\u00fd\u0161en\u00fd konjugovan\u00fd bilirub\u00edn. Av\u0161ak ani norm\u00e1lne koncentr\u00e1cie vitam\u00ednu B12 a holoTC nevylu\u010duj\u00fa poru\u0161en\u00fd metabolizmus Cbl pri s\u00fa\u010dasne zv\u00fd\u0161enej koncentr\u00e1cii Hcy v plazme a\/alebo kyseliny metylmal\u00f3novej v mo\u010di, je potrebn\u00e9 diferenci\u00e1lne diagnosticky vyl\u00fa\u010di\u0165 poruchu metabolizmu Cbl na intracelul\u00e1rnej \u00farovni(15). Na z\u00e1klade v\u00fdsledkov m\u00f4\u017eeme predpoklada\u0165 pr\u00ed\u010dinu deficitu Cbl a ur\u010di\u0165 \u010fal\u0161\u00ed diagnostick\u00fd postup (tabu\u013eka 1).<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Selekt\u00edvne fluktu\u00e1cie vitam\u00ednu B12 <\/strong><\/p>\n<p>\u0160tandardn\u00e9 met\u00f3dy stanovuj\u00fa z\u00e1rove\u0148 neakt\u00edvnu a akt\u00edvnu frakciu vitam\u00ednu B12. To zni\u017euje ich senzitivitu a \u0161pecificitupri diagnostike deficitu kobalam\u00ednu, preto\u017ee selekt\u00edvne fluktu\u00e1cie holoHC m\u00f4\u017eu skresli\u0165 re\u00e1lny stav akt\u00edvnej frakcie vitam\u00ednu. Tieto fluktu\u00e1cie s\u00fa pozorovan\u00e9 pri dedi\u010dn\u00fdch deficitoch haptokor\u00ednu, v tehotenstve a neutropenick\u00fdch stavoch, ke\u010f pacienti maj\u00fa celkov\u00e9 mno\u017estvo B12 zn\u00ed\u017een\u00e9, ale netrpia deficitom B12. Naopak, selekt\u00edvne zv\u00fd\u0161enie holoHC s funk\u010dn\u00fdm deficitom Cbl sa vyskytuje pri ochoreniach pe\u010dene, zlyhan\u00ed obli\u010diek a niektor\u00fdch mal\u00edgnych ochoreniach. Stanovenie holoTC, ktor\u00fd nie je ovplyvnen\u00fd fluktu\u00e1ciami holoHC, je tedasenzit\u00edvnej\u0161\u00edm a \u0161pecifickej\u0161\u00edm ukazovate\u013eom funk\u010dn\u00e9ho deficitu vitam\u00ednu B12 (16,17,18). O\u010dak\u00e1van\u00e9 hodnoty pre holoTC u zdrav\u00fdch jedincov s\u00fa 35 \u2013 171 pmol\/l. Doln\u00e1 a horn\u00e1 hranica pre referen\u010dn\u00e9 rozmedzie holoTC v plazme sa pohybuje od 19 do 42 pmol\/l, resp. 134 \u2013 157 pmol\/l(19). S\u00fa\u010dasn\u00e9 multicentrick\u00e9 \u0161t\u00fadie navrhuj\u00fa hrani\u010dn\u00fa hodnotu pre holoTC 32 pmol\/l pre skr\u00edning deficitu kobalam\u00ednu zalo\u017een\u00fd na hodnote kyseliny metylmal\u00f3novej &gt; 0,45 \u03bcmol\/l. Pracovn\u00e1 skupina tvoriaca<br \/>\nodpor\u00fa\u010dania (Guidelines Writing Group) odpor\u00fa\u010da, aby si jednotliv\u00e9 laborat\u00f3ri\u00e1 zadefinovali ich vlastn\u00e9 referen\u010dn\u00e9 hodnoty v z\u00e1vislosti od pou\u017e\u00edvan\u00e9ho konkr\u00e9tneho testu pre holoTC alebo implementuje v\u00fdrobcom odpor\u00fa\u010dan\u00e9 referen\u010dn\u00e9 rozhranie pod\u013ea \u0161t\u00fadie, na ktorej bol test vykonan\u00fd(20). V laborat\u00f3rnej spolo\u010dnosti Medirex je hrani\u010dnou hodnotou pre holoTC vy\u0161etrovan\u00fd v s\u00e9re 35 pmol\/l(21). Fyziologick\u00e9 referen\u010dn\u00e9 rozhranie koncentr\u00e1cie vitam\u00ednu B12 v s\u00e9re je 156 \u2013 672 pmol\/l, hodnoty 150 \u2013 300 pmol\/l pova\u017eujeme za tzv. siv\u00fa z\u00f3nu(22).