AMERICAN
ACADEMY
OF
PEDIATRICS
COMMITTEE
ON
NUTRITION
VITAMIN
B6 REQUIREMENTS
IN MAN
I
rc 1934 Gyorgy1 reported experimental studies on the relation of a dietary fac-tor to rat dermatitis and established this nutrient as a new member of the B-Corn-plex, calling it vitamin B6. The vitaminsubsequently isolated26 and synthesized was found to be 2 methyl-3 hydroxy-4, 5
hydroxy methyl pyridine and called
pyri-doxine.7
By means of an elegant series of experi-ments, Snell discovered that vitamin B6
ex-ists in three interchangeable forms,
pyri-doxine, pyridoxal, pyridoxamine, all of which are phosphorylated in vivo, as shown in Figure 1.8,9 The vitamin is eventually metabolized to pyridoxic acid and excreted in the urine.10 Pyridoxal phosphate, bio-chemically the major active form of this
group, functions as a coenzyme in virtually all of the reactions involving amino acids,
such as transamination, deamination,
decar-boxylation, racemization, amine ixodation,
as well as elimination and additive
reac-tions.11’12 Pyridoxal phosphate is also a sig-nificant component of muscle phosphorylase
a and b, the enzyme that initiates the first
step in glycogenolysis, leading to formation of glucose1phosphate.l3 Furthermore, pyr-idoxal phosphate has been implicated in fat
metabolism through its relation to phospho-lipids and cholesterol esters, fatty acid
trans-port, and control of adipose tissue composi-tion.14
Since vitamin B6 is involved in such a large number of crucial biochemical reac-tions, a variety of metabolic disorders may result from a deficiency of this vitamin.15
The integrity of each biochemical reaction seems to depend on the individual rank
order of affinity of the apoenzyme for pyri-doxal phosphate and the avidity of binding
with pyridoxal phosphate.16
In the disease states referred to as
“vita-mm
B6 dependency,” it has been proposedthat an inborn or acquired structural ab-normality has changed the binding
capac-ity of the specific B-dependent apoenzymes
to the cofactor and that only larger
amounts of pyridoxal phosphate can over-come adverse binding kinetics’7’18 Bon-ner19 has demonstrated specific mutations affecting the B6 binding site of an apo-enzyme. Frimpter2#{176} recently presented
evi-dence which strongly supports the concept of an altered binding site as the mechanism of B6 dependency. It has also been con-firmed that both metabolism and
avail-ability of the vitamin are normal in at least one form of B6 dependency.21 In an mdi-vidual with B6 dependency, in contrast to the excessive needs by the abnormal
en-zymes for pyridoxine, the other enzymatic
reactions requiring B6 proceed normally in
the presence of the usual concentrations of the vitamin.
MEASUREMENT
Since vitamin B6 participates in the many biochemical reactions mentioned above,
procedures to detect the effect of the deficiency state on most of these have been developed. One of the most sensitive
mdi-cators of pyridoxine deficiency is the in-creased excretion in urine of xanthurenic acid and related intermediary metabolites such as hydroxykynurenmne, 3-hydroxy
an-thranilic acid, nicotinic acid, etc. following the ingestion of a tryptophan load.2225 Other determinations of diagnostic value include: changes in activity of enzymes, such as glutamic pyruvic transaminase and glutamic oxaloacetic transaminase; 26-27
ex-cretion in urine28 of pyridoxic acid; and variations in the levels of vitamin B6 in blood and urine.293’
Discrepancies in the values reported by
different laboratories preclude an accurate compilation of data on the levels of the
VITAMIN B6 CONTENT OF VARIOUS TYPES OF FooDs4
Milks
Human Cow
Eggs
Ieats
Beef liver Beef steak
Chicken
Pork, Ham
Grains Wheat Oats Rice
Corn
Yeast, Brewer’s, dry
Vegetables
Bean, lima
Carrots
Onion Potato, White
Soy bean
Fruits
Apple Banana Orange
0.01-0.10 0.35-0.60
0.22
7.3
2.8
1.2 3.9
5.8
0.92
3.4 4.9
47.3
6.0 2.1 0.63
1.8
10.2
0.26
3.2
0.31
4 Reported as micrograms of pyridoxine per gram or
per milliliter.
