Clinically Significant Vitamin B12 Deficiency Secondary to Malabsoption of Protein-Bound Vitamin B12

8/13/2019 Clinically Significant Vitamin B12 Deficiency Secondary to Malabsoption of Protein-Bound Vitamin B12

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C linical ly S ignificant Vitam in B12 D ef ic ie n cySecon dary t o M alabsorpt ion o f Pro te in

B o u n d V i ta m in B 2C H A R L E S E . K IN G , M D , JO H N L E I B A C H , M D , an d P H I L L I P P . T O S K E S , M D

P ro te in - ( c h i c k e n s e ru m ) b o u n d [~ rC o ]c y a n o c o b a la m in a b so rp t io n w a s e v a lu a t e d i n f i v eh y p o c h lo rh y d r i c p a t i e n t s w h o h a d d e v e lo p e d B 12 d e f i c i e n c y d e sp i t e h a v in g n o rm a l a b so rp -t i o n o f u n b o u n d c ry s ta l li n e v i t a m in B 12. A l l f i v e p a t i e n t s h a d d e c re a se d u r in a ry e x c re t i o no f p ro t e in - b o u n d B 12 ( 0 .0 6 - 0 . 3 4 ) a s c o m p a re d t o tw e l v e n o rm a l c o n t ro l s ( 0 . 6 1 -5 . 6 ) ,P < .0 0 1. I m p ro v e m e n t i n p ro t e in - b o u n d B 12 a b so rp t io n i n f o u r o f t h e f i v e p a t i e n t s o c -c u r re d w i th t h e e x o g e n o u s a d m in i s t ra t i o n o f h y d ro c h lo r i c a c id , p e p s in , g a s t r i c i n tr i n s icfa c to r , o r a c o m b in a t io n t h e re o f . V i t a m in B 12 d e f i c i e n c y d e v e lo p in g i n t h e s e t ti n g o f h y -p O c h lo rh y d ria m a y r e su l t f ro m d e f i c i e n c y o f a c id - p e p ti c d ig e s t i o n o f B 12 b o u n d to p ro t e ina n d~ o r a r e la t iv e d e f i c i e n c y o f i n t r in s i c f a c to r . T h i s d ig e s t i v e d e f e c t i s n o t d e t e c t e d w i tht e s t s w h ic h m e a su re t h e a b so rp t io n o f u n b o u n d c ry s ta l l in e B 12 b u t i s d e t e c t e d b y a s im p let e s t w h ic h e m p lo y s B 1 2 b o u n d to c h i c k e n s e ru m a s t h e f o r m o f p ro t e in - b o u n d B x 2.

T h e a b s o r p t i o n o f v i ta m i n B 1 2 i s u s u a l ly t h o u g h t o fi n t e rm s o f e v e n t s o c c u i x i n g i n t h e s t o m a c h , i n t h el u m e n o f t h e s m a l l i n t e s t in e , a n d a t t h e i l e al r e c e p -to r f o r t h e v i t a min B 1 2 - g a s tr ic i n t r i n s i c f a c to r c o m -p l e x . A s a n a l y z e d b y t h e u s u a l t e s t s o f a b s o r p t io n o fu n b o u n d c r y s t al l i n e v it a m i n B 12 , t h e p r i m a r y a b n o r -ma l i t i e s f e l t t o p a r t i c i p a t e i n t h e ma la b s o r p t i o n o fv i t a min B 12 h a v e i n c lu d e d d e f i c i e n c y o f g a s t r i c i n -t r i n s i c f a c to r ; p a n c r e a t i c i n s u f f i c i e n c y ; b a c t e r i a l o rp a r a s i t i c i n f e s t a t i o n o f t h e s m a l l i n t e s t i n e ; a n d d a m-a g e , r e s e c t i o n , o r c o n g e n i t a l a b n o r m a l i t i es o f t h espec i f ic i lea l r eceptor for the in t r ins ic f ac tor -v i taminB12 co m ple x (1).

F r o m t h e V e t e r a n s A d m i n i s t r a t i o n H o s p i t a l a n d D e p a r t m e n to f M e d i c i n e , U n i v e r s i t y o f F l o r i d a C o l l e g e o f M e d i c in e , G a i n e s -v i l l e , F l o r i d a .D r . K i n g is t h e r e c i p i e n t o f a R e s e a r c h A s s o c i a t e A w a r df r o m t h e V e t e r a n s A d m i n i s t r a t i o n . D u r i n g t h e p e r f o r m a n c e o ft h e s e s t u d i e s D r . T o s k e s w a s a C l i n i c a l I n v e s t i g a t o r w i t h t h eV e t e r a n s A d m i n i s t r a t i o n .S u p p o r t e d i n p a r t b y G r a n t R R - 8 2 f r o m t h e N a t i o n a l I n s t i t u t e so f H e a l t h .P r e s e n t e d i n p a r t a t t h e A n n u a l M e e t i n g o f t he A m e r i c a n G a s -t r o e n t e r o l o g y A s s o c i a t i o n i n T o r o n t o , C a n a d a , M a y 1 9 7 7.A d d r e s s f o r r e p r i n t r e q u e s t s : D r . P . P . T o s k e s a t t h e G a s t r o e n -t e r o l o g y S e c t i o n , V e t e r a n s A d m i n i s t r a t i o n H o s p i t a l , G a i n e s v i l l e ,F l o r i d a 3 2 6 0 2 .