<\/p>\n<p>Za vysok\u00fa koncentr\u00e1ciu s\u00e9rov\u00e9ho vitam\u00ednu B12 pova\u017eujeme hodnoty nad 701 pmol\/l, \u010do pod\u013ea biologick\u00fdch \u0161tandardov zodpoved\u00e1 hornej hranici biologickej normality pri nepr\u00edtomnosti<br \/>\nak\u00e9hoko\u013evek pr\u00edznaku alebo klinickej anom\u00e1lie. Vysok\u00e9 koncentr\u00e1cie kobalam\u00ednu m\u00f4\u017eu by\u0165 vysvetlen\u00e9 t\u00fdmito patofyziologick\u00fdmi mechanizmami(16): priamy vzostup Cbl v plazme nadbyto\u010dn\u00fdm pr\u00edjmom alebo podan\u00edm, uvo\u013enen\u00edm zo z\u00e1sob organizmu, vzostupom transkobalam\u00ednov nadbyto\u010dnou produkciou alebo nedostato\u010dn\u00fdm kl\u00edrensom, kvantitat\u00edvnym nedostatkom alebo absenciou afinity Cbl k transkobalam\u00ednu. Na rozdiel od deficitu kobalam\u00ednu patofyziologick\u00e9 pozadie a klinick\u00e9 d\u00f4sledky vysok\u00fdch koncentr\u00e1ci\u00ed Cbl v s\u00e9re boli doteraz ve\u013emi m\u00e1lo \u0161tudovan\u00e9. V s\u00fa\u010dasnosti sa predpoklad\u00e1, \u017ee vysok\u00e9 koncentr\u00e1cie Cbl m\u00f4\u017eu by\u0165 indik\u00e1torom funk\u010dn\u00e9ho deficitu s klinick\u00fdmi d\u00f4sledkami paradoxne podobn\u00fdmi nedostatku Cbl. Zv\u00fd\u0161en\u00e1 v\u00e4zbovos\u0165 Cbl k haptokor\u00ednu (holoHC tvor\u00ed hlavn\u00fa \u010das\u0165 cirkuluj\u00faceho Cbl) vedie k sekund\u00e1rne zv\u00fd\u0161enej koncentr\u00e1cii Cbl, m\u00e1 v\u0161ak za n\u00e1sledok potenci\u00e1lne ni\u017e\u0161iu v\u00e4zbov\u00fa schopnos\u0165 Cbl k transkobalam\u00ednu, a t\u00fdm aj zn\u00ed\u017een\u00fd pr\u00edsun akt\u00edvnej formy do buniek. Tento funk\u010dn\u00fd deficit Cbl so zv\u00fd\u0161en\u00edm homocyste\u00ednu a\/alebo kyseliny metylmal\u00f3novej sa m\u00f4\u017ee objavi\u0165, aj ke\u010f po\u010diato\u010dn\u00e1 pr\u00ed\u010dina tohto stavu nie je v deficite Cbl(16,18). Okrem tohto mechanizmu funk\u010dn\u00fd deficit Cbl m\u00f4\u017ee by\u0165 zapr\u00ed\u010dinen\u00fd zlyhan\u00edm vychyt\u00e1vania Cbl zo s\u00e9ra po\u0161kodenou pe\u010de\u0148ou a\/alebo unikan\u00edm holoHC z pe\u010de\u0148ov\u00e9ho tkaniva do plazmy(23). Vysok\u00e9 koncentr\u00e1cie Cbl s\u00fa v\u00fdznamne spojen\u00e9 s hematologick\u00fdmi malignitami, alkoholizmom, u pacientov s obli\u010dkov\u00fdmi, autoimunitn\u00fdmi a bronchopulmon\u00e1lnymi ochoreniami(16,17,18,24). Pri chronickej myelocytovej leuk\u00e9mii je deficit Cbl maskovan\u00fd, preto\u017ee granulocyty vo zv\u00fd\u0161enej miere produkuj\u00fa haptokor\u00edn, a tak zost\u00e1va hladina Cbl navonok v norme. Z \u010fal\u0161\u00edch hematologick\u00fdch ochoren\u00ed je to prim\u00e1rny hypereozinofiln\u00fd syndr\u00f3m a ak\u00fatna promyelocytov\u00e1 leuk\u00e9mia. Lymfoproliferat\u00edvne ochorenia s\u00fa zriedka pr\u00ed\u010dinou vysok\u00e9ho Cbl, okrem mnohopo\u010detn\u00e9ho myel\u00f3mu, kde m\u00f4\u017eu by\u0165 pozorovan\u00e9 aj vysok\u00e9, aj n\u00edzke koncentr\u00e1cie Cbl(18).