EFFECT OF CORTICOTROPIN ON THE ABSORPTION OF VITAMIN
B
1 2IN 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
2 3, 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.
3 1, 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
1 2was
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
2 5— was not comparable to the brilliant hematologic
effect. In spite of the fact that some authors stress that the deficiency of
vitamin B
1 2is a fundamental stone in the building up of SCDSC
24, 2 7
, and
although Spillane and W e l l s
3 2have adopted the term " B
1 2neuropathy"
suggested by Richmond and Davidson
2 7, it has been demonstrated that the
deficiency of vitamin B
1 21, 3, 6, 9, 12, 22, 25, 34, 35
and even achlorhydria
2, 11, 27, 30,34, 37
are not constant in SCDSC. According to Boudin et al.
3, in SCDSC
there is a more complex deficiency than an isolated avitaminosis B
1 2. And
even Richmond and Davidson
2 7, owing to tome significant exceptions to the
rule of vitamin B
1 2deficiency, were constrained to formulate the hypothesis
that another substance, neuropoetin, besides vitamin B
1 2but 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
20) 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
5.
The results were fully analyzed in 1960
4and it was evidenced that A C T H
alone had an effect similar to liver extract, though inferior to vitamin B
1 2.
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
2 8in 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
1 2absorption promoted by this hormone, according to the pioneer
report of Glass (1955) in a case of sprue
1 3. Since then, many other authors
7.
8.
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
1 2absorption which can be counteracted,
respectively, by A C T H and corticosteroids
3 6.
The hypothesis that corticotropin would enhance the secretion of intrinsic
factor
1 6is hardly admissible, because it woud not be in agreement with the
results in cases of pernicious anemia with atrophic gastritis
1 5. 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
1 2- I F complex. Besides this way of action, A C T H mobilizes the
organic stores of vitamin B
1 2(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
18, 2 6, since the deficiency of vitamin B
6, leading to
cortico-adrenal atrophy
3 6, gives rise to a vicious circle hindering the absorption
of vitamin B
1 2. On the other hand, in swines, a B
6-deficient diet can produce
demyelination of the peripheral nerves and dorsal funiculi
3 5.
In this paper the effect of A C T H on vitamin B
1 2absorption 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
1 2absorption 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 ,
2absorption, 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
1 6found no effect
of prednisone on the vitamin B
1 2absorption). 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
1 2through the intestinal
wall.
The failure of A C T H to increase vitamin B
1 2absorption occurred in a
case with undetermined deficient absorption (the test B
1 2+ I F was not done)
and in a case of malabsorption syndrome.
Though the rate of increment in B
1 2absorption 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
1 2absorption
S U M M A R Y
The absortion of vitamin B
1 2was 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
1 2was 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
1 2absorption. 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
1 2absorption through the intestinal wall, and not by means of
an increase of intrinsic factor secretion or a mobilization of vitamin B
1 2stores.
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
1 2em 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
1 2radioativa 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
1 2resultante
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
1 2através 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
1 2stores, 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
1 2absorption 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
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