VITAMIN B6 IN HUMAN NUTRITION: A
AND AN OBJECT LESSON#{176}
Bzj CHARLES D. MAYf
iowa City, Iowa
CRITIQUE
269
Pediatrics
VOLUME 14 SEPTEMBER 1954 NUMBER 3
SPECIAL
SECTIONS
REVIEW
ARTICLE
W
ITHIN the past year a dramaticout-break of a singular type of convulsive
seizures in babies has provided convincing
evidence of an essential role for Vitamin B,;
in human nutrition under natural
circum-2 This is a general review of the
circumstances surrounding this outbreak
and of the present state of our knowledge of vitamin B,;.
But it is also important that this episode be considered as a reminder of the complex interrelationships which permeate studies of
nutritional factors and as a warning against
hasty conclusions. It also serves as an
illus-tration of the hazard in premature or
un-controlled application to human nutrition of
isolated fragments of knowledge concerning
nutritional factors.
The existence of Vitamin B, was
dis-aThe Twenty-ninth Ludvig Hektoen Lecture of the Frank Billings Foundation of the Institute of Medicine. Delivered before a Joint Meeting of the
Institute of Medicine of Chicago and the Chicago Pediatric Society, March 16, 1954.
f From the Department of Pediatrics, College of
Medicine, State University of Iowa.
Reprinted, with minor alterations, by permission.
From the Proceedings of the Institute of Medicine of Chicago, Vol. 20, No. 4, April 15, 1954.
covered in 1934 by experiments with rats.3
Symptoms of deficiency of this vitamin were soon described in several species of animals
but not in man. Within a few years the
chemistry of the vitamin was determined
and the synthesis achieved. Considerable information as to the metabolic reactions
affected by a deficiency of Vitamin B1 was
rapidly accumulated. Only recently, 16
years after the discovery of Vitamin B;, the
Council on Pharmacy and Chemistry of the
American Medical Association reviewing
the status of our knowledge of the role of
Vitamin B in human nutrition reached only
a cautious acceptance of an essential dietary
requirement for Vitamin B6 in the human.5
The original observations which called
attention to the problem of unusual
convul-sions in infants and pointed the way to its
solution were made by a doctor in practice,6 just as were similar observations which led
a few years ago to an appreciation of the
circumstances producing a deficiency of
folic acid in infancy.7 This should encourage practitioners to realize that close observa-tion of their patients still permits
funda-mental contributions to be made without
a Liquid-Synthetic Milk Adapted ( Wyeth Co.).
center. It should also remind professors that
conspicuous phenomena are still passing
before them unseen.
The critical observations referred to were that an unusual number of infants of about
two months of age were being brought to
this doctor with a type of convulsive seizure which struck him as odd; that all were being
fed the same commercially prepared
modi-fication of cow’s milk; and that as soon as
such an infant was given some other cow’s
milk formula the convulsions ceased with
amazing abruptness. These observations
were promptly confirmed by numerous
re-ports which came to official agencies and
to the manufacturer involved. It became
apparent that some property of this one
product was responsible for convulsive
seizures in an alarming number of babies.
The manufacturer disclosed that a change
in the product had been made just prior to
the widespread appearance of convulsions
in babies fed the product. There was a
natural flurry of suspicion of some toxic or infectious contaminant but none was found.
Furthermore, the convulsions followed
in-gestion of only the liquid form of the prod-uct; a dried form of identical composition had caused no difficulties. Careful
examina-tion and study of the infants failed to reveal
a cause for the seizures.
The changes in the incriminated product
which had preceded this widespread
ap-pearance of convulsions was the substitution of palm oil for coconut oil in the formula,
and, according to one report,1 the liquid
product was also sterilized under more
vigorous conditions to assure freedom from
harmful organisms.
The characteristics of the convulsions
under consideration were universally
rec-ognized to be unusual. In most instances
the seizures began between six weeks and
four months of age and were unaccompan-ied by signs of infection. Neither neonatal
nor rachitic forms of tetany would be
ex-pected in this age period. Quite regularly
the babies were described as “nervous,”
“jumpy,” easily “startled” by noise, or colicy
and irritable. Seizures appeared abruptly
with marked opisthotonus and the
convul-sive movements were stiff and jerky.