<br \/>\nVysok\u00e9 koncentr\u00e1cie Cbl v s\u00e9re m\u00f4\u017eu by\u0165 sprievodn\u00fdm n\u00e1lezom pri t\u00fdchto n\u00e1doroch: hepatocelul\u00e1rny karcin\u00f3m, sekund\u00e1rne pe\u010de\u0148ov\u00e9 n\u00e1dory, n\u00e1dory prsn\u00edka, \u017eal\u00fadka, pankreasu. V pr\u00edpadoch metastatick\u00e9ho postihnutia pe\u010dene s\u00fa to a\u017e extr\u00e9mne vysok\u00e9 hodnoty Cbl. Prim\u00e1rnym mechanizmom v procese zv\u00fd\u0161enia s\u00e9rov\u00e9ho Cbl v pr\u00edpade pe\u010de\u0148ov\u00fdch n\u00e1dorov je zn\u00ed\u017een\u00fd hepat\u00e1lny kl\u00edrens holohaptokor\u00ednu a zv\u00fd\u0161en\u00e9 plazmatick\u00e9 koncentr\u00e1cie transkobalam\u00ednov v d\u00f4sledku zv\u00fd\u0161en\u00e9ho rozpadu hepatocytov. Zd\u00e1 sa, \u017ee pokles hepat\u00e1lneho kl\u00edrensu je sp\u00f4soben\u00fd slabou vaskulariz\u00e1ciou pe\u010dene a redukciou po\u010dtu haptokor\u00ednov\u00fdch receptorov na povrchu n\u00e1dorov\u00fdch hepatocytov. V pr\u00edpade in\u00fdch sol\u00eddnych n\u00e1dorov by mohli vysok\u00e9 koncentr\u00e1cie Cbl s\u00favisie\u0165 s nadmernou synt\u00e9zou transkobalam\u00ednov alebo so zv\u00fd\u0161en\u00edm haptokor\u00ednu v d\u00f4sledku indukcie hyperleukocyt\u00f3zy(18,24). Vysok\u00e9 koncentr\u00e1cie Cbl m\u00f4\u017eu by\u0165 v d\u00f4sledku ak\u00fatnej, chronickej hepatit\u00eddy \u010di cirh\u00f3zy pe\u010dene, kde hodnoty Cbl m\u00f4\u017eu by\u0165 a\u017e p\u00e4\u0165kr\u00e1t vy\u0161\u0161ie ako horn\u00e1 hranica referen\u010dn\u00e9ho rozhrania, pri\u010dom stupe\u0148 zv\u00fd\u0161enia Cbl koreluje so stup\u0148om z\u00e1va\u017enosti cirh\u00f3zy(16,24). Ren\u00e1lna insuficiencia predstavuje be\u017en\u00fa a ve\u013emi d\u00f4le\u017eit\u00fa v\u00fdnimku v interpret\u00e1cii ukazovate\u013eov stavu kobalam\u00ednu. Napriek norm\u00e1lnym \u010di vysok\u00fdm koncentr\u00e1ci\u00e1m celkov\u00e9ho vitam\u00ednu B12 a\/alebo holoTC t\u00edto pacienti maj\u00fa \u010dasto zv\u00fd\u0161en\u00e9 s\u00e9rov\u00e9 koncentr\u00e1cie kyseliny metylmal\u00f3novej a homocyste\u00ednu. Pravdepodobnou pr\u00ed\u010dinou je naru\u0161en\u00e1 bunkov\u00e1 absorpcia holoTC, ktor\u00e1 vedie k vn\u00fatrobunkov\u00e9mu deficitu B12. Mo\u017en\u00fdm vysvetlen\u00edm je \u00faloha obli\u010diek vo filtr\u00e1cii transkobalam\u00ednu a vo v\u00fdslednej sekund\u00e1rnej akumul\u00e1cii holoTC(25). Falo\u0161ne zv\u00fd\u0161en\u00e9 s\u00e9rov\u00e9 koncentr\u00e1cie kyseliny metylmal\u00f3novej a homocyste\u00ednu v r\u00e1mci r\u00f4znych klinick\u00fdch stavov s\u00fa hlavn\u00fdm obmedzen\u00edm t\u00fdchto parametrov. Oba parametre toti\u017e koreluj\u00fa so s\u00e9rov\u00fdmi koncentr\u00e1ciami kreatin\u00ednu a st\u00fapaj\u00fa u\u017e pri miernom stupni ren\u00e1lnej