4-PYRLDOXIC ACID
I
oxidasePYRIDOXINE iiiiiii PYRIDOXAL( 2PYRIDOXAMINE
phosphatase kinase
PYRIDOXINE PHOSPHA TEPYRIDOXAL PHOSPHATEPYRIDOXAMINE PHOSPHATE
Fic. 1. The metabolism of the members of the vitamin B group.
three B6 cofactors in either biological
samples or food. Microbiological assays
employing Saccharomyces carlsbergensis3l
have been generally accepted as the
stan-TABLE I
Food JAg/gm
dard for estimating total B6 content of
foods. Typical data derived from this assay
are listed in Table It is worth noting that advances in the use of column
chroma-tography for separation of the specific co-factors in the pyridoxmne group and the
de-velopment of methods for spectropho-tofluorometric measurement promise to
provide more accurate quantitation of each
of the specific forms.41
In foodstuffs of animal origin, particular-ly milk, most of the vitamin B. is present as heat-labile pyridoxal and pyridoxine rather
than the more heat as stable pyridoxmne.
Exposure of foods to temperatures above 100#{176}Cduring processing may result in
de-struction of an appreciable portion of
natu-rally occurring vitamin B6.4244 In milk, an
inactive disulfide-pyridoxal complex may
be formed during heating.45 The heat
labil-ity of the vitamin is a factor to be consid-ered as in the commercial processing of
in-fant formulas containing fluid or skim milk, especially since these preparations are often subjected to additional sterilization by commerical formula services, hospital
formula rooms, and at home. Most, if not all, commercially prepared formulas manu-factured in the United States are
adequate-ly supplemented with pyridoxine to
com-pensate for any such losses.
VITAMIN B6 REQUIREMENTS IN THE
NORMAL POPULATION
Although the data on vitamin B6
1070 ViTAMIN B REQUIREMENTS
TABLE II
ESTIMATED VITAMIN B6 REQUIREMENTS FOR
VARIOUS AGE GROUPS
(mg/Day)
individual Amount
Infant
Child Adolescent Elderly Adult Adult
0 .10-0.5k 0.5-1.5 1.5-2.0 2.0-4.0 1.5-2.0
4 20 JAg/gm protein. These ranges are related to
normal ranges of protein intake.
of the vitamin by normal people of various
ages.4#{176}48 In general the needs are related
to levels of protein intake.
Pregnancy
It has been noted that most pregnant women have decreased levels of vitamin B6
in blood4950 and increased urinary
excre-tion of xanthurenic acid is observed
fol-lowing a tryptophan load.5’ These findings,
generally considered evidence of a B6
de-ficiency state in nonpregnant subjects, may
reflect insufficient intake of the vitamin, an
increased urinary excretion of B6 or
pla-cental transfer of B to the fetus. The
pla-centa actively transports B6 to the fetus to
maintain a five-fold concentration gradi-ent favoring the fetus.5253 In the majority
of women studied, daily oral doses of 5 to
10 mg of pyridoxine corrected biochemical
signs of vitamin B6 deficiency. The exact significance of these biochemical changes
in the normal pregnant woman is as yet
poorly understood but suggests that needs
for pyridoxmne are increased during preg-nancy.