Con-sciousness seemed to be lost, the seizures
were brief, two to three minutes, and
con-sciousness was usually quickly recovered.
Attacks varied in frequency from
occa-sional, more often one to three daily and
sometimes much more numerous. Between
attacks the baby would remain “jumpy,”
and by the time seizures appeared, became
anorexic and gained poorly. In the milder
cases the change to some other formula
brought an end to the symptoms either
im-mediately or within a few days, the baby
began to thrive again, and no sequelae were evident. A slight elevation of spinal fluid
protein was frequent. Only a few of many
such babies examined were found to have
anemia. Numerous other studies
customar-ily done in seeking a cause for seizures in
this age period were regularly normal.
Electroencephalographic tracings were
sometimes abnormal but were not
recog-nized as specific.
The infants had all been fed liquid SMA#{176} from birth or shortly thereafter with little
or no supplementation from solid foods or
vitamin preparations (all the vitamins
known to be essential were incorporated
into the product during manufacture). It
was finally estimated that seizures
devel-oped in about three per thousand babfes
fed exclusively on this product. No
con-vulsions of this type were reported on simi-lar products or other modifications of cow’s milk, perhaps due to faulty observation, but certainly such seizures must have been rare.
As the magnitude of the problem became
clear the manufacturers returned to the
formlua for SMA in use before the palm oil
was substituted for coconut oil. To every-one’s dismay the incidence of convulsions
amongst babies fed liquid SMA continued
unabated.
If one could recapture the grave concern
271
those giving thought to the problem one
might more fully appreciate the astuteness of Dr. 0. L. Kline of the Division of Nu-trition of the U.S. Food and Drug Adminis-tration, who must receive credit for pointing
out the likely cause for the development of
convulsions in these infants. After a few
hours’ scrutiny of the massive reports he
concluded these infants were suffering from a deficiency of Vitamin B.
How could Dr. Kline arrive at this
opinion with such apparent ease when for
16 years numerous attempts had failed to
find unequivocal evidence that deficiency
of Vitamin B6 develops in humans under
natural circumstances? Here we have
an-other confirmation of Pasteur’s maxim, “In
the field of observation chance favors only the prepared minds.” In 1940, Daniel, Kline,
and Tolle had conducted some neat
experi-ments to explain a deficiency of Vitamin B
which had been observed as an incidental
finding in previous animal experiments
ac-tually arranged for another purpose.8 With
this experience as a background Dr. Kline
quickly noticed the close resemblance
be-tween occurrences in young rats deficient
in Vitamin B,; and the sequence of events
surrounding the advent and cure of the con-vulsive seizures in infants. The idea that a deficiency of Vitamin B6 might be respon-sible for the seizures in infants fed liquid
SMA was given substantial support from
the timely report of a similar syndrome in
an infant fed a synthetic diet deficient in
Vitamin B. and shown to be cured by
pyri-doxine.
The obvious next step was to try the
effect of pyridoxine on infants with
sei-zures from feeding liquid SMA. Just as this
idea was broadcast a suitable candidate on
liquid SMA, having frequent seizures daily,
was admitted to the University Hospital of
the State University of Iowa. No further
convulsions occurred after the injection of
10 mg. of pyridoxine though the same batch
of offending product was continued
Un-changed for several days before discharging
the baby. The subsequent course on a fresh
cow’s milk formula was uneventful.