T h e a s s imi l a t i o n o f v i t a min B 1 2 f r o m f o o d s r e -q u i r e s a n a d d i t i o n a l s t e p : t h a t o f f r e e in g v i t a min B 12f r o m t h e f o o d . D e s p i t e t h e p r e d o m i n a n t p r o t e i n -b o u n d s t a t e o f d i e t a r y v i t a min B 1 2 , i t h a s b e e n g e n -e r a l l y a c c e p t e d t h a t v i t a min B lz d e f i c i e n c y d o e s n o to c c u r a s a r e s u l t o f m a l d i g e s t i o n o f p r o t e i n - b o u n dvi tam in B12 (2). Vi ta m in B12 de f ic ien cy fo l lowingp a r ti a l g a s t r e c t o m y h a s b e e n t h o u g h t t o b e d u e p r i-m a r i l y to i n t ri n s i c f a c t o r d e f i c i e n c y a n d s e c o n d a r i l yto s m a l l i n t e s t i n a l i n f e s t a t i o n ( 3 , 4 ) . A l th o u g h D e l -l e r s s t u d y ( 3) i s o f t e n q u o t e d t o s u p p o r t t h e imp o r -t a n c e o f i n t r in s i c f a c t o r d e f i c i e n c y i n p a t ie n t s w h oh a v e h a d p a r t i a l g a s t r i c r e s e c t i o n s , t h e f i n d in g t h a t13 o f 26 p a t i e n t s i n t h a t s t u d y w i th s u b n o r m a l l e v e l so f v i t a min B i2 i n t h e s e r u m a b s o r b e d v i t a min B 1 2n o r m a l l y i s n o t w e l l a p p r e c i a t e d . T h e f a c t t h a t t h e s e1 3 v i t a min B a 2 - d e f i c i e n t s u b j e c t s h a d n o r ma l a b -s o r p t i o n o f u n b o u n d c r y s t a l l i n e v i t a min B 1 2 s u g -g e s t s t h a t t h e y m a y h a v e b e c o m e d e f i c ie n t i n t h ev i t am i n b e c a u s e o f a f a i lu r e t o a b s o r b p r o t e i n -b o u n d v i t a m in B 1 2.T h e s u s p e c t e d l a c k o f a c i d a n d p e p s i n s e c r e t i o ni n th e s e p a t i e n t s w h o h a d g a s t ri c s u r g e r y m a y h a v el e d to t h e m a l a b s o r p t i o n o f p r o t e i n - b o u n d v i t a m i nB 1 2 d u e t o a n i n a b i l it y t o c l e a v e t h e v i t a m in B ~2 f r o m

Digestive Diseases and Sciences, Vol. 24, No. 5 May 1979)0163-2116/79t0500-0397503.00/19 1979DigestiveDisease Systems, Inc.

3 9 7


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K I N G E T A LTABLE 1. PATIENT DATA

S t a g e IS e r u m B 12 c r y s t a l l i n e B 12Age (normal absorptionPatient (years) Sex >200 pg /m l) (n or ma l>8 )

G a s t r i cacid output(mEq/hr)B A O / M A O

N e u r o l o g i c a ls y m p o m sHct( )

1 6 8 M 75 252 67 M 118 21 0 / 1 30/03 59 M 107 14.4 0/04 66 F 159 19 2.0/14.15 51 M 177 20 0/0

Dementia ataxiaMemory loss,ataxia, dysesthesiasDysesthesiasDysesthesias

3045353643

*Alkaline, bile-stained residual gastric fluid prior to c ollection of basal specimen .

i ts p r o t e i n b o n d . M a h m u d e t a l ( 5) d e m o n s t r a t e dm a l a b s o r p t i o n o f u n b o u n d c r y s t a l li n e v i t a m i n B lz i no n l y '/3 o f v i t a m i n B l ~- d ef ic ie n t p o s t g a s t r e c t o m y p a -t i e n t s , w i t h t h e o t h e r 2/3 ( o f 6 2 p a t i e n t s ) h a v i n g n o r -m a l u n b o u n d c r y s t a l li n e B~2 a b s o r p t i o n . F u r t h e rs u p p o r t f o r t h e i m p o r t a n c e o f p r o t e i n - b o u n d v i ta -m i n B 12 m a l a b s o r p t i o n i n t h e d e v e l o p m e n t o f v i t a -m i n B 12 d e f i c i e n c y w a s s e e n i n t h e r e c e n t r e p o r t o fR y g v o l d , w h o n o t e d l o w s e r u m v i t a m i n B I 2 l e v e l s i n6 7 o f 35 1 p a t i e n t s w h o h a d u n d e r g o n e a B i ll r o th I Ip a r t ia l g a s t r e c t o m y ( 6) . I n t h o s e p a t i e n t s w i t h l o wserum B12 l e v e l s , 3 1 % w e r e n o t e d t o h a v e n o r m a la b s o r p t i o n o f u n b o u n d c r y s t a l l i n e B ~2 ( s t a g e IS c h il li n g t e s t) i m p l y i n g m a l a b s o r p t i o n o f v i ta m i nB a r f r o m f o o d a s t h e e t i o l o g y o f th e v i t a m i n B 12 d e f i-c i e n c y . O n l y 3 3 % h a d S c h il li n g te s t r e s u l t s s u p p o r t -i n g i n t r i n s i c f a c t o r d e f i c i e n c y a s t h e c a u s e f o r t h el o w s e r u m v i t a m i n B a2 l e v e l s. T h e p r e s e n t s t u d ye v a l u a te s t h e a b s o r p t i o n o f p r o te i n - b o u n d v i t a m i nB~2 b y 5 p a t ie n t s w h o w e r e r e f e r r e d t o u s f o r e v a l u a -t io n o f v i ta m i n B ,2 d e f ic i e n c y d e v e l o p i n g i n th e f a c eo f n o r m a l a b s o r p t i o n o f u n b o u n d c r y st a ll in e v i t a m i nB ~2 . V i t a m i n B ,2 b o u n d t o c h i c k e n s e r u m ( 7 ) w a su t i li z e d a s t h e t e s t o f p r o t e i n - b o u n d v i t a m i n B 12 a b -s o r p t i o n .

