Efeito da corticotropina sobre a absorção de vitamina B12 na mielose funicular.

EFFECT OF CORTICOTROPIN ON THE ABSORPTION OF VITAMIN

B

IN THE SUBACUTE COMBINED DEGENERATION OF THE

SPINAL CORD

HORACIO M . CANELAS *

N E L S O N DE CARVALHO * *

ARNALDO G A M A DA ROCHA *

The treatment of subacute combined degeneration of the spinal cord

(SCDSC) is based on a pretended etiological unity between the hematologic

and neurologic manifestations, according to the old concept of the

neuro-ane-mic syndrome. The first attempt of treatment of that disease was the liver

therapy, introduced in 1926 by Minot and Murphy

, but the neurologic results

did not correspond to the success observed in the anemic condition. In 1947,

the discovery of the folic acid strengthened the doubts on the etiological unity

of the hematologic and neurologic syndromes; actually, the initial findings of

Spies et al.

, later confirmed by several investigators, showed that the folic

acid, although improving the blood conditions, had no effect on the neural

involvement or even made it worse. The advent of the vitamin B

was

received as the solution of the therapeutic problem, for it influenced both the

hematologic and neurologic manifestations.

Unfortunately the initial enthusiasm did not last very long and it was

found that the neurologic improvement, though generally greater than that

yielded by the liver extract alone — and opposite results were reported by

Murphy and H o w a r d

— was not comparable to the brilliant hematologic

effect. In spite of the fact that some authors stress that the deficiency of

vitamin B

is a fundamental stone in the building up of SCDSC

24, 2 7

, and

although Spillane and W e l l s

have adopted the term " B

neuropathy"

suggested by Richmond and Davidson

, it has been demonstrated that the

deficiency of vitamin B

1, 3, 6, 9, 12, 22, 25, 34, 35

and even achlorhydria

34, 37

are not constant in SCDSC. According to Boudin et al.

, in SCDSC

there is a more complex deficiency than an isolated avitaminosis B

. And

even Richmond and Davidson

, owing to tome significant exceptions to the

rule of vitamin B

deficiency, were constrained to formulate the hypothesis

that another substance, neuropoetin, besides vitamin B

but closely related

to it, is necessary for the integrity of the nervous system.

F r o m t h e D e p a r t m e n t o f N e u r o l o g y o f t h e M e d i c a l S c h o o l * ( C h a i r m a n : P r o f . A d h e r b a l T o l o s a ) a n d t h e C e n t e r o f N u c l e a r M e d i c i n e ** ( H e a d : D r . T e d e E s t o n de E s t o n ) o f t h e U n i v e r s i t y o f S ã o P a u l o .

On the other hand, the long-term study of the experimental demyelinating

encephalomyelitides (Wolf et al., apud Kolb

) showed histopathologic features

in many ways comparable with those of the so-called primary demyelinations,

the poverty of the inflammatory process, the reaction of the astroglia, and in

the oldest lesions the relative preservation of the axons and the marked gliosis,

deserving particular mention.

Taking into account that such experimental demyelinations have an allergic

mechanism, and owing to the good results afforded by A C T H in some

de-myelinating diseases, w e started in 1953 to use it in the treatment of SCDSC

.

The results were fully analyzed in 1960

and it was evidenced that A C T H

alone had an effect similar to liver extract, though inferior to vitamin B

.

Therefore, corticotropin was used on the assumption that the

demyeli-nation of SCDSC was due to an auto-immune process, a viewpoint defended by

Roger

in 1954. Now, however, we ought to accept an additional justification

for the use of A C T H in the treatment of SCDSC, owing to the increase of

vitamin B

absorption promoted by this hormone, according to the pioneer

report of Glass (1955) in a case of sprue

. Since then, many other authors

.

.

9 , 10, 14, 16, 17, 2 1 , 3 3

have confirmed that finding, regarding both the A C T H and

corticosteroids, and either in the malabsorption syndrome or in pernicious

ane-mia. It was demonstrated also that the hypophysectomy and the

adrenalec-tomy cause a deficiency of vitamin B

absorption which can be counteracted,

respectively, by A C T H and corticosteroids

.