Our experience in the Department of
Pediatrics at the State University of Iowa
proved, in retrospect, to be quite typical of
the situation which had arisen during the
same period throughout this nation.#{176} In this clinic, between January, 1951 and July,
1953, 15 infants under six months of age
were admitted because of convulsive
sei-zures and after careful study no cause was
discovered; 10 of these infants were found, in retrospect, to have been reared on liquid
SMA of the condemned lots and their
sei-zures had ceased promptly after they were
given some other formula. It has been
pos-sible to follow six of this latter group and
no more convulsions have occurred. It
should be noted that the remaining five
infants with unexplained seizures were
being fed fresh or evaporated cow’s milk
formulae but none of them had received
Similac, Bremil, or other products of a
composition approximately that of human
milk. The causes of the convulsions in this
latter group remain obscure, two of them
are still having severe seizures, and in the others, seizures ceased during hospitaliza-tion.
The relief of convulsions in our patient
few liquid SMA was confirmed uniformly
by others.2 Analyses for Vitamin B6
re-vealed a content of 60 micrograms per liter
in liquid SMA and of 200 micrograms per
liter in reconstituted dried powder SMA
compared to 130 micrograms per liter found
in human milk. Subsequently, liquid SMA
was fortified with 450 micrograms of
pyri-doxine per liter. No convulsions were
re-ported from this product during several
months of use.
Everything seemed to indicate that a
deficiency of Vitamin B6 in liquid SMA had
permitted a syndrome characteristic of
Vita-mm B6 deficiency to develop in infants fed
this product. It would have been easier to
accept this as the entire explanation if: (1) 0 Acknowledgment is gratefully given to l)r.
Joh-i C. MacQueen and Dr. J. A. \lcArthur for
simple restoration of the level of Vitamin
B,, in liquid SMA to the amount in human
milk or the dried powder form of SMA had
been shown to be adequate to prevent the
convulsion syndrome in infants fed liquid
SMA, or (2) cure of the convulsion
syn-drome with modest doses of pyridoxine,
such as the 70 micrograms per day by which
human milk exceeded liquid SMA, had been
demonstrated to match the cures from
simply changing the feeding.
From the available data it is not possible to be sure some feature of liquid SMA, in addition to its low Vitamin B6 content, did not further promote a deficiency in the
in-fant by increasing the need for Vitamin B6;
such as the fatty acid content, an effect on the intestinal bacterial flora, or some
conse-quence of processing the liquid form. That
infants fed the dried powder form of SMA
did not develop convulsions does not alter
the matter as by milder treatment in the
final processing any deleterious effect from high temperature autoclaving of the liquid
form might be avoided, at the same time
preserving a higher level of Vitamin B6.
In this connection it may be instructive to review some of the features of Vitamin B6 deficiency in experimental animals and
the known metabolic functions of Vitamin
B6 for comparison with the manifestations in the infants presumed to have developed Vitamin B6 deficiency. It will then be
pos-sible to decide whether the matter is as
simple as it may seem at first glance-a
simple deficiency from a marginal reduction in the Vitamin B6 content of one milk prod-net-or perhaps requires further exploration.
MANIFESTATIONS OF DEFICIENCY OF VITAMIN
B6 ir EXPERIMENTAL ANIMALS
For the purpose of comparisons between
the symptoms of the infants and reported
symptoms of Vitamin B6 deficiency in adults
and animals the literature concerning the
effects of an antagonist of Vitamin B6
(des-oxypyridoxine), however interesting, may
properly be ignored. The infants did not
develop seizures from ingestion of this
corn-pound, which certainly was not in their milk
product. There is ample evidence that the
effects of the antagonist are not identical
with those resulting from a deficiency of
Vitamin B6, either symptomatically or meta-bolically.’#{176}’”
One result of an effort to assemble a
corn-plete description of the syndrome of
Vita-mm B6 deficiency from the experimental
literature is to gain an increased respect for
a well-known principle underlying disorders of nutrition: the manifestations of a
defi-ciency will be profoundly affected by the
age, sex, or species of the animal and by
other ingredients of the diet besides the one
under observation. Amongst the commonly
recorded manifestations are anemia and
leu-213 dermatoses,’ and neurological
,t,3 15 But which of these appear
and the time of appearance are markedly
influenced by the conditions of the
experi-ment. Convulsions have not been observed
in the deficient 617 nor has anemia
in the rat.18
Convulsions occur readily from
defi-ciency in the young of a susceptible species but only after prolonged severe deprivation in the mature animals, if at all.’12,12’’5 Qualitative or quantitative alterations in the
protein, fat, or carbohydrate in the diet
have been shown to prevent or change the
symptoms or the sequence of events in Vita-mm B6 deficiency.’9
Taking the rat as an example; in the suck-ling stage convulsions are virtually the sole
manifestation of deficiency. If Vitamin B
is not withdrawn from the diet until after
weaning, the typical sequence in the
mani-festations is:
(
1) loss of appetite and slow-ing of weight gain in a few days, becoming stationary within three weeks;(
2) at aboutsix weeks acrodynia becomes evident, and
(3) convulsions will not appear until after
such animals have survived an average of
20 weeks of severe deficiency.
