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21-09-2012

Àíòèòåëà ê âíóòðåííåìó ôàêòîðó

 

Ââåäåíèå

Äåôèöèò âèòàìèíà B12 ÿâëÿåòñÿ ÷àñòûì íàðóøåíèåì, âñòðå÷àþùèìñÿ â ïîïóëÿöèè, ãëàâíûì îáðàçîì â ñòàðîñòè, äåôèöèò âèòàìèíà Â12 ÷àñòî ïðèâîäèò ê ðàçâèòèþ ïåðíèöèîçíàÿ àíåìèÿ. Ðàñïðîñòðàíåííîñòü ïåðíèöèîçíîé àíåìèè èëè áîëåçíè Áèðìåíà îöåíèâàåòñÿ êàê 0,1% îò îáùåãî íàñåëåíèÿ è óâåëè÷èâàåòñÿ ñ âîçðàñòîì äî 1%. Îäíàêî íåäàâíèå èññëåäîâàíèÿ âûÿâèëè, ÷òî 1,9% ëþäåé ñòàðøå 60 ëåò ñòðàäàþò ýòèì çàáîëåâàíèåì (11).

Âèòàìèí Â12 (öèàíêîáàëàìèí)

Âèòàìèí Â12 (öèàíêîáàëàìèí) íåîáõîäèì äëÿ âîñïðîèçâîäñòâà ýðèòðîöèòîâ è íîðìàëüíîãî ôóíêöèîíèðîâàíèÿ íåðâíîé ñèñòåìû. Ïîä äåéñòâèåì ñîëÿíîé êèñëîòû è ïåïñèíà â æåëóäêå ïðîèñõîäèò âûñâîáîæäåíèå âèòàìèíà Â12 ïîñòóïàþùåãî ñ ïèùåé, ïîñëå ÷åãî îí âçàèìîäåéñòâóåò ñ îäíèì èç äâóõ âèòàìèí Â12-ñâÿçûâàþùèõ áåëêîâ æåëóäî÷íîãî ñîêà.  òîíêîì êèøå÷íèêå ïàíêðåàòè÷åñêèå ïðîòåàçû ðàñùåïëÿþò ñâÿçûâàþùèå áåëêè, âèòàìèí Â12 ïåðåõîäèò â ñâîáîäíóþ ôîðìó è ñâÿçûâàåòñÿ ñ âíóòðåííèì ôàêòîðîì.  êîíå÷íîì èòîãå ðåöåïòîðû âíóòðåííåãî ôàêòîðà â ñëèçèñòîé îáîëî÷êå ïîäâçäîøíîé êèøêè ñâÿçûâàþò îáðàçîâàâøèéñÿ êîìïëåêñ, è âèòàìèí Â12 ïîñòóïàåò â êðîâîòîê.

Ïåðíèöèîçíàÿ àíåìèÿ

Ïåðíèöèîçíàÿ àíåìèÿ ó âçðîñëûõ, êàê ïðàâèëî, âñòðå÷àåòñÿ â âîçðàñòå îò 40 äî 70 ëåò. Ïåðíèöèîçíàÿ àíåìèÿ ìîæåò ñî÷åòàòüñÿ ñ àóòîèììóííûìè ýíäîêðèíîïàòèÿìè è àóòîèììóííûìè çàáîëåâàíèÿìè ñ íàëè÷èåì àíòèòåë ê ðàçëè÷íûì ðåöåïòîðàì, òàêèìè êàê õðîíè÷åñêèé àóòîèììóííûé òèðåîèäèò (òèðåîèäèò Õàñèìîòî), èíñóëèíîçàâèñèìûé ñàõàðíûé äèàáåò, áîëåçíü Àääèñîíà, Ãðýéâà è âèòèëèãî. Çàáîëåâàíèå âïëîòü äî ïîçäíèõ ñòàäèé èìååò íåâûðàæåííóþ ñèìïòîìàòèêó, íî ïîðàæåíèÿ ñëèçèñòîé æåëóäêà âîçíèêàþò çà ìíîãî ëåò äî ðàçâèòèÿ àíåìèè. Êëèíè÷åñêèå ïðîÿâëåíèÿ çàáîëåâàíèÿ âêëþ÷àþò îáùóþ ñëàáîñòü, ïîòåðþ âåñà, ãëîññèò è ïîðàæåíèå ïåðèôåðè÷åñêîé íåðâíîé ñèñòåìû (íàèáîëåå ðàñïðîñòðàíåííûå – ïàðåñòåçèè). Ïåðíèöèîçíàÿ àíåìèÿ õàðàêòåðèçóåòñÿ äåôèöèòîì âèòàìèíà B12, ìåãàëîáëàñòíîé àíåìèåé, íåéðîïàòèåé è ãàñòðèòîì ñ íàëè÷èåì àíòèòåë ê âíóòðåííåìó ôàêòîðó (1,2). Íåîáõîäèìî îòìåòèòü, ÷òî ïåðíèöèîçíàÿ àíåìèÿ ìîæåò ïðîòåêàòü áåç ìàêðîöèòîçà è ñ íåçíà÷èòåëüíûì èëè óìåðåííûì äåôèöèòîì âèòàìèíà Â12 (12).