insuficiencie. T\u00e1to d\u00f4le\u017eit\u00e1 v\u00fdnimka vn\u00e1\u0161a ur\u010dit\u00fa neistotu do vyu\u017eitia holoTC ako markera stavu Cbl u obli\u010dkov\u00fdch pacientov a star\u0161\u00edch \u013eud\u00ed so subklinick\u00fdm stup\u0148om obli\u010dkov\u00e9ho po\u0161kodenia. Laborat\u00f3rna diagnostika deficitu Cbl u obli\u010dkov\u00fdch pacientov vy\u017eaduje v\u00e4\u010d\u0161iu pozornos\u0165 pri s\u00fa\u010dasnom vzostupe kyseliny metylmal\u00f3novej a holoTC. Herrmann a Obeid vo svojej \u0161t\u00fadii u pacientov s obli\u010dkovou dysfunkciou a u star\u0161\u00edch pacientov so stredn\u00fdm stup\u0148om obli\u010dkov\u00e9ho po\u0161kodenia odpor\u00fa\u010daj\u00fa vyl\u00fa\u010denie deficitu Cbl jedine po substitu\u010dnej lie\u010dbe Cbl. Ak sa predpoklad\u00e1 deficit Cbl u obli\u010dkov\u00e9ho pacienta a po lie\u010dbe Cbl d\u00f4jde k signifikantn\u00e9mu poklesu kyseliny metylmal\u00f3novej (pribli\u017ene o 250 nmol\/l), poukazuje to na deficit Cbl. Zvy\u0161n\u00fd vzostup kyseliny metylmal\u00f3novej je d\u00f4sledkom obli\u010dkovej dysfunkcie(26). V tehotenstve je pozorovan\u00fd pokles Cbl v s\u00e9re. Po\u010das fyziologick\u00e9ho tehotenstva doch\u00e1dza k tomuto poklesu o 30 % hlavne v tre\u0165om trimestri. V niektor\u00fdch longitudin\u00e1lnych \u0161t\u00fadi\u00e1ch zdrav\u00e9 \u017eeny vykazovali mierny vzostup v biochemick\u00fdch parametroch nedostatku Cbl (kyselina metylmal\u00f3nov\u00e1 a homocyste\u00edn) v tre\u0165om trimestri poukazuj\u00faci na funk\u010dn\u00fd vn\u00fatrobunkov\u00fd deficit Cbl. Koncentr\u00e1cia holoTC v\u0161ak ostala nezmenen\u00e1. Pokles v Cbl je vysvet\u013eovan\u00fd hlavne poklesom haptokor\u00ednu, \u010do podporuje n\u00e1zor, \u017ee holoTC je lep\u0161\u00edm markerom na hodnotenie kobalam\u00ednov\u00e9ho statusu u tehotn\u00fdch. Hodnoty Cbl v s\u00e9re v rozhran\u00ed 110 \u2013 148 pmol\/l po\u010das tehotenstva m\u00f4\u017eu by\u0165 fyziologick\u00e9, no s\u00fa potrebn\u00e9 \u010fal\u0161ie biochemick\u00e9 testy na potvrdenie<br \/>\njeho deficitu(27).<\/p>\n<p><strong>Z\u00e1ver<\/strong><br \/>\n\u0160tandardn\u00e9 met\u00f3dy stanovuj\u00fa s\u00fa\u010dasne neakt\u00edvnu a akt\u00edvnu frakciu vitam\u00ednu B12 v s\u00e9re. Holohaptokor\u00edn tvor\u00ed 70 \u2013 90 % cirkuluj\u00faceho vitam\u00ednu B12, no predstavuje biologicky neakt\u00edvnu,<br \/>\ninertn\u00fa formu. Len 10 \u2013 30 % z celkov\u00e9ho vitam\u00ednu B12 tvor\u00ed holotranskobalam\u00edn, biologicky dostupn\u00e1 akt\u00edvna forma kobalam\u00ednu. Vy\u0161etrenie holotranskobalam\u00ednu je preto senzit\u00edvnej\u0161\u00edm<br \/>\na \u0161pecifickej\u0161\u00edm ukazovate\u013eom re\u00e1lneho deficitu kobalam\u00ednu v organizme, nielen v r\u00e1mci diferenci\u00e1lnej diagnostiky makrocytovej an\u00e9mie z nedostato\u010dn\u00e9ho pr\u00edjmu \u010di absorpcie kobalam\u00ednu, neurologick\u00fdch