Anemia and leucopenia were not noted
dif-Linoleic Acid - Arachidonic Aicd
ferent leucocytes, and a sluggish response to hemorrhage were observed.’8
Upon the basis of these facts the most
reasonable analogy between the symptoms
of infants developing seizures and the
symptoms of deficiency of Vitamin B in
animals was provided by the conditions in
the experiments of Daniel, Kline, and Tolle.8
Offspring of rats maintained on diets
de-ficient in Vitamin B6 when suckled by their
own mothers, and thus presumably
receiv-ing milk deficient in Vitamin B6, regularly
developed seizures between the eleventh
and eighteenth days. These investigators also contrived the convincing
demonstra-tions that: (a) the offspring of rats
main-tamed on diets containing adequate
Vita-mm B6 did not develop seizures when
nursed by their own mothers, but if the
young of such mothers were transferred for
nursing to mothers maintained on diets
de-ficient in Vitamin B6 convulsive seizures
developed though the onset of symptoms
was delayed;
(
b) contrariwise, if theoff-spring from deficient mothers were nursed
by mothers maintained on diets adequate
in Vitamin B6 the convulsion syndrome did
not appear, and
(
c) administration ofpyri-doxine orally to the mother or to the
off-spring prevented or cured the convulsion
syndrome in the deficient animals.
These experiments indicate that the
young of a species may be extremely
sus-ceptible to a deficiency of Vitamin B6 and
that convulsions would be the expected
manifestation, not necessarily being
ac-companied by other symptoms of Vitamin
B6 deficiency such an anemia, acrodynia, or obvious ill health. These experiments also point to the possibility of convulsions in infants being due to a deficiency of
Vita-mm B6 even though they are fed at the
breast, or on cow’s milk formulae other than the unfortunate lots of liquid SMA. It might be predicted that fortification of this one
product with pyridoxine would not put an
end to convulsions in infants from Vitamin
B, deficiency. Attention will have to be di-rected towards assuring an adequacy of this
vitamin to all infants, however fed,
espe-cially during the early months of life before supplementation with solid food containing Vitamin B6 might provide a safeguard.
METABOLIC RicrIoNs AFFECrED BY A
DEFICIENCY OF VITAMIN B6
An ultimate goal of nutritional science is
to describe or predict symptoms of
defi-ciency of a nutritional factor in terms of the
derangement of metabolic functions which
it serves. The gaps in this sort of knowledge concerning Vitamin B6 are indicative of the remoteness of this objective. Still the prog-ress in this direction made in the short time since the discovery of the identity of Vita-mm B6 is impressive.4
It is difficult to translate disturbances in
these metabolic reactions into symptoms in
the intact animal. One reason which may
make achievement of the ultimate goal
impossible is that the innumerable
meta-bolic systems in a higher organism are so
Soiti OF THE METABOLIC FUNCFIONS OF VITAMIN B6
l)ecarboxylation of amino acids
RCHNH2COOH ---* RCH2NH2 + CO,
Transamination
RCHNH,COOH + R’COCOOH RCOCOOH + R’CHNH2COOH
Deamination
RCH-CHCOOH ---* RCH = CCOOH ---+ RCH,COCOOH + NH3
OH NH, NH2
Desulfhydration
RCH-CHCOOH ---4 RCH-CCOOH -- RCH2COCOOH
274 CHARLES D. MAY
inextricably interrelated. Disruption of one
reaction is apt to be prompfly followed by
widespread disturbances in other reactions dependent upon it for energy and reaction
products or from accumulation of harmful
intermediates. Nevertheless some one
met-abolic function of a vitamin may be
suffi-ciently predominant to permit its
identifi-cation with a deficiency or symptom of the
deficiency.