M T E R I L S N D M E T H O D SAl l s t ud i e s we r e ca r r i ed ou t und e r ca r e f u l l y con t r o l l edcond i t i ons i n a c l i n i ca l r e sea r ch cen t e r war d . I n f o r medcons en t wa s g r an t ed b y a l l sub j ec t s , and a l l i nves t i ga t i onsw e r e a p p r o v e d b y t h e U n i v e r s i t y o f F lo r i d a H e a l t h C e n -t e r C o m m i t t e e f o r th e P r o t e c t i o n o f H u m a n S u b j e c t s .S e r um v i t ami n B12 l eve l s wer e de t e r m i ned by t he Eu-glena gracilis a s s a y ( 8 ). A b s o r p t i o n o f u n b o u n d c r y s t a l-l ine v i t ami n BI ~ was de t e r mi ned by t he u r i na r y exc r e t i ont e s t o f S ch i l l ing ( 9 ). O r a l admi n i s t r a t i on o f pT C o] v i t ami nB12 was f o l l owed by a f l ush ing pa r en t e r a l d ose o f 1000 / zgo f u n la b e l e d c y a n o c o b a l a m i n a n d 2 4 - h r c o l le c t io n o f

ur ine. Ur inary excret ion of [57Co]vi tamin B,2 was calcu-l a t ed , f o l l owi ng de t e r m i na t i on o f 57Co con t en t o f an a l i -q u o t o f w e l l - m i x ed u r in e i n a s t a n d a r d w e l l -t y p e g a m m acount e r . Abso r p t i on o f unbo und c r ys t a l l ine v i t ami n B12was d e t e r m i ned wi t h o r a l admi n i s t r a t ion o f 1 p.g ( 0 .6 / zC i )[ 5 7 C o ] c y a n o c o b a l a m i n ( R u b r a t o p e , E . R . S q u i b b an dS o n s , I n c . , P r i n c e t o n , N e w J e r s e y ) . P r o t e i n - b o u n d v i t a -mi n B ,2 doses wer e made by mi x i ng 4 ml o f s t e r i l i zed ,pa t hogen- f r ee ch i cken se r um ( Gr and I s l and B i o l og i ca lC o . , G r a n d I s l a n d , N e w Y o r k ) w i t h a p p r o x i m a t e l y 0 .5~ Ci and 1 / zg o f [~ T Co] cyanocoba lami n ( Amer sh am, E n-g l and) . D i a l ys i s f o r 72 h r wa s f o l l owed by c heck i ng f o ra d e q u a c y o f r e m o v a l o f f re e B , 2 w i th a m o d i fi c at io n o f t h echa r coa l a s say o f Got t l ieb e t a l ( 10) . Adm i n i s t r a t i on o fgas t r i c i n t r i ns i c f ac t o r w i t h p r o t e i n - bound v i t ami n B ,2w a s p e r f o r m e d b y m i x i n g th e c o n t e n t s o f o n e c a p s u l e o fi n t r i ns i c f ac t o r ( I F ) concen t r a t e ( 1 NF XI un i t pe r cap-s u l e, E . R . S q u i b b a n d S o n s , I n c . , P r i n c e t o n , N e w J e r s e y )wi t h t he p r o t e i n - B ,2 so l u ti on . A c i d and / o r peps i n was ad-mi n i s t e r ed v i a o r agas t r i c t ube ( 100 ml o f 0 .1 N hydr o -ch l o r i c ac i d and / o r 500 mg of 2 c r ys t a l l i zed hog gas t r i cpeps i n ) ( S i gma Chemi ca l Co . , S t . L ou i s , M i s sour i ) , f o l -l o w e d b y e x t u b a t i o n a n d i m m e d i a t e o r a l a d m i n i s tr a t io n o ft he p r o t e i n - v i t ami n B ,2 so l u t i on .G a s t r ic a c i d o u t p u t w a s d e t e r m i n e d f o ll o w in g n a s o g a s -t r ic i n t uba t i on , w i t h f l u r oscop i c gu i dance o f t he t ube i n t ot he an t r um . F o l l owi ng a sp i r a t i on o f r e s idua l con t en t s ,f our 15-mi n basa l a sp i r a t i ons w er e f o l l owed b y s i x 15-mi nasp i r a t i ons a f t e r t he subcu t aneo us adm i n i s t r a t ion o f 6 / zg /k g b o d y w e i g h t p e n t a g a s t r i n ( P e p t a v l o n , A y e r s t , N e wY o r k , N e w Y o r k ) A l i q u o ts o f s t ra i n e d g a s t r ic a s p i r a t ewer e t i t r a t ed t o pH 7 w i t h 0 .1 N sod i um h ydr ox i de . Basa la c id o u t p u t ( B A O ) w a s c o m p u t e d f r o m t h e t o t a l t it r a ta b l eac i d i t y f o r t he hour basa l co l l ec t i on . M a xi ma l ac i d ou t pu t( M A O ) i s e x p r e s s e d a s t h e s u m o f t h e m a x i m a l f o u r ( o fs i x ) c o n s e c u t i v e 1 5 - m in a c i d o u t p u t s i n t h e p o s t -s t i mul a t i on pe r i od .P a t i en t s . Da t a on t he f i ve pa t i en t s who p r esen t ed w i t hvi tamin B12 def ic iency and normal absorpt ion of unboundcr ys t a l l ine v i t am i n B ,~ a r e sho wn i n T ab l e 1 . P a t i en t s 1and 2 wer e admi t t ed w i t h cen t r a l and pe r i phe r a l neur o-p a t h i c s y m p t o m s , p a t i e n t 1 m a n i f e s ti n g s e v e r e d e m e n t i ap r o m p t i n g a d m i s s i o n t o t h e N e u r o l o g y S e r v i c e . F o l l o w -i n g t h e d i s c o v e r y o f s e v e r e l y d e p r e s s e d s e r u m v i t am i n B , 2l eve l s in each , pa r en t e r a l v i t ami n B12 t he r ap y w as begu n ,