Newborn Period and Infancy
The normal newborn infant has suffi-cient tissue stores of vitamin B6 to meet
needs during the neonatal period even though the diet may be virtually devoid of
the vitamin. The concentration of B6 in
human milk is approximately 10 to 20 tg
per liter during the first month of lactation, thereafter gradually increasing to 100 g
per liter.39 While the daily requirements of
B6 are met by the consumption of ade-quate quantities of normal human milk, the relation of vitamin B6 and protein appears
to be critical. Cow’s milk, which has a higher (3.3%) protein level than human milk, also contains more vitamin B6, 350
to 600 lL per liter. If vitamin B concen-tration fails to rise above 60 to 80 i.&g per
liter in human milk, clinical and
biochemi-cal abnormalities characteristic of the
de-ficiency state may occur when protein
con-sumption exceeds the infant’s metabolic ca-pacity. The situation is similar to that seen
in infants receiving formulas containing in-adequate amounts of B6 in whom clinical
manifestations of deficiency disappear im-mediately following the addition of
B6-containing solid foods to the diet. Meta-bolic requirements for B6 are satisfied at 6 months of age if the vitamin is present in amounts of 20 per gram of dietary pro-tein.55 Evaluation of commercially
pre-pared baby foods has shown that in rela-tion to their content of protein they
con-tam more than adequate amounts of vita-mm B6.55”
Childhood
The requirement for vitamin B6 of the older infant and young child, estimated to be 0.5 to 1.0 mg per day, is readily sup-plied by a suitably balanced diet. In de-veloping countries, where marginal or
frankly deficient intakes of B6 are very
common,56’57 infants and children may have no clinical signs of deficiency, since
the amount of protein in the diet is rela-lively low and individual B6 requiring
en-zyme systems are usually adapted to a
lower level of metabolic activity. Vitamin
B6 deficiency, even if not clinically mani-fest, may have long-term detrimental ef-fects on physical and mental growth and development.
Adolescence and Adult Life
and the adolescent, but it is presumably in
the range of 1.5 to 2.0 mg daily. Calcula-tions based on “market-basket” types of
surveys suggest that if individuals in these
age groups ingest the selected diet they
can obtain 2.0 to 2.5 mg per day of vita-mm B6; since none of the known deficiency syndromes have been seen in normal
peo-plc in this age range consuming these
diets, such intakes are presumably
ade-quate. Unfortunately, the wide
fluctua-tions in the quantity and quality of food
consumed by the adolescent, the lack of information concerning the destructive ef-fects of cooking on the B; food content of
food, and the absence of adequate
mea-surements of possible biochemical
altera-tions with varying intakes of B6 during these periods of growth and development
preclude making a final statement on the
matter.
In considering the vitamin B6
require-ment of older adolescents, it is possible to
utilize data from controlled studies of healthy young adult males to estimate
needs in relation to level of protein intake.
A daily requirement for B6 of 1.25 to 1.50 mg was established for a low (30 gm/day)
protein diet and 1.75 to 2.0 mg for a high
(100 gm/day) protein diet.58
CONDITIONS REQUIRING VITAMIN B6
SUPPLEMENTATION OR THERAPY
Deficiency States
In 1950, Snyderman, et observed biochemical changes in two infants 2 and
8 months of age following ingestion of B6-free diet for 76 and 120 days, respectively,
with ultimate development of anemia in the younger child and convulsions in the older. Each child’s symptoms were
re-lieved and the biochemical alterations
cor-rected after administration of pyridoxine. In 1954, a number of investigators
re-ported the occurrence of hyperirritability,
convulsive seizures, and hyperacusis in
in-fants receiving a prepared milk formula
containing 15 gm of protein and 60 p.g of vitamin B6 per liter.6#{176}6
Electroencephalo-graphic changes and abnormal responses
to tryptophan loading were consistently demonstrated, but they were promptly
alleviated by administration of vitamin B6 in appropriate amounts. Similar findings
have been described in infants nursing at the breast of mothers whose milk was found to contain less than 100 p.g of vita-mm B6 per liter.46
Bessey and coworkers46 evaluated the
daily requirements of several infants who developed clinical symptoms of pyridoxine
deficiency due to inadequate intakes of
vitamin B6. They found that these infants required between 1.0 to 1.4 mg/day of
pyridoxmne, a dose somewhat in excess of the usual daily requirements for normal infants. Scriver and Hutchinsonds described
a 20-month-old infant with unequivocal stigmata of vitamin B6 deficiency whose
daily maintenance requirement of the vita-mm was greater than normal. It is
possi-ble that pyridoxine-deficient infants may for unknown reasons become deficient in coenzyme because of some idiosyncrasy of
coenzyme metabolism which is similar to or distinct from that seen in the “B6 de-pendency state.” Patients with
malabsorp-tion syndromes may exhibit laboratory cvi-dence of vitamin B6 deficiency; the latter
is reversed with pyridoxine 6667
Miscellaneous Problems
Vitamin B6 activity in blood is reduced in a variety of disease states, including leukemia, liver disease, and rheumatic fever6 69 Isoniazid, used in treatment of
tuberculosis, irreversibly combines with B6 to form an inactive isonicotinic acid
hydra-zide-pyridoxal phosphate complex. Since continued administration of the drug may lead to symptoms of B6 deficiency,#{176} B,; supplementation is recommended in
pa-tients receiving isoniazid and for a simi-lar reason in those under treatment with chelating agents.