Another consideration to be employed in
associating symptoms with a deficiency of
a vitamin is the fact that as the deficiency
of the vitamin becomes progressively more
severe the enzyme systems in which the
vitamin serves as co-enzyme are not all
affected simultaneously and to the same
degree. Thus, a degree of deficiency of
Vitamin B. sufficient to inactivate one
en-zyme system may not affect another. The
various metabolic functions of the vitamin
will be disturbed in a sort of step-wise
fashion. The lesions produced will depend
on the functional importance of -each
en-zyme system in the tissues and biochemical processes.
So the irregularity in the appearance of
anemia, acrodynia, and convulsions in
Vita-mm B6 deficiency in different species and
in the young compared to the mature
be-comes comprehensible.
Incidentally, it would also seem more
proper to think of “subclinical” deficiency states as an early stage when the least
con-spicuous metabolic functions dependent on
a vitamin are disturbed while other depend-ent enzyme systems are still unaffected,
rather than to visualize a mild or
“sub-clinical” deficiency as a mild disruption of
all enzyme systems dependent on the
par-ticular vitamin.
BIociisMIcAL FINDINGS IN VITAMIN
B6 DEFICIENCY
From reference to the metabolic
func-tions known to be dependent upon Vitamin
B6 one would expect deficiency in animals to produce interference with protein metab-olism. All the evidence on hand indicates
that other biochemical systems are
dis-turbed before protein or amino acid
metab-olism. The failure of animals deficient in
Vitamin B,, to gain in weight is due to ces-sation of deposition of body fat.” Protein
continues to accumulate. Amino acid
utili-zation is actually increased, as revealed by
increased urea ‘1 This has been
interpreted to mean that the Vitamin B
deficient animal is inefficient in obtaining
energy from its food and must turn to fat
and a large portion of the ingested amino
acids for energy. The only role of Vitamin
B6 in fat metabolism known at present is in
the interconversion of fatty acids, e.g., lino-leic acid to arachidonic acid.”
But Vitamin B, deficiency appears sooner
when the diet contains excessive protein or
amino 22 This indicates that
degra-dation of these substances increases the
need for Vitamin B,, as its role in the
meta-bolic reactions of amino acids would
re-quire. This seeming paradox suggests that
deprivation of Vitamin B6 affects systems
employed in securing energy from food
(
perhaps carbohydrate) before seriouslyinterfering with the metabolism of amino
acids. The physical condition of the
de-ficient animals may not allow survival until
deficiency of Vitamin B,; can become
suf-ficiently severe to cause a demonstrable
dis-turbance in the enzymes involved in
metab-olism of amino acids. The amount of
Vita-mm B6 in the liver of rats placed on defi-cient diets promptly decreases but after four
to six weeks the residual stores remain
rather static at appreciable levels
(
3.8micrograms per gram of liver compared to
7.0 micrograms per gram in controls).2
Of the many studies of activity of various
enzyme systems served by Vitamin B6 only
one will be mentioned because of special
interest in connection with convulsions in
deficient animals. Glutamic acid
decar-boxylase activity has been found to be
de-creased in brain tissue from Vitamin B,
ad-VITAMIN B6 IN HUMAN NUTRITION 275
ministration of glutamic acid to Vitamin B6
deficient rats raised the electroshock
thresh-old of the brain, in the same manner as
did treatment with pyridoxine.”