98 Diges t i ve Di sease s and Sc i ences , Vo l . 24, No . 5 (Ma y 1979)


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ig 1. A bsorption o f protein-bound vitamin B12 by twelve nor-mal co ntrols and five patients w ith vitamin B12 deficiency andnorm al absorption o f unbound crystalline vitamin B~2.

l e a d ing to fu l l r e mis s ion o f ne u ro log ic s igns a nd s ymp-toms . P a t i e n t 1 ha d , i n a dd i t ion , a ne mia o f c om bine de t io logy , i nc lud ing v i t a min B 12 de f i c i e nc y a nd c h ron ic d i s -e a s e . Pa t i e n t 3 ha d the c o n fus ing p i c tu re o f v i ta min B 12de f i c i e nc y , G ra ve s ' d i s e a s e w i th c i r c u la t ing a n t i i n t r in s i cfa c to r a n t ibody , a nd a c h lo rhyd r i a , a l l f e l t t o r e p re s e n tc l a s si c a l pe rn ic ious a ne m ia un t i l unbou nd c rys t a l li ne v i t a -m i n B I~ a b s o r p t i o n t e s ts w e r e r e p e a t e d l y n o r m a l a t> 14% . Se rum fo la t e w a s e l e v a te d a t 22 ng /ml a nd de -c re a s e d to 6 ng /ml du r ing pa re n te ra l v i t a min B I~ the ra p y ,as is of ten note d in 9 v i tam in B12 defic ie ncy.A ne m ia w a s fe l t t o be due to i ron d e f i c i e nc y a nd pos s ib l evi tam in B12 d e f i c ie n c y , r e sp o n d i n g t o c o n c u r r e n t t h e r a p yw i th i ron a nd v i t a min B12 Pa t i e n t s 4 a nd 5 de mons t ra t e dp r ima r i ly mi ld pe r iphe ra l ne u ropa th i c s ympto ms , w i th a s -s oc ia t e d a ne m ia o f c h ron ic d i s e a s e a nd a lka l ine ga s t r i cre f lux in pa t i e n t 4 a nd hyp oc h lo rhy d r i a s e c onda ry to aB i l l ro th I I pa t r i a l ga s t re c to my in pa t i e n t 5 . N one o f t hepa t i e n t s ha d d i a be te s , a l c oho l a bus e , o r fo l a t e de f i c i e nc ya s e t io log ic f a c to r s fo r t he i r ne u ropa th i c s ym ptoms a nd /o ra ne mia , a nd a l l ha d no rma l d i e t a r y B a~ in t a ke by h i s to ry .Fou r o f t he f ive pa t i e n t s de mo ns t ra t e d a c h lo rhyd r i a o r s e -ve re hypo c h lo rh yd r i a on ga s t r i c a na ly s is , a nd one Pa t i e n tha d a lka l ine , b i l e - s t r a ine d ba s a l ga s t r i c s e c re t ions a t t het ime o f tw o o f t h re e ga s t r i c i n tuba t ions . Pa t i e n t 5 w a s theon ly pa t i e n t w i th p re v ious ga s t r i c s u rge ry .D a ta Eva lua t ion . G roups w e re c ompa re d u s ing S tu -d e n t ' s t t e st a n d th e W i l c o x o n - M a n n - W h i t n e y r a n k s u mtes t (11) . Al l da ta a re ex pre ssed as m ean --_ SEM.

R E S U L T SF i g u r e 1 s h o w s t h e r e s u l t s o f t h e u r i n a r y e x c r e -

t i o n t e s t f o l l o w i n g t h e o r a l a d m i n i s t r a t i o n o f c h i c k -e n s e r u m - [~ T C o ] B i2 t o t w e l v e n o r m a l c o n t r o l s a n dt h e f i v e p a t i e n t s . C o n t r o l s e x c r e t e d 2 . 3 2 _+ 0 . 4 2 %( m e a n -+ S E M ) o f t h e d o s e o v e r 2 4 h r , w i t h a r a n g eo f 0 . 6 1 - 5 . 6 % . T h e f i v e p a t i e n t s e x c r e t e d f r o m 0 . 0 6t o 0. 3 4 % o f th e d o s e , P < 0 . 01 i n c o m p a r i s o n t o t h ec o n t r o l s .