Vitamin B6 has been reported to have some role in antibody response to
anti-genie 71 oxalate 72
1072 VITAMIN B6 REQUIREMENTS
as myoclonic 7475
phenylketo-nuria,76 and mongolism.7779
Recently Hagberg, et reported
finding an abnormal urinary excretion of xanthurenic acid following a tryptophan
load test in 26 of 43 infants and children who had the clinical symptomatology and the electroencephalographic changes of
cryptogenic epilepsy. Although these find-ings were interpreted as evidence of
vita-mm
B6 deficiency, the pyridoxal phosphate levels in the blood of these patients werewithin normal limits. Furthermore, the
dose of pyridoxine necessary to correct the
excessive xanthurenic acid excretion and to improve clinical and
electroencephalo-graphic evidence of cerebral dysfunction was found to be in the range of 160 mg
per day, a level far in excess of the daily
dose of 1 to 10 mg that ordinarily will
re-store to normal the patient with the usual
forms of B6 deficiency. As yet it is not possible to determine whether the
exces-sive B5 requirement of these patients
represents an acquired state or is the
cx-pression of a genetic abnormality.
Dependency States
In the syndrome(s) referred to as “vita-mm B6 dependency,” coenzyme
availa-bility is normal and there is no evidence of depletion of the B6 pool of the body.21
The disorder is probably inherited as a
recessive condition and may be caused by
a modification of the coenzyme binding site in a specific apoenzyme.18
Hunt, et al.17 described the first
mdi-vidual with vitamin B6 dependency in
1954.17 The patient had repeated convul-sive seizures and was mentally retarded. A
tryptophan load test was normal. Daily
doses of 10 to 25 mg of pyridoxmne were necessary to control the seizures. Several additional cases have since been reported
by other mnvestigators.885
Harris, et al.86 have described a
vita-mm B6 dependency syndrome involving the hematopoietic system that usually
ap-pears in early adult life but may be seen
in children. Among 72 patients reported to have had a pyridoxmne-responsive
anemia, four were infants and five were
older children.87 This anemia is character-ized by severe hypochromia, microcytosis, and hyperferremia, and it responds to
therapy with vitamin B6 at levels of 25
mg/day. The patients require maintenance doses at this level to prevent anemia. The defect may be genetically determined,
since the disease frequently affects several members of a given family and may be an example of late manifestation of a
geneti-cally controlled metabolic defect. In pa-tients with the molecular disease
cystathio-ninuria, the ability of the apoenzyme to bind coenzyme is severely limited, and, therefore, a continuous high intake of vita-mm B6 is required to control the metabolic
disturbance.
UNTOWARD RESPONSES TO VITAMIN
B6 ADMINISTRATION
To date there has been no report of
deleterious effects associated with daily oral ingestion of large doses of vitamin B6 (0.2 to 1 gm per day).
There have been a few unpublished re-ports of the induction of convulsive seizures and at times the occurrence of status epi-lepticus following rapid parenteral
admin-istration of pyridoxmne to patients who were pyridoxine-dependent and to patients re-ceiving isoniazid. While treatment with the vitamin is indicated in these circumstances, it should be administered slowly and with caution.
Undesirable reactions were observed by Hottinger, et al.88 in a heterogeneous group
of patients with central nervous system dis-orders. They exhibited an abnormal excre-tory pattern of metabolites in urine follow-ing tryptophan load tests. Following
thera-py with pyridoxine several of these
individ-uals experienced a marked increase in se-verity of clinical symptoms and showed deterioration of their electroencephalo-grams. These symptoms disappeared with
SUMMARY
Because of the limited information avail-able, it is not possible to derive precise figures for daily requirements of vitamin B6 in infants and children at