Animals and humans deficient in Vitamin
B6 given a dose of tryptophane have been
shown to excrete xanthurenic acid, a
prod-uct of tryptophane metabolism not normally found in the urine.’6’ 27
At present the readily detectable
bio-chemical abnormalities in Vitamin B6
de-ficiency are:
(
1) an elevated fasting urea inthe blood or an abnormal increase in urea
production following administration of
amino acids, particularly alanine, and (2)
excretion of xanthurenic acid in the urine
if sufficient tryptophane is administered.
POSSIBLE FACrORS IN DEVELOPMENT OF
VITAMIN B DEFICIENCY IN EARLY INFANCY
The definite demonstration of Vitamin B6
deficiency in two human infants by
Snyder-man, et al., is unfortunately of limited
serv-ice in tracing the pathogenesis of the
con-vulsions occurring in infants fed liquid
SMA. This is because an unnatural
syn-thetic diet was used. Still the manifestations
in one of their infants appear identical in
every respect to those of the infants
devel-oping seizures from feeding liquid SMA. It
is noteworthy that convulsions occurred
after two and one-half months on the
de-ficient synthetic diet but only in the
younger infant who was placed on the diet
at two months of age.
There seems no reason to doubt that the
convulsion syndrome in infants fed liquid
SMA was due to a deficiency of Vitamin B,,.
The important questions to be settled are:
(
1) did some other features of liquid SMA, beside the content of Vitamin B6, promotea deficiency by increasing the requirement
for Vitamin B6, (2) is there evidence that
seizures due to Vitamin B deficiency might
have been, and may still be, appearing in
infants fed on other regimens, and (3) what
are the factors conducive to development of
a deficiency of Vitamin B6 in infancy which
therefore determine the requirement?
The answers to such questions might
sug-gest an explanation for the incidence of
convulsions estimated as only three per one
thousand babies reared on the condemned
lots of liquid SMA.
Some factors to be considered in an
eluci-dation of the pathogenesis of Vitamin B,
deficiency in infants are listed below:
POSSIBLE FACTORS IN DEVELOPMENT OF
Vi-TAMIN B6 DEFICIENCY IN EARLY INFANCY
Related to diet
Inadequate Vitamin B,; in diet Inadequate synthesis in intestine Increased consumption in intestine
Faulty absorption from intestine
Inadequate stores from mother
Related to increased requirement
Infection Rapid growth Composition of diet
Fatty acids Protein Carbohydrate
Effects of heat treatment Other vitamins
Assay of milk products for Vitamin B6
may not be exact but the relative values for
different milk products may be accepted as
sgnificant. Liquid SMA was found to
con-tam 60 micrograms of Vitamin B,; per liter
compared to 220 micrograms in
reconsti-tuted powdered SMA and 130 micrograms
in fresh human milk.6
Vitamin B6 compounds as they exist in
milk are unstable to heat so that 60-70%
may be lost under customary conditions
of sterilization of commercial canned
liquid products. The amount destroyed
during processing may well be affected by
other ingredients in milk formulae,
espe-cially in the liquid state, such as metallic
ions, oxidation products formed from
heat-ing, etc. Subsequent losses during storage
would obviously be important. Added
pyri-doxine is much more stable, only about
con-DAILY INTAKE AND ExciTIoN OF VITAMIN B COMPOUNDS (IN MICROGRAMS) IN BABIES FED Cow’s MILK EXCLUSIVELY0
Age
6 weeks
Excretion
Intake Urine Feces
698 686 146
Total
832
0 From MolIer.
Diet
720 gm. of
50% milk
4 months 1000 gm. of
80% milk
ditions, permitting fortification to insure an adequate amount of the vitamin in finished products.
Proof is lacking that just the modest
differences in the content of Vitamin B.
in various milk products could account for
deficiency with such frequency at the lower
level but rarely at the higher levels. The
relative importance in supplying the human need for Vitamin B6 from the dietary source or from synthesis by the intestinal bacteria has not been ascertained. The only investi-gation in this regard indicates that in milk
fed infants more Vitamin B6 may be
syn-thesized in the intestine than is ingested in the diet.2’
That the synthesis or consumption of
Vitamin B6 by the intestinal bacteria is of
importance to the host has been shown
re-peatedly in animal experiments.29
There-fore, the absolute or relative amounts of
Vitamin B6 in the diet may not be so critical as the effect of the diet on the intestinal flora.