prejavov bez zn\u00e1mok makrocytovej an\u00e9mie, \u010di poru\u0161en\u00e9ho metabolizmu kobalam\u00ednu na intracelul\u00e1rnej \u00farovni, ale tie\u017e selekt\u00edvnych zn\u00ed\u017eeniach holohaptokor\u00ednu pri dedi\u010dn\u00fdch deficitoch haptokor\u00ednu, v tehotenstve, neutropenick\u00fdch stavoch, ale aj selekt\u00edvnych zv\u00fd\u0161eniach holohaptokor\u00ednu pri ochoreniach pe\u010dene a niektor\u00fdch mal\u00edgnych ochoreniach.<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Pou\u017eit\u00e9 skratky:<\/strong><br \/>\nDNA \u2013 deoxyribonukleov\u00e1 kyselina<br \/>\nCbl \u2013 kobalam\u00edn<br \/>\nCoA \u2013 koenz\u00fdm A<br \/>\nHC \u2013 haptokor\u00edn<br \/>\nHcy \u2013 homocyste\u00edn<br \/>\nholoTC \u2013 holotranskobalam\u00edn<br \/>\nholoHC \u2013 holohaptokor\u00edn<br \/>\nIF \u2013 vn\u00fatorn\u00fd faktor<br \/>\nRNA \u2013 ribonukleov\u00e1 kyselina<\/p>\n<p>&nbsp;<\/p>\n<p><strong>Literat\u00fara<\/strong><br \/>\n1. Oh R, Brown L. Vitamin B12 Deficiency. Am Fam Physician 2003; 67(5): 979-986.<br \/>\n2. Callender ST, Denborough MA. A family study of pernicious anaemia. Br J Haematol 1957; 3(1): 88-106.<br \/>\n3. Combs GF Jr., McClung JP. Vitamin B12. In: Combs GF, Jr., ed. The Vitamins. Fundamental Aspects in Nutrition and Health, 5th ed. Academic Press 2017: 431-452.<br \/>\n4. Shane B. Folate and vitamin B12 metabolism: Overview and interaction with riboflavin, vitamin B6, and polymorphisms. Food Nutr Bull 2008; 29(2): 5-16.<br \/>\n5. Shane B. Folate, vitamin B12 and vitamin B6. In: Stipanuk MH, ed. Biochemical, physiological, molecular aspects of human nutrition, 2nd ed. New York: Saunders 2006: 693-732.<br \/>\n6. Christensen EI, Birn H. Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol 2001; 280(4): F562-73.<br \/>\n7. Verroust PJ, Christensen EI. Megalin and cubilin \u2013 the story of two multipurpose receptors unfolds. Nephrol Dial Transplant 2002; 17(11): 1867-1871.<br \/>\n8. Gropper SAS, Smith J.L, Groff, JL. Advanced nutrition and human metabolism. 5th ed. Australia: Wadsworth\/Cengage Learning, 2009.<br \/>\n9. Hy\u00e1nek, J. Aktivn\u00ed vitamin B12 (holotranskobalamin) a diagnostick\u00fd v\u00fdznam jeho stanoven\u00ed [online]. V\u00fd\u017eiva a potraviny. 2011. http:\/\/www.vyzivaspol.cz\/aktivni-vitamin-b12 holotranskobalamin-a-diagnosticky-vyznam-jeho-stanoveni\/ [cit. 20. 04. 2019].<br \/>\n10. Ne\u010das, E. Obecn\u00e1 patologick\u00e1 fyziologie. 3. vyd. Praha: Karolinum,2009; 377.<br \/>\n11. Green R, Allen LH, Bj\u00f8rke-Monsen AL, et al. Vitamin B12 deficiency. Nat Rev Dis Primers 2017; 29; 3: 17040.<br \/>\n12. Honzik T, Adamovicova M, Smolka V, et al. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B(12) deficiency. What have we learned? Eur J Paediatr Neurol 2010; 14(6): 488-95.<br \/>\n13. Dali-Youcef N, Andr\u00e8s E. An update on cobalamin deficiency in adults. QJM 2009; 102(1): 17-28.