Õîòÿ ïåðíèöèîçíàÿ àíåìèÿ êëèíè÷åñêè ðàññìàòðèâàåòñÿ êàê çàáîëåâàíèå êðîâè, îíà ïðåäñòàâëÿåò ñîáîé êîíå÷íóþ ñòàäèþ àóòîèììóííîãî çàáîëåâàíèÿ, ðàçðóøàþùåãî ñëèçèñòóþ îáîëî÷êó æåëóäêà. Ê íàðóøåíèþ âñàñûâàíèÿ âèòàìèíà B12 è ðàçâèòèþ ìåãàëîáëàñòíîé èëè “ïåðíèöèîçíîé” àíåìèè ïðèâîäÿò äâà àóòîèììóííûõ ïðîöåññà:

  • Ïåðâûé – ñíèæåíèå âûðàáîòêè âíóòðåíåãî ôàêòîðà ïàðèåòàëüíûìè êëåòêàìè æåëóäêà. Âíóòðåííèé ôàêòîð – ãëèêîïðîòåèí, êîòîðûé ñèíòåçèðóåòñÿ èñêëþ÷èòåëüíî ïàðèåòàëüíûìè êëåòêàìè æåëóäêà. Îí íåîáõîäèì äëÿ òðàíñïîðòà è âñàñûâàíèÿ âèòàìèíà Â12 â òîíêîì êèøå÷íèêå. Äëÿ ïåðíèöèîçíîé àíåìèè õàðàêòåðíî óìåíüøåíèå ñèíòåçà âíóòðåííåãî ôàêòîðà.
  • Âòîðîé ïðîöåññ íàáëþäàåòñÿ ïðè áëîêèðîâàíèè àóòîàíòèòåëàìè ñâÿçûâàþùèõ ó÷àñòêîâ âíóòðåííåãî ôàêòîðà, íåîáõîäèìîãî äëÿ âñàñûâàíèÿ âèòàìèíà B12. Äëÿ ïåðíèöèîçíîé àíåìèè õàðàêòåðíî ïîÿâëåíèå àíòèòåë ê ïàðèåòàëüíûì êëåòêàì æåëóäêà è àíòèòåë ê âíóòðåííåìó ôàêòîðó. Ïàòîëîãè÷åñêèé ðåçóëüòàò äåéñòâèÿ àíòèòåë ê âíóòðåííåìó ôàêòîðó òàêîé æå – îòñóòñòâèå âñàñûâàíèÿ âèòàìèíà Â12 â êèøå÷íèêå.

Àíòèòåëà ê âíóòðåííåìó ôàêòîðó

Íàëè÷èå öèðêóëèðóþùèõ àóòîàíòèòåë ê âíóòðåííåìó ôàêòîðó âåñüìà ñïåöèôè÷íî äëÿ ïåðíèöèîçíîé àíåìèè è ðåäêî âñòðå÷àåòñÿ â íîðìàëüíîé ïîïóëÿöèè (1). Îïèñàíî äâà ðàçíûõ òèïà àóòîàíòèòåë ê âíóòðåííåìó ôàêòîðó:

  • Àóòîàíòèòåëà òèïà I, áëîêèðóþùèå âíóòðåííèé ôàêòîð, áëîêèðóþò ó÷àñòîê âíóòðåííåãî ôàêòîðà, ñâÿçûâàþùèé âèòàìèí B12, è ïðåïÿòñòâóþò çàõâàòó âèòàìèíà B12.
  • Àóòîàíòèòåëà òèïà II, ñâÿçûâàþùèå âíóòðåííèé ôàêòîð, ðåàãèðóþò ñ äðóãèì ó÷àñòêîì âíóòðåííåãî ôàêòîðà è ìîãóò ïðåïÿòñòâîâàòü ñîåäèíåíèþ êîìïëåêñà âíóòðåííåãî ôàêòîðà ñ âèòàìèíîì B12 ñî ñâÿçûâàþùèìè ó÷àñòêàìè â òîíêîé êèøêå (1).

 èññëåäîâàíèè Conn D. A. áûëî ïîêàçàíî, ÷òî â ãðóïïå èç 66 îáðàçöîâ, ïîëîæèòåëüíûõ ïî àíòèòåëàì ê âíóòðåííåìó ôàêòîðó, âñå îáðàçöû ñîäåðæàëè àíòèòåëà êàê I, òàê è II òèïà (10).

Ïåðíèöèîçíàÿ àíåìèÿ è íàëè÷èå àíòèòåë ê âíóòðåííåìó ôàêòîðó ñâÿçàíû ñ ðÿäîì àóòîèììóííûõ çàáîëåâàíèé, òàêèõ êàê òèðåîèäèò Õàñèìîòî, èíñóëèíîçàâèñèìûé ñàõàðíûé äèàáåò, áîëåçíü Ãðåéâñà, ðåâìàòîèäíûé àðòðèò, ìèàñòåíèÿ áåðåìåííûõ, ãèïîïàðàòèðåîç è ñèíäðîì Ëàìáåðòà-Èòîíà. (1,3,6,7,8,9). Íåîáõîäèìî òàêæå îòìåòèòü, ÷òî àíòèòåëà ê âíóòðåííåìó ôàêòîðó ìîãóò ïðèñóòñòâîâàòü ó 3 – 6% ëþäåé ñ ãèïåðòèðåîèäèçìîì èëè èíñóëèíîçàâèñèìûì ñàõàðíûì äèàáåòîì.

Äèàãíîñòèêà ïåðíèöèîçíîé àíåìèè

Äëÿ äèàãíîñòèêè ïåðíèöèîçíîé àíåìèè îñíîâíîå çíà÷åíèå èìååò êîìáèíàöèÿ ìåãàëîáëàñòíîé àíåìèè, íèçêîãî óðîâíÿ âèòàìèíà B12 â ñûâîðîòêå è íàëè÷èÿ â ñûâîðîòêå àóòîàíòèòåë ê âíóòðåííåìó ôàêòîðó (4). Ïðè îïðåäåëåíèè àíòèòåë ê âíóòðåííåìó ôàêòîðó äàëüíåéøèå èññëåäîâàíèÿ äëÿ äèàãíîñòèêè ïåðíèöèîçíîé àíåìèè, òàêèå êàê òåñò Øèëëèíãà, ìîãóò áûòü íå íóæíû (5). ×óâñòâèòåëüíîñòü ðàçíûõ òåñòîâ íà àíòèòåëà ê âíóòðåííåìó ôàêòîðó ðàçëè÷àåòñÿ, íî, êàê ïðàâèëî, îíà âûøå 50%. Áîëüøèíñòâî òåñòîâ â íàñòîÿùåå âðåìÿ âûïîëíÿåòñÿ âðó÷íóþ. Òåñò êîìïàíèè Beckman Coulter – ýòî åäèíñòâåííûé àâòîìàòèçèðîâàííûé òåñò.  êëèíèêî-äèàãíîñòè÷åñêîé ëàáîðàòîðèè ÎÎÎ «ÁÈÎÍ» èññëåäîâàíèå àíòèòåë ê âíóòðåííåìó ôàêòîðó âûïîëíÿåòñÿ íà èììóíîõèìè÷åñêèõ àíàëèçàòîðàõ UniCel DxI 800 ôèðìû Beckman Coulter, òåñò-íàáîðû ôèðìû Beckman Coulter. Ïðè äàííîì èññëåäîâàíèè îïðåäåëÿþòñÿ àíòèòåëà ê âíóòðåííåìó ôàêòîðó òèïà I.