F i g u r e 2 c o m p a r e s t h e r a n g e o f [ SrC o]B 12 e x c r e -t i o n in c o n t r o l s t o t h a t o f t h e f i ve p a t ie n t s w h e n t h ep a t i e n t s h a d t h e p r o t e i n - b o u n d v i t a m i n B 12 a d m i n i s -t e r e d c o n c o m i t a n t l y w i t h e x o g e n o u s i n t r i n si c f ac -t o r , h y d r o c h l o r i c a c id , p e p s i n , o r a c o m b i n a t i o nt h e r e o f . O n e o f t h e fi v e p a t i e n t s r e a c h e d t h e l o w -n o r m a l r a n g e w i t h t h e a d m i n i s t r a ti o n o f in t r in s i cf a c t o r a l o n e , w i t h a f u r t h e r r e m a r k a b l e i n c r e a s ew i t h th e e x o g e n o u s a d m i n i s t r a t i o n o f a c i d a n d p e p -s in a l o n g w i t h t h e I F . I n t w o o f f o u r p a t ie n t s t e s t e d ,t h e a d m i n i s t r a t i o n o f a c id a l o n e c o r r e c t e d t h e m a l -a b s o r p t i o n o f p r o t e i n - b o u n d B ~ , w i t h a f u r t h e r i n -c r e a s e i n o n e w i t h t h e a d d i t i o n a l a d m i n i s t r a t i o n o fp e p s i n . P a t i e n t 3 h a d s l i g h t i n c r e a s e s o v e r b a s e l i n e( st il l b e l o w t h e n o r m a l r a n g e ) w i t h t h e a d d i t i o n o f I Fa l o n e , a c i d a l o n e , a n d w i t h a c i d p l u s p e p s i n , a n dh a d a s y n e r g i s t i c e f f e c t i n t o t h e c l e a r l y n o r m a l r a n g ew h e n a l l t h r e e g a s t r ic f a c t o r s w e r e a d m i n i s t e r e d t o -g e t h e r . P a t i e n t 5 , w h o h a d t h e B i l l ro t h I I a n a s t o -m o s i s , f a i l e d t o n o r m a l i z e p r o t e i n - b o u n d B a2 a b -s o r p t i o n w i t h a n y c o m b i n a t i o n t e s t e d , i m p l y i n g i n -a d e q u a t e n v vo f u n c t i o n o f t h e e x o g e n o u sf a c i l i t a t o r s o f p r o t e i n - b o u n d B 12 a b s o r p t i o n , p o s s i -b l y d u e t o r a p i d g a s t r i c e m p t y i n g .

D I S C U S S I O NT h i s r e p o r t , a l o n g w i t h t h e d a t a o f o t h e r s ( 3 , 5 -

7 ) , d e m o n s t r a t e s t h e d e v e l o p m e n t o f v i t a m i n B I2d e f i c i e n c y d u e t o v i t a m i n B 12 m a l a b s o r p t i o n u n d e -t e c t e d b y t h e u s u a l m e a n s o f as s e ss i n g a b s o r p t i o n o ft h is v i t a m i n . A l l fi v e p a t i e n t s h a d d e p r e s s e d s e r u mB 1~ l e v e l s , t h r e e w i t h c e n t r a l a n d / o r p e r i p h e r a l n e u -r o p a t h i c s y m p t o m s r e s p o n s i v e t o p a r e n t e r a l B12t h e r a p y , d e s p i t e n o r m a l a b s o r p t i o n o f u n b o u n dc r y s t a l l i n e v i t a m i n B 12 ( s t a g e I S c h i l l i n g t e s t ) . I n a d -d i t i o n , o n e p a t i e n t h a d t h e c l i n i c a l l y e n i g m a t i c p r e -s e n t a t i o n t h a t l o o k e d l i k e c l a s s i c a l p e r n i c i o u sa n e m i a b y s e v e r a l c r it e r i a e x c e p t f o r o n e t h i ng , t h el a c k o f m a l a b s o r p t i o n o f u n b o u n d c r y s t a ll i n e v i ta -m i n B 1 2 . L o w - g r a d e a n e m i a s e e n i n t w o o f t h e p a -t i e n ts m a y h a v e b e e n p a r t i a l l y r e l a t e d t o v i t a m i n B ~d e f i c i e n c y ; i n a d e q u a t e e v a l u a t i o n o f a n e m i a t o o k

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P E P S I N I , F .F i g 2 . E f fe c t o f in t r in s i c f a c to r , a c i d , p e p s i n , o r a c o m b i n a t i o n t h e r e o f o n p r o t e i n - b o u n dv i t a m i n B 1 2 a b s o r p t i o n i n fi v e v i t a m i n B i 2 - d e f i c ie n t s u b j e c t s .

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p l a c e i n al l c a s e s p r i o r to c o m m e n c e m e n t o f p a r e n t-e r a l v i t a min B 12 th e r a p y a n d r e f e r r a l t o u s f o r e v a lu -a t i o n o f v i t a min B 12 ma la b so r p t i o n .