<br \/>\n14. Fabriciov\u00e1 K., Beh\u00falov\u00e1 D, \u0160kodov\u00e1 J, et al. Poruchy metabolizmu vitam\u00ednu B12. Pediatr Prax 2012; 13(4): 166-170.<br \/>\n15. Zwickler T, Lindner M, Aydin HI, et al. Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J Inherit Metab Dis 2008; 31(3): 361-367.<br \/>\n16. Andr\u00e8s E, Serraj J, Zhu J, et al. The pathophysiology of elevated vitamin B12 in clinical practice. QJM: An International Journal of Medicine 2013; 106(6): 505-515.<br \/>\n17. Arendt JFB, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS One 2012; 7(9): e45979.<br \/>\n18. Chiche L, Jean R, Romain F, et al. Clinical implications of high cobalamin blood levels for internal medecine. Rev Med Interne 2008; 29(3): 187\u2011194.<br \/>\n19. Sobczy\u0144ska-Malefora A, Gorska R, Pelisser M, et al. An audit of holotranscobalamin (\u201eActive\u201c B12) and methylmalonic acid assays for the assessment of vitamin B12 status: application in a mixed patient population. Clin Biochem 2014; 47(1-2): 82-86.<br \/>\n20. Devalia V, Hamilton MS, Molloy AM, et al. British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol 2014; 166(4): 496-513.<br \/>\n21. Nexo, E., Hoffmann- L\u00fccke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr 2011; 94(1): 359-365.<br \/>\n22. Axis-Shield. Clinical utility \u2013 correlation between active-B12 and total B12. [online]. Active-B12. 2014.Dostupn\u00e9 na: https:\/\/www.active-b12. com\/clinical-utility\/. [cit. 20. 04. 2019].<br \/>\n23. Solomon, LR: Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment. Blood Rev 2007; 21(3): 113-130.<br \/>\n24. Ermens AA, Vlasveld LT, Lindemans J. Significance of elevated cobalamin (vitamin B12) levels in blood. Clin Biochem 2003; 36(8): 585-590.<br \/>\n25. Obeid R, Kuhlmann M, Kirsch C, et al. Cellular uptake of vitamin B12 in patients with chronic renal failure. Nephron Clin Pract 2005; 99: 42-48.<br \/>\n26. Herrmann W, Obeid R. Holotranscobalamin \u2013 An Early Marker for Laboratory Diagnosis of Vitamin B12 Deficiency. European Haematology 2009; 3(1): 7-11.<br \/>\n27. Greibe E, Andreasen BH, Lildballe DL, et al. Uptake of cobalamin and markers of cobalamin status: a longitudinal study of healthy pregnant women. Clin Chem Lab Med 2011; 49(11): 1877-1882.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper. &nbsp; \u00davod Kobalam\u00edn je nevyhnutn\u00fd pre transform\u00e1ciu metyltetrahydrofol\u00e1tu na tetrahydrofol\u00e1t, a t\u00fdm pre spr\u00e1vnu synt\u00e9zu deoxyribonukleovej kyseliny (DNA), tvorbu erytrocytov a spr\u00e1vnu funkciu nervov\u00e9ho syst\u00e9mu (predov\u0161etk\u00fdm tvorbu myel\u00ednov\u00fdch obalov). Nedostatok<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[294],"tags":[1261,1263,1262],"class_list":["post-1793","post","type-post","status-publish","format-standard","hentry","category-hematology","tag-cobalamin","tag-haptocorrin","tag-holotranscobalamin","typ_clanku-review-article"],"acf":{"abstrakt":"<p>Vitamin