The hypothesis that corticotropin would enhance the secretion of intrinsic

factor

is hardly admissible, because it woud not be in agreement with the

results in cases of pernicious anemia with atrophic gastritis

. It is more

probable that the hormone interferes at the intestinal level, enhancing the

absorption of the vitamin regardless of a binding with intrinsic factor to make

up the B

- I F complex. Besides this way of action, A C T H mobilizes the

organic stores of vitamin B

(Meites et al., apud G l a s s

1 5

) .

Another mechanism of the A C T H action would be through the increment

of the pyridoxine synthesis

, since the deficiency of vitamin B

, leading to

cortico-adrenal atrophy

, gives rise to a vicious circle hindering the absorption

of vitamin B

. On the other hand, in swines, a B

-deficient diet can produce

demyelination of the peripheral nerves and dorsal funiculi

.

In this paper the effect of A C T H on vitamin B

absorption in 9 cases of

SCDSC is analyzed.

M A T E R I A L A N D M E T H O D S

Material — N i n e cases o f S C D S C w e r e s t u d i e d . T h e d i a g n o s i s w a s b a s e d on t h e

f o l l o w i n g c r i t e r i a : ( a ) C h a r a c t e r i s t i c n e u r o l o g i c p i c t u r e , a l w a y s r e p r e s e n t e d , in v a -r i e d d e g -r e e , by p e -r i p h e -r a l n e -r v e s a n d d o -r s a l f u n i c u l i i n v o l v e m e n t , a n d in m o s t cases by a p y r a m i d a l s y n d r o m e . ( b ) G a s t r i c a n a c i d i t y in e v e r y case, h i s t a m i n e - f a s t in a l l cases b u t o n e ( c a s e 5 ) ; a c h l o r h y d r i a w a s c o n s t i t u t i o n a l in 7 cases a n d d u e to p a r t i a l g a s t r i c r e s e c t i o n in cases 5 a n d 8. ( c ) C h a n g e s o f t h e p e r i p h e r a l b l o o d in 6 cases, e i t h e r in t h e sense o f m a c r o c y t i c h y p e r c h r o m i c o r i r o n - d e f i c i e n t a n e m i a , ( d ) I n h i b i t i o n o f m a t u r a t i o n a t b o n e - m a r r o w e x a m i n a t i o n in 4 cases.

A c c o r d i n g t o 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 test o f l a b e l e d v i t a m i n B1 2, t h e

Methods — C o r t i c o t r o p i n w a s a d m i n i s t e r e d by i n t r a v e n o u s p e r f u s i o n in an a v e

-r a g e dosis o f 12.5 t o 25.0 m g m . / d a y , d i l u t e d in 500 m l . o f a 10 p e -r c e n t g l u c o s e so-l u t i o n , a t a r a t e o r 20 d r o p s / m i n u t e . T h e t h e r a p e u t i c s c h e m e so-l a s t e d f r o m 19 t o 43 d a y s , a n d t h e t o t a l dosis o f A C T H v a r i e d f r o m 237 t o 505 m g m . ( T a b l e 1 ) . T h e usual c a r e w i t h t h i s kind o f t r e a t m e n t w a s t a k e n .

T h e a b s o r p t i o n o f l a b e l e d v i t a m i n B1 2 ( f o r m e r l y C o 6 0

a n d l a t e r C o5 7

) w a s studied t h r o u g h t h e S c h i l l i n g ' s u r i n a r y e x c r e t i o n t e s t2 0

. E x c r e t i o n l e v e l s l o w e r t h a n 10 p e r c e n t w e r e c o n s i d e r e d as i n d i c a t i v e o f d e f i c i e n t a b s o r p t i o n . W h e n a b n o r m a l r e s u l t s w e r e f o u n d , t h e test w a s r e p e a t e d w i t h t h e a s s o c i a t i o n o f i n t r i n s i c f a c t o r *, e x c e p t , in t h e last t h r e e cases.

T h e S c h i l l i n g ' s test w a s r e p e a t e d e i t h e r i m m e d i a t e l y a f t e r c o m p l e t i o n o f t r e a t m e n t (6 c a s e s ) o r 28 d a y s ( 2 c a s e s ) a n d 45 d a y s l a t e r ( 1 c a s e ) . I n cases 3 a n d 4 t h e test w i t h v i t a m i n B1 2 plus i n t r i n s i c f a c t o r w a s d o n e , r e s p e c t i v e l y , 10 a n d 5 d a y s a f t e r

t h e t r e a t m e n t w i t h A C T H h a d been s t a r t e d ( t a b l e 1 ) , t h u s i n t r o d u c i n g a n e r r o r o f i n t e r p r e t a t i o n c o n c e r n i n g t h e e f f e c t o f i n t r i n s i c f a c t o r on t h e a b s o r p t i o n o f t h e v i -t a m i n , a -t l e a s -t in c a s e 3, w h e r e an i n c r e a s e d a b s o r p -t i o n w a s e v i d e n c e d .

R E S U L T S

T h e r e s u l t s a r e s u m m a r i z e d in t a b l e s 1 a n d 2. E x c e p t in cases 6 a n d 9 an i n c r e a s e in t h e a b s o r p t i o n o f v i t a m i n B12 w a s f o u n d . T h e m e a n d i f f e r e n c e o f t h e

D I S C U S S I O N

The increase of vitamin B

absorption was observed either in cases of

malabsorption syndrome or in cases of lack of intrinsic factor probably due to

gastric atrophy. In case 1, with a pernicious anemia pattern of deficient B ,

absorption, a test of absorption of labeled triolein showed steatorrhea,

suggest-ing that there was also impairment of the intestinal absorption, besides the

lack of intrinsic factor. The effect of A C T H was evidenced also in two

patients submitted to partial gastric resection (we have no experience in

cases of total gastrectomy, a condition in which G o r d i n

found no effect

of prednisone on the vitamin B

absorption). In one of these cases (n.° 5)

the test with labeled triolein showed a fecal excretion of 31.4 percent,

point-ing to a marked degree of steatorrhea; so, in this case, the ineffectiveness

of the association of intrinsic factor and the deficient fat absorption pointed

to an impairment of the absorption of vitamin B

through the intestinal

wall.

The failure of A C T H to increase vitamin B

absorption occurred in a

case with undetermined deficient absorption (the test B

+ I F was not done)

and in a case of malabsorption syndrome.

Though the rate of increment in B

absorption after the A C T H series

was small in most of cases, the results in cases 3 and 5 must be emphasized,

since the degree of urinary excretion raised, respectively, more than 11 and 7

percent. It deserves to be stressed that in these two cases there was a

malab-sorption syndrome, namely an impairment of the vitamin B

absorption

S U M M A R Y

The absortion of vitamin B

was studied in 9 cases of subacute combined

degeneration of the spinal cord before and after the administration of

intra-venous A C T H in a therapeutic scheme lasting from 19 to 43 days. In 7 cases

an increase of absorption was evidenced. The mean difference of change in

the urinary excretion test of radioactive vitamin B

was near the limit of

significance.

This finding reinforces the indication of the use of corticotropin in subacute

combined degeneration of the spinal cord, since the hormone will act both

on the allergic component of the demyelinating process and on the deficiency

of vitamin B

absorption. Though the material here analyzed is too small

to.warrant a definite conclusion, our results suggest that A C T H influences

the vitamin B

absorption through the intestinal wall, and not by means of

an increase of intrinsic factor secretion or a mobilization of vitamin B

stores.

R E S U M O

Efeito da corticotropina sobre a absorção de vitamina B¡2 na mielose funicular

Foi estudada a absorção de vitamina B

em 9 casos de mielose funicular

antes e após a administração de A C T H por via intravenosa em um esquema

te-rapêutico com duração variável entre 19 e 43 dias. Em 7 casos foi verificado

aumento da absorção. A diferença média de modificação no teste de excreção

urinaria de vitamina B

radioativa situou-se próximo do nível de significancia

estatística.

Este resultado reforça a indicação do emprego de corticotropina na

mie-lose funicular, pois o hormônio irá atuar tanto sobre o componente alérgico do

prccesso desmielinizante, quanto sobre a carência de vitamina B

resultante

do déficit de absorção. Embora o material aqui analisado seja muito pequeno

para garantir uma conclusão definitiva, nossos resultados demonstram que,

pro-vavelmente, o A C T H age sobre a absorção da vitamina B

através da mucosa

intestinal, e não mediante o aumento de secreção do fator intrínseco ou a

mobilização dos depósitos dessa vitamina.

In order to study a possible mobilizing effect of A C T H on the radioactive

vitamin B

stores, the intervals between the last urinary excretion test and

the test after completion of treatment were analyzed (Table 1 ) . It is easily

noticed that in the 7 cases with increase of vitamin B

absorption these

pe-riods were the most varied, lasting from 9 to 62 days. And also in the 2 cases

with decrease of absorption the intervals were very dissimilar, namely 15 and

56 days. So, it seems that this effect of A C T H did not play a significant

role in the results.

R E F E R E N C E S

1. A D A M S , J. F., a n d T I M B U R Y , G. C. — S u b a c u t e c o m b i n e d d e g e n e r a t i o n d e -v e l o p i n g d u r i n g l i -v e r t h e r a p y . B r i t . m e d . J. i : 833-834, 1959. 2. B J Ö R K E N H E I M , G. — N e u r o l o g i c a l c h a n g e s in p e r n i c i o u s t a p e w o r m a n a e m i a . A c t a m e d . scand., suppl. 260, 1951. 3. B O U D I N , G . ; B A R B I Z E T , J., a n d L A B E T , R . — L e s n e u r o p a t h i e s a c h y l l q u e s . R e v . n e u r o l . 91:361-366, 1954. 4. C A N E L A S , H . M . — M i e l o s e s f u n i c u l a r e s : c o n s i d e r a ç õ e s a p r o p ó s i t o de 110 casos. A r q . N e u r o - p s i q u i a t . ( S . P a u l o ) 18:105-132, 1960. 5. C A N E L A S , H . M . , a n d L E V Y , J. A . — R e s u l t a d o s p r e l i m i n a r e s d o e m p r ê g o d o A C T H nas d e g e n e r a ç õ e s c o m b i n a d a s da m e d u l a . A r q . N e u r o - p s i q u i a t . ( S . P a u l o ) 11:253-258, 1953, 6. C A N E L A S , H . M . ; T E I X E I R A - P I N T O , J., a n d S H N A I D E R , J. — A b s o r ç ã o d a v i t a m i n a B1 2 nas m i e l o s e s f u n i c u l a r e s : e s t u d o d a a b s o r ç ã o da r a d i o

-c i a n o -c o b a l a m i n a e m 16 -casos. A r q . N e u r o - p s i q u i a t . ( S . P a u l o ) 19:1-10, 1961. 7. D O I G , R . K . — G a s t r i c b i o p s y a n d t h e i n v e s t i g a t i o n of t h e m e g a l o b l a s t i c a n a e m i a s . P r o c . r o y . Soc. M e d . 47:425-431, 1954. 8. D O I G , A . , G I R D W O O D , R . H . , D U T H I E , J. J. R . , and K N O W , J. D . E. — R e s p o n s e o f m e g a l o b l a s t i c a n a e m i a t o p r e d n i s o l o n e . L a n c e t , i i : 966-972, 1957. 9. F R O S T , J. W . , a n d G O L D W E I N , M . I . — O b s e r v a t i o n on v i t a m i n B12 a b s o r p t i o n in p r i m a r y p e r n i c i o u s a n e m i a d u r i n g a d m i n i s t r a t i o n o f

a d r e n o c o r t i c a l s t e r o i d s . N e w E n g l . J. M e d . 258:1096-1098, 1958. 10. F R O S T , J. W . , G O L D W E I N , M . I . , a n d K A U G M A N , B . D . — S t u d i e s o f B1 2 C o

6 0

a b s o r p t i o n in m a -l a b s o r p t i o n s y n d r o m e : r e s u -l t s b e f o r e a n d d u r i n g s p e c i f i c t h e r a p y . A n n . i n t e r n . M e d . 47:293-299, 1957. 11. G E I G E R , W . , a n d F u h r m a n n , W . — Z u r D i f f e r e n t i a l d i a g n o s e d e r f u n i k u l ä r e n S p i n a l e r k r a n k u n g . N e r v e n a r z t , 24:290298, 1953. 12. G É L I N , G . ; C O I -R A U L T , -R., a n d H A M E D , E. B . — V i t a m i n e B1 2 e t s y n d r o m e s n e u r o - a n é m i q u e s . A n n .

M é d . 53:172216, 1952. 13. G L A S S , G. B . J. — B i o c h e m i s t r y a n d p h y s i o l o g y of C a s -t l e ' s i n -t r i n s i c f a c -t o r a n d i-ts r e l a -t i o n s h i p -t o -t h e m e -t a b o l i s m o f v i -t a m i n B1 2. R e v .

H é m a t . 10:137-179, 1955. 14. G L A S S , G . B . J. — I n t e s t i n a l a b s o r p t i o n a n d h e p a t i c u p t a k e o f v i t a m i n B1 2 in diseases o f t h e g a s t r o i n t e s t i n a l t r a c t . G a s t r o e n t e r o l o g y ,

30:37-52, 1956. 15. G L A S S , G. B . J. — G a s t r i c i n t r i n s i c f a c t o r a n d its f u n c t i o n in t h e m e t a b o l i s m o f v i t a m i n B1 2. P h y s i o l . R e v . 43:529-849, 1963. 16. G O R D I N ,

R . — V i t a m i n B1 2 a b s o r t i o n in c o r t i c o s t e r o i d - t r e a t e d p e r n i c i o u s a n a e m i a . A c t a . m e d .

scand. 164:159-165, 1959. 17. H A L V O R S E N , S. — E f f e c t s o f A C T H on e r y t h r o p o i e s i s in r a b b i t . A c t a p h y s i o l . scand. 58:30-39, 1963. 18. H S U , J. M . , and C H O W , B . F .

— E f f e c t o f p y r i d o x i n e d e f i c i e n c y on t h e a b s o r p t i o n o f v i t a m i n B1 2. A r c h . B i o c h e m .

B i o p h y s . 72:322330, 1957. 19. J E W E S B U R Y , E . C. — S u b a c u t e c o m b i n e d d e g e n e r a t i o n o f t h e c o r d a n d a c h l o r h y d r i c p e r i p h e r a l n e u r o p a t h i e s w i t h o u t a n a e m i a . L a n -cet, i i : 307-312, 1954. 20. K O L B , L . C. — T h e r e l a t i o n s h i p o f t h e d e m y e l i n a t i n g diseases t o a l l e r g i c e n c e p h a l o m y e l i t i s . M e d i c i n e , 29:99-121, 1950. 21. K R I S T E N S E N , H . P . O., a n d F R I I S , R . — E f f e c t o f p r e d n i s o n e on B12 a b s o r p t i o n in p e r n i c i o u s a n e

-m i a . A c t a -m e d . s c a n d . 166:249-254, 1960. 22. L A F O N , R . , P A G E S , P., L A B A U G E , R . , a n d T E M P L E , J. P . — L e s y n d r o m e n e u r o a n a c h l o r h y d r i q u e : à p r o p o s de 31 o b s e r -v a t i o n s . R e -v . n e u r o l . 91:321-329, 1954. 23. M I N O T , G. R . , a n d M U R P H Y , W . P . — T r e a t m e n t o f p e r n i c i o u s a n e m i a by a s p e c i a l d i e t . J. A m e r . m e d . A s s . 87:470-476, 1926. 24. M O L L I N , D . L . , a n d R O S S , G. I . M . — V i t a m i n B12, d e f i c i e n c y in t h e m e g a

-l o b -l a s t i c a n e m i a . P r o c . r o y . S o c . M e d . 47:428-431, 1954. 25. M U R P H Y , W . P., and H O W A R D , I . — A c o m p a r i s o n o f t h e e f f e c t o f v i t a m i n B1 2 w i t h t h a t o f l i v e r e x t r a c t

in t h e t r e a t m e n t o f p e r n i c i o u s a n e m i a d u r i n g r e l a p s e a n d f o r m a i n t e n a n c e . N e w E n g l . J. M e d . 247:838-840, 1952. 26. N A K A H A R A , I . , a n d S A K A M O T O , Y . — S t u d i e s on p y r i d o x i n e m e t a b o l i s m . V I I I : T h e e f f e c t o f a d r e n a l a n d h y p o p h y s e a l h o r m o n e s on p y r i d o x i n e m e t a b o l i s m . J. B i o c h e m . 52:358-362, 1962. 27. R I C H M O N D , J., and D A V I D S O N , S. — S u b a c u t e c o m b i n e d d e g e n e r a t i o n of t h e spinal c o r d in n o n a d d i s o -n i a -n m e g a l o b l a s t i c a -n a e m i a . Q u a r t . J. M e d . 27:517-531, 1958. 28. R O G E R , H . — L e s s y n d r o m e s n e u r o - a n é m i q u e s . M a r s e i l l e m é d . , 91:473-490, 1954. 29. S C H I L L I N G , R . G. — I n t r i n s i c f a c t o r studies. I I : T h e e f f e c t o f g a s t r i c j u i c e on 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 t h e o r a l a d m i n i s t r a t i o n o f r a d i o a c t i v e v i t a m i n B1 2.

-r a t i o n o f t h e spinal c o -r d . P o s t g -r a d . M e d . 4:89-95, 1948. 32. S P I L L A N E , J. D . , a n d W E L L S , C. E . C. — N u t r i t i o n a l d i s o r d e r s o f t h e n e r v o u s s y s t e m . I n E l l i o t t , K . A . C , P a g e , I . H . & Q u a s t e l , J. H . : N e u r o c h e m i s t r y , 2nd e d . C h a r l e s C. T h o m a s , S p r i n g f i e l d , 1962, pp. 930953. 33. S T E V E N S O N , T . D . — R e s p o n s e o f m e g a l o b l a s t i c a n a e -m i a to p r e d n i s o l o n e . L a n c e t , i :48, 1958. 34. V I C T O R , M . , a n d L E A R , A . A . — S u b a c u t e c o m b i n e d d e g e n e r a t i o n o f t h e s p i n a l c o r d : c u r r e n t c o n c e p t s o f t h e d i s e a s e p r o c e s s . A m e r . J. M e d . 20:896-911, 1956. 35. W I N T R O B E , M . M . — T h e s e a r c h f o r a n e x p e r i m e n t a l c o u n t e r p a r t o f p e r n i c i o u s a n e m i a . A r c h , i n t e r n . M e d . 100:862-869, 1957. 36. Y E H , S. D . , a n d C H O W , B. F . — V i t a m i n B1 2 a b s o r p t i o n in p y r i d o x i n e

-d e f i c i e n t r a t s . A m e r . J. c l i n . N u t r . 7:426-432, 1959. 37. Z E M A N , W . , an-d D e L A N D , F . H . — C o n t r i b u t i o n t o t h e p a t h o g e n e s i s o f s u b a c u t e c o m b i n e d d e g e n e r a t i o n o f t h e s p i n a l c o r d : r e p o r t o f t w o cases. A m e r . J. c l i n . P a t h . 28:515-523, 1957.