T h e e v a lu a t i o n o f p r o t e in - b o u n d v i t a min B12 a b -s o r p t i o n w a s m a d e i n t h e p r e s e n t s t u d y u t i l i z i n gc h i c k e n s e r u m - b o u n d [ ~ T C o ] c y a n o c o b a l a m i n ( 7 ) .B i n d i n g o f v i t am i n B I~ i n c h i c k e n s e r u m p r o b a b l yinvo lves a t leas t tw o v i tam in B12 b ind e rs (12 , 13) .A l t h o u g h t h i s f o r m o f l iq u i d p r o t e i n - b o u n d v i t a m i nB 12 me a l i s c e r t a in ly n o t t h e s a m e a s a m e a l in w h ic hp r o t e in - b o u n d v i t a min B I ~ i s i n c o r p o r a t e d i n so l i df o o d , t h e r e su l t s o f t h i s s t u d y d e m o n s t r a t e i t s a bi li tYt o d e t e c t a d i g e s t i v e d e f e c t in t h e a b s o r p t i o n o f p r o -t e in - b o u n d v i t a m in B 1 2. I n f a c t , i t i s p r o b a b l e t h a tn o o n e t e s t o f p r o t e i n - b o u n d v i t a m i n B 12 a b s o r p t i o nw o u l d c l e a r l y re p r e s e n t t h e a b s o r p t i o n o f al l f o r m so f p r o t e i n - b o u n d v i t a m i n B 12 b e c a u s e o f t h e v a r i-a b l e r e q u i r e m e n t f o r p r o t e o l y t i c r e l e a s e o f p r o t e i n -b o u n d v i t a min B 12 d e p e n d in g o n t h e a n im a l ( b e e f ,p ig , sh e e p , o r c h i c k e n ) a n d /o r o r g a n ( l i v e r , mu sc l e ,k id n e y ) t h a t i s e mp lo y e d ( 1 4 - 1 8 ) a n d t h e v a r i a b i l i tyo f ab s o r p t i o n a n d / o r p o s t a b s o r p t i v e m e t a b o l i s m d e -p e n d i n g o n t h e c h e m i c a l f o r m o f v i t a m i n B 12 ( c o e n -z y m e B 1 2 , h y d r o x y c o b a l a m i n , c y a n o c o b a l a m i n ,e tc ) tha t i s inges ted (18-20) .

I n t h e p r e s e n t s t u d y , m a l a b s o r p t i o n o f p r o te i n -b o u n d v i t a m i n B I~ w a s c o r r e c t e d i n f o u r o f t h e f i v ep a t i e n ts w i t h t h e a d m i n i s t r a t i o n O f h y d r o c h l o r i ca c id , p e p s in , g a s t r i c i n t r i n s ic f a c to r a n d /o r a c o m b i -n a t i o n o f t w o o r t h r e e o f t h e s e g a s t r i c f ac i li t at o r s o fp r o t e in - b o u n d B 1 2 a b so r p t i o n . n v i t r o a n d i n v i v od a t a r e g a r d in g r e l e a se o f v i t a m in B 12 f r o m p r o t e in i nt h e p r e s e n c e o f a c i d - p e p s i n i s c o n t r o v e r s i a l, s h o w -i n g a r e q u i r e m e n t fo r a c i d - p e p t i c a c t i v it y in s o m estudie s (7 , 17 , 21), n o req ui r em en t in o the r s (16),a n d v a r i a b l e r e su l t s i n o th e r s ( 1 4 , 2 2) . O u r d a t a su p -p o r t a r e q u i r e m e n t f o r a c i d , p e p t i c a c t iv i t y in t h e a b -s o r p t io n o f p r o t e i n - b o u n d B 12 . F u r t h e r s t u d ie s w i t ho t h e r t y p e s o f p r o t e i n - b o u n d B 12 m e a l s e m p l o y i n ge x o g e n o u s a d m i n i s t r a t i o n o f a c i d - p e p t i c a c t i v i t yw i l l b e i n t e r e s t i n g .T h e n o r m a l a b s o r p t i o n o f u n b o u n d c r y s t a l l i n e vi -t a min B 12 in a l l fi v e o f o u r p a t i e n t s imp l i e s t h a t t h e r ei s n o d e f i c i e n c y ( b y t h e c o m m o n l y a c c e p t e d c r i t e -r i o n ) o f g a s t r ic i n t r i n s i c f a c to r i n t h e se p a t i e n t s .H o w e v e r , t h e r e s u l t s o f p r o t e i n - b o u n d v i t a m i n B12a b s o r p t i o n i n t w o o f o u r p a t i e n t s ( w h 9 h a d s y n e r -g i st ic i m p r o v e m e n t i n p r o t e i n - b o u n d B12 a b s o r p t i o nw h e n a d m i n i s t e r e d e x o g e n o u s I F , a c i d , a n d p e p s i n )imp l i e s a p o s s ib l e r e l a t i v e d e f i c i e n c y o f I F i n t h e se

4 Digestive Diseases and Sciences, Vol. 24, No. 5 May 1979)


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p a t i e n t s . I t i s a p p r e c i a t e d t h a t g a s t r i c i n t r in s i c fa c -t o r i s n o r m a l l y s e c r e t e d i n g r e a t e x c e s s b y h u m a n s ,w i t h t h is e x c e s s d e c r e a s i n g f o l l o w i n g g a s t r i c s u r-g e r y o r d e v e l o p m e n t o f g a s t r i c a t r o p h y ( 23 , 2 4 ). I ti s p o s s i b l e t h a t t h is e x c e s s i s n o r m a l l y s e c r e t e d i no r d e r to c o u n t e r a c t n o r m a l c o m p e t e t i v e b i n d i n g o fv i t a m i n B 12 b y o t h e r v i t a m i n B 12 b i n d e r s ( 25 ) a n d / o rd e g r a d a t i o n o r b i n d i n g o f i n t r i n s ic f a c t o r b y c o n s t i t -u e n t s o f t h e m e a l a n d / o r s e c r e t i o n s o f t h e m o u t h ,s t o m a c h , o r s m a l l i n t e s t i n e . P e r h a p s t h e r e l a t i v e I Fd e f i c i e n c y n o t e d i n o u r t w o p a t i e n t s ( a s m a n i f e s t e db y p r o t e i n - v i t a m i n B 12 m a l a b s o r p t i o n i m p r o v e d b ye x o g e n o u s I F ) is a p h a s e i n t h e d e v e l o p m e n t o fm o r e o v e r t I F d e f i c i e n c y , i e, m a l a b s o r p t i o n o f u n -b o u n d c r y s t a l l i n e v i t a m i n B 12 w i t h c o r r e c t i o n b y e x -o g e n o u s I F a d m i n i s t r a t i o n . I n t h e s a m e l i g h t, o u rp a t i e n t w i t h G r a v e s d i s e a s e , a n t i - I F a n t i b o d i e s ,a n d a c h l o r h y d r i a m a y r e p r e s e n t a n e a r l y p h a s e o fw h a t m a y b e c o m e m o r e c l a s s i c a l p e r n i c i o u s a n e m i ai n th e f u t u r e . I t w i l l b e i n t e r e s t i n g t o s e e i f p a t i e n t sw i t h t h i s r e l a t i v e d e f i c i e n c y o f i n t r in s i c f a c t o r p r o g -r e s s to m o r e o v e r t d e f i c ie n c y o f I F ( a s m e a s u r e d b yb o t h c o r r e c t i b l e m a l a b s o r p t i o n o f u n b o u n d c r y s t a l -l i n e v i t a m i n B 12 a n d m e a s u r e d o u t p u t o f g a s t r i c in -t r i n s ic f a c t o r ) . E v e n t h o u g h a l l p a t i e n t s i n t h is s t u d yc o u l d a b s o r b u n b o u n d c r y s t a l l i n e v i t a m i n B12 n o r -m a l l y , t h e r a p y w i t h o r a l c r y s t a l l i n e v i t a m i n B 12w o u l d b e s o m e w h a t r i s k y , b e c a u s e o f t h e p o t e n t i a ls u b t l e d e v e l o p m e n t o f m o r e o v e r t I F d e f i c i e n c y a t al a t e r t i m e .

T h e p r e s e n t s t u d y s u g g e s t s t h a t m a l a b s o r p t i o n o fp r o t e i n - b o u n d v i t a m i n B ~2 m a y o c c u r i n t h e s e t t i n go f a c i d - p e p s i n d e f i c i e n c y , b e i t s p o n t a n e o u s l y d e -v e l o p i n g o r f o l l o w i n g g a s tr i c s u r g e r y . W h e t h e r a p -p r o p r i a t e c a r e o f p a t i e n t s w i t h h y p o c h l o r h y d r i as h o u l d i n v o l v e p e r i o d i c d e t e r m i n a t i o n o f v i t a m i nB~2 s t o r e s i n th e b o d y , p e r i o d i c a s s e s s m e n t o f s o m et y p e o f p r o t e i n - b o u n d v i t a m i n B~2 a b s o r p t i o n t e s t( s u c h a s t h e o n e d e s c r i b e d i n t h i s r e p o r t ) , a n d / o rp r o p h y l a c t i c v i t a m i n B 12 t h e r a p y r e m a i n s t o b e d e -t e r m i n e d .

A C K N O W L E D G M E N T ST h e a u t h o r s g r a t e f u l ly a c k n o w l e d g e t h e e x p e r t te c h n i -c a l a s s i s t a n c e o f M r s . C h e r y l C u r i n g t o n , M s D e b b i e D u n -c a n , M r . G e o r g e S m i t h , M r s . E u g e n i a A h m e d , a n d M r .M a r s h a l l S u n d e r l a n d ; t h e s e c r e t a r i a l e f fo r t o f M r s .F r a n c e s T . T u c k e r ; a n d t h e c o o p e r a t i o n o f M r s. S h i r le yB l o o d w o r t h a n d t h e N u r s i n g S t a f f o f th e C l i n ic a l R e -s e a r c h C e n t e r , S h a n d s T e a c h i n g H o s p i t a l , G a i n e s v i l l e ,F l o r i d a .

R E F E R E N E S1. Tosk es PP, De ren J J: Vi t amin B12 absorpt ion and ma labsorp-t ion . G as t roentero log y 65:662-683, 19732 . D o n a l d s o n R M , J r : M e c h a n i s m s o f m a l a b s o r p t i o n o f c o b a l a -min . Cobalam in . M Bab ior ( ed). N ew Y ork , John Wi ley and