B12, cobalamin is essential for the cell metabolism, DNA synthesis and myelinisation of nerve fibres. The most frequent neurological manifestations of cobalamin deficiency are non-specific and may be irreversible. A standard test for the screening of cobalamin deficiency is the assay of total serum vitamin B12 concentration. Measurement of holotranscobalamin \u2013 the active form of vitamin B12 has better sensitivity and specificity in the detection of its deficiency at early stages. Its key advantage for clinical practice is the ability of the test to confirm or rule out the diagnosis of vitamin B12 deficiency in patients who present with borderline levels of total B12, with selective haptocorrin fluctuations or with cobalamin metabolism disorders at the intracellular level.<\/p>\n<p><strong>Keywords:<\/strong> vitamin B12, cobalamin, holotranscobalamin, haptocorrin<\/p>\n","casopis":[{"ID":1883,"post_author":"7","post_date":"2019-10-28 13:35:57","post_date_gmt":"2019-10-28 12:35:57","post_content":"<ul>\r\n \t<li>Detection and validation of subchromosomal aberrations detected as additional findings in routine noninvasive prenatal testing for common trisomies<\/li>\r\n \t<li>Finding of a marker chromosome in a child with Cat-eye syndrome (case study)<\/li>\r\n \t<li>Experimental therapy with stem cells is promissing in the treatment of chronic diabetic ulcer \u2013 a case study<\/li>\r\n \t<li>Colonic mucosal Schwann cell hamartoma with tactile corpuscle-like bodies: a case report<\/li>\r\n \t<li>Accidental capture of the toxic strain Corynebacterium diphteriae<\/li>\r\n<\/ul>","post_title":"newsLab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-004","to_ping":"","pinged":"","post_modified":"2019-11-04 13:53:35","post_modified_gmt":"2019-11-04 12:53:35","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.newslab.sk\/casopis\/newslab-4\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"85-89","upload_clanok":{"ID":1791,"id":1791,"title":"NEWSLAB_2-2019_Joppov\u00e1","filename":"NEWSLAB_2-2019_Joppov\u00e1.pdf","filesize":182020,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2019\/10\/NEWSLAB_2-2019_Joppov\u00e1.pdf","link":"https:\/\/www.newslab.sk\/en\/uloha-holotranskobalaminu-v-diferencialnej-diagnostike-nedostatku-b12\/newslab_2-2019_joppova-2\/","alt":"","author":"7","description":"","caption":"","name":"newslab_2-2019_joppova-2","status":"inherit","uploaded_to":1793,"date":"2019-10-28 13:01:21","modified":"2019-10-28 13:01:21","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1793","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=1793"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1793\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1793"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1793"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1793"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}