A calculated effort was made to alter the
intestinal flora by the change in that
for-mula of SMA which was followed by the
convulsion syndrome.’#{176} Whether the type of
flora which was produced synthesized less
Vitamin B6, consumed more, or both is not
known. The various forms of Vitamin B6
compounds appear to be equally well
utilized’s so that any differences in this
re-spect were probably not crucial.
It is not difficult to believe that variations in the stores of Vitamin B6 received in utero
might have conditioned some infants to be
less susceptible to deficiency induced
through the diet and so account for the fact
1680 1502 310 1812
that relatively few infants developed the
convulsions syndrome. Also, as has been
suggested by Hunt,3’ some infants may be
made dependent upon an exceptionally
high intake by prolonged exposure to a
high level of Vitamin B. in utero.
These consideration do not exhaust the
unsolved problems concerning the natural
and proper provision of Vitamin B6 in the
diet of an infant. The problems can be
ob-scured or circumnavigated by the simple
device of addition of an abundance of
pyri-doxine to milk products. This practice may
be desirable and harmless but some
hesita-tion should govern any move that might
create an imbalance between nutritional
factors because our knowledge of all the
implications is so imperfect. Nor should we
condone “patching” the infant’s diet to
cover any deficiencies the composition may
have engendered. The safest procedure
might be to restore the content of Vitamin B6 in processed milks to that found in
human milk with full realization that the
requirements induced by various milk
products may be very different.
As to factors which might increase the
requirement for Vitamin B6 in infancy,
there is ample evidence that infection
de-pletes the bodily stores of vitamins. The
period of rapid growth and correspondingly
active metabolism of protein have been
shown to increase the requirement for
Vita-mm B. in experimental animals.’ These
are factors common to all infants and should
not have played a specific role in the
de-velopment of Vitamin B,, deficiency in one
group of infants fed a particular product. The nature of the carbohydrate component of a diet has clearly demonstrable effects
VITAMIN B,; IN HUMAN NUTRITION 277
through its effect on the intestinal flora in tlic niatiner already (115C1I5SC(l. The
carl)o-hydrate in liquid S\IA did not (lillerfrom
that in many other formulae.
As a change in the fats was one of the
modifications in the manufacture of liquid
SMA which preceded the episodic of
seizures in infants consuming the prolttct it
is of particular interest to examine the
in-terrelation of fatty acids and Vitamin B,;. It
will be recalled that the typical convulsions
dud not occur in infants fed the powdered
form of SMA made from the same batch of
raw materials. Although Vitamin B is
in-VO1VCd1 ill the transformation of linoleic acid
to arachidonic acid,” there does not seem
to be any reason to suppose the
require-rnents for this purpose would be any greater
with the liquid SMA than for the powdered
form of the same fatty acid composition.
Presumably another change in
mann-facture was more prolonged and intense
heating of the liquid form as a final step in
manufacture to insure sterility.’ This might
have accelerated destruction of Vitamin B,;
or produced! substances which led to an
in-creased requirement for Vitamin B,,. These possibilities are suggested by the fact that
changing the formula back to its original
composition dud not eliminate the
occur-rence of seizures.
One effect of heat treatment of fats is to produce oxidative or other toxic products.’
The effect of these on the requirement for
Vitamin B,; are unknown. It does not tax the
imagination to conceive of substances being
formed during prolonged autoclaving at
high temperature of a complex mixture of
fats, carbohydrate, protein, and other
in-gredients in a product such as liquid SMA
which would increase the requirement for
Vitamin B,,.