Sons, 1975, p 337-3683. De l l er DJ , Richards WCD , Wi t t s LJ : Changes in t he b loodaf t er par t i a l gas t r ec tomy wi th speci a l r ef er ence to v i t aminBI~. I I . Th e cause o f the f a l l in s e rum vi t amin B12. Q J Med31:89-102, 19624. Hines JD, Hof fbrand AV, Mol l in DL: The hematologica lcom pl i ca t ions fo llowing pa r t i a l gas t r ec tom y. Am J Me d43:555-569, 19675 . M a h m u d K , R i p l e y D , D o s c h e r h o l m e n A : V i ta m i n B 2 ab-sorpt ion t es t s : The i r unre l i ab i l i t y i n pos tga s t r ec tomy s t a t es .J Am Med Asso c 216:1167-1171, 19716. Ryg vold O: Hyp ovi t am inos i s B12 fo l lowing par t i a l gas t r ec-t o m y b y t h e B i l lr o t h I I m e t h o d . S c a n d J G a s t r o e n t e r o l 9(Supp l 29) :57-64, 19747 . S t r e e t e r A M , B a l a s u b r a m a n i a m D , B o y l e R , O N e i l l B J ,Phei l s MT: Malabsorpt ion of v i t amin B12 af t er vagotomy.Am J Surg 128:340-343, 19748. Ross GSM : Vi t amin B~2 as say in bod y f lu ids us ing E u g l e n ag r a c i l i s . J Cl in Pathol 5:250-256, 19529. Schi l l ing RF : In t r ins i c f ac tor s tudies . I I . The ef fec t of gas t r i cj u i c e o n t h e u r i n a r y e x c r e t i o n o f r a d i o a c t i v i t y a f t e r th e o r a ladmini s t r a t i on of r adioact ive v i t amin B12. J Lab Cl in Med42:860-866, 19531 0 . G o t t l i e b C , L a u K - S , W a s s e r m a n L R , H e r b e r t V : R a p i dcharco al as say fo r i n t r ins ic f ac tor ( IF) , gas t r i c j u i ce un satu-r a t ed B~2 binding capaci ty , an t ibod y to IF , and s erum un-satur ated B~2 binding cap aci ty . Bloo d 25:875-884, 196511. Sned ecor GW , Cochran W G: Sta t i s t i ca l Me thods , 6 th ed .A m e s , I o w a , I o w a S t a t e U n i v e r s i ty P r e s s , 1 9 6 712. Kidro ni G, Gros sow icz N: Pur i f i ca t ion and proper t i es of twovi t amin BI~ b inder s f rom chicke n s erum. Biochim Biop hysActa 118:113-123, 196913. S onneb orn DW , Hansen H J : Vi t am in Bx2 b inder s of ch i ckenserum and chicken prov ent r i culus ar e immun ologica l ly s imi -lar . Science 168:591-592, 197014. Cooper BA, Cas t l e WB: Sequent i a l mechani sms in t he en-hanced absorpt ion of v i t amin B12 by in t r ins i c f ac tor i n t herat . J Cl in Invest 30:199-214, 196015. Reizen s t e in PF: Ef f ec t of d iges t ive enzym es on bound v i t a-min B12. Ac ta Med Scan d 165:481-486, 195916. Hey sse l RM, B ozian RC, D arby W J , Bel l MC: V i t amin B~2turnov er i n m an: The as s imi l a t ion of v it amin BI~ f rom n atu-r a l f oods tuf f by m an and es t imates o f minimal da i ly d i e t aryrequi r emen t s . Am J C l in Nu t r 18:176-184, 1966

1 7. A d a m s J F , K e n n e d y E H , T h o m p s o n J , W i l l ia m s o n J : T h eef f ec t of ac id pept i c d iges t ion on f r ee and t i s sue-bound co-balamins . Br J Nutr 22:111-114, 19681 8. D o s c h e r h o l m e n A , M c M a h o n J , R i p l e y D ; V i t a m i n B ~ a s -s imi l a tion f rom c hicken me at . Am J Cl in Nut r 31:825-830,19781 9. A d a m s J F , R o s s S K , M e r v y n L , B o d d y K , K i n g P : A b s o r p -t i o n o f c y a n o c o b a l a m i n , c o e n z y m e B 1 2 , m e t h y l c o b a l a m i na n d h y d r o x o c o b a l a m i n a t d i f f e re n t d o s e l e v e l s . S c a n d J G a s -t roe nter ol 6:249-252, 19712 0 . H e r b e r t V , S u l li v a n L W : A c t i v i t y o f c o e n z y m e B l z in m a n .Ann NY Acad Sci 112:855-870, 1964

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6/6

K I N G E T A L

2 1 . O k u d a K T a k a r a I F u j i i T : A b s o r p t i o n o f l i v e r - b o u n d v i t a -mi n B 1~ n re l a t i o n to i n t r i n s i c fa c t o r . B l o o d 3 2 : 3 1 3 -3 2 3 1 9 68

2 2 . S c h a d e S G S c h i l li n g R F : E f f e c t o f p e p s i n o n t h e a b s o r p t i o no f fo o d v i t a m i n B1 2 a n d i ro n . A m J C l i n Nu t r 2 0 : 6 3 6 -6 4 01967

2 3 . A r d e m a n S C h a n a r i n I : A s s a y o f i n tr i n s i c f a c t o r i n t h e d ia g -n o s i s o f A d d i s o n i a n p e r n i c i o u s a n a e m i a . B r J H a e m a t o l11:305-314 1965

2 4. A r d e m a n S C h a n a r i n I : I n t r i n s i c f a c t o r s e c r e t i o n i n g a s t r i ca t ro p h y . Gu t 7 : 9 9 -1 0 1 1 9 66

2 5 . A l l e n R H S e e t h a r a m B A l l e n N C P o d e l l E R A l p e r s D H :C o r r e c t i o n o f c o b a l a m i n m a l a b s o r p t i o n i n p a n c r e a t i c i n s u f -f i c i e n c y w i t h a c o b a l a m i n a n a l o g u e t h a t b i n d s w i t h h i g ha f f i n it y t o R p ro t e i n b u t n o t t o i n t r i n s i c fa c t o r . J C l i n In v e s t61 :1628-1634 1978

4 2 Digestive Diseases and Sciences, Vol. 24, No. 5 May 1979)

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