Ñïåöèôè÷íîñòü äàííîãî ìåòîäà âûñîêà, ïîñêîëüêó àíòèòåëà ê âíóòðåííåìó ôàêòîðó ÷ðåçâû÷àéíî ðåäêî âñòðå÷àþòñÿ â òåõ ñëó÷àÿõ, êîãäà äåôèöèò âèòàìèíà Â12 íå ñâÿçàí ñ ïåðíèöèîçíîé àíåìèåé (13).

Êîìïëåêñ ëàáîðàòîðíûõ òåñòîâ äëÿ äèàãíîñòèêè ïåðíèöèîçíîé àíåìèè:

  • Îáùèé àíàëèç êðîâè CBC/Diff
  • Ëåéêîöèòàðíàÿ ôîðìóëà (ìèêðîñêîïèÿ)
  • Ñêîðîñòü îñåäàíèÿ ýðèòðîöèòîâ (ÑÎÝ) ìåòîä Westergren
  • Ðåòèêóëîöèòû
  • Âèòàìèí Â12
  • Àíòèòåëà ê âíóòðåííåìó ôàêòîðó
  • Ôîëèåâàÿ êèñëîòà

Íåñâîåâðåìåííîå âûÿâëåíèå ïåðíèöèîçíîé àíåìèè è îòñóòñòâèå àäåêâàòíîãî ëå÷åíèÿ ìîæåò ïðèâåñòè ê íåîáðàòèìûì èçìåíåíèÿì ñî ñòîðîíû íåðâíîé ñèñòåìû, êîòîðûå íå ïîääàþòñÿ çàìåñòèòåëüíîé òåðàïèè âèòàìèíîì Â12. Èìåííî ïîýòîìó âûÿâëåíèå íå äèàãíîñòèðîâàííûõ ñëó÷àåâ èìååò âàæíåéøåå çíà÷åíèå, îñîáåííî äëÿ ïîæèëûõ ëþäåé (11).

Ëèòåðàòóðà 

1. Chanarin I. The Megaloblastic Anaemias. Second edition. London, Blackwell Scientific Publications, 1979.

2. Gueant JL. Autoantibodies in pernicious anemia type I patients recognize sequence 251-256 in human intrinsic factor. Proc Assoc Am Physicians 1997. 109(5) : 462-469.

3. Whittingham S, MacKay IR. Pernicious Anemia and Gastric Atrophy. In The Autoimmune Diseases. Academic Press; Orlando, Fla. 1985: 243-266.

4. Lindenbaum J. Status of laboratory testing in the diagnosis of megaloblastic anemia. Blood 1983. 61 (4): 624-627.

5. Nimo RE, Carmel R, Increased sensitivity of detection of the blocking (type I) anti-intrinsic factor antibody. American Journal Clinical Pathology, 1987. 88(6), 729-733.

6. Carmel R. Reassessment of the relative pervalences of antibodies to gastric parietal cell and to intrinsic factor in patients with pernicious anaemia: influence of patient age and race. Clin. exp. Immunol. 1992. 89: 74-77.

7. Glass JB. Gastric Intrinsic Factor and Other Vitamin B12 Binders. Georg Thieme publishers Stuttgart, 1974: 29-36.

8. Mardh S. Occurrence of autoantibodies against intrinsic factor, H, K-ATPase, and pepsinogen in atrophic gastroenteritis and rheumatoid arthritis. Scand J of Gastroenterology, 1991. 26(16):1089-96.

9. Chanarin I. The Megaloblastic Anaemias. Second edition. London, Blackwell Scientific Publications, 1979: 332.

10. Conn D.A. Detection of type I and type II antibodies to intrinsic factor. Medical Laboratory Sciences, 1986:43:148-151.

11. Carmel R. Prevalence of Undiagnosed Pernicious Anemia in the Elderly. Arch Inter Med, 1996:156:1097-1100.

12. Carmel R. Pernicious Anemia: The expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med, 1988:148:1712-1714.

13. Sourial N. Rapid protein A assay for intrinsic factor and its binding antibody. J Clin Pathol, 1988:41:568-572.