Finally, very little is known, about the
“sparing effects” or interrelationship of
other vitamins and Vitamin B,,. One cannot
ignore the role of Vitamin B,, in the metab-olism of nerve tissue. The synthetic Vitamin B6 deficient diet of Snyderman, et al., was
not supplemented with Vitamin B,, and it
was 1lI1(iOtIl)tedlv also low in this vitamin
comnpare(i to milk. This is not to suggest
that tlu’ amount of \Titamnin l3 in
ctts-tornary milk feedings is not adequate under
normal circumstances. It is possible that
Vitamin B1, was lost excessively along with
Vitamin B in the revised formula and
man-ufacturing lrocedittre of liquid SNIA.
Syn-thesis or consumption of Vitamin B1, may
have been adversely affected by the change
in the intestinal flora. It will be important
to determine whether Vitamins B1, and B,;
have any synergistic effects in nerve cell
metal)olism. We know of one infant having
seizures while on liquid SMA that ceased
promptly after treatment with Vitamin B,,
alone.
CONcLUDING REMARKS
Thus, this new chapter in the story of
Vitamin B,, in human nutrition arose from
a sincere effort to improve the nutrition of
babies, who must be reared on artifical
formulae. Although feeding at the mother’s
breast under ideal circumstances produces
a nutritional state in the baby which has
never been surpassed by any form of
arti-ficial feeding this is not always feasible.
Many formulae for modifying cow’s milk
for infant feeding may be reasonably
sue-cessful and yet be extremely crude
approxi-mations of the composition of human milk.
The most significant advances in infant
nutrition have been steps towards achieving
a modification of cow’s milk making it
equivalent to human milk, particularly as
to sterility, curd tension, qualitative and
quantitative composition. Some of the most
widely used modifications of fresh or
evap-orated cow’s milk have been devised
em-pirically and depend on accident more than
design for satisfactory results: the
com-mercial processing undertaken to attain
stability provided sterility amid low curd
tension; the relatively excessive solids
com-pared to human milk miraculously covered
most nutritional requirements without
deleterious effects from excessive intake of
CHARLES D. MAY
Amongst the features of infants reared
OH COWS inilk modifications is an intestinal
bacterial flora which is distinctly (lifferent
from the characteristic flora of an infant
consuming human milk. In the light of
cur-rent knowledge concerning the relation of
the intestinal bacterial flora to nutrition, this
difference might be assumed to be
signifi-cant.” J was with this end in view that the
manufacturer of SMA altered the product,
and an unforeseen implication of Vitamin B;
in infant nutrition was disclosed.
However, it would be both unfair and
foolish to condemn those who may have
stumbled on the stony path which must be
followed to reach an understanding and
imitation of the ways of Nature. It is
reason-able to expect that further pitfalls await
those whose good fortune might encourage
arrogance and complacency in the face of
the undiscovered implications of customary artificial feeding practices. One need only refer to the imperfection in our knowledge concerning the pathogenesis of neonatal
tet-any, and the attendant dramatic convulsive
seizures, in newborn babies being fed those
modifications of cow’s milk which do not
correct the unfavorable ratio or
concentra-tion of calcium and phosphorus in cow’s
milk as compared to human milk. And as
has been stated, “the basis of the conceded superiority of human milk seems still to be
something of a nutritional mystery,” and
cannot be attributed to differences in the
protein requirement if protein is supplied by cow’s milk rather than human milk.34
Indeed until explanation is found for
‘idiopathic” seizures in other infants during
the same age period as those fed liquid
SMA, but who were fed pasteurized fresh
cow’s milk and evaporated milk formulae,
we cannot be sure Vitamin B6 deficiency is
not more widespread. Perhaps more
con-spicuous involvement of one product has
served to create an awareness of the
syn-drome. This proved to be the case with
megaloblastic anemia in infancy which
seemed at first to be intimately associated with particular types of infant feeding, but
finally this was shown to l)e of only relative significance.
It is hoped this critique ina’ serve to
bring out this object lesson : Mere treatment of a suspected deficiency state with unphys-iologically large doses of a vitamin throws
little light on the pathogenesis and fails to
remove the responsibility for finding and
correcting the cause; it may even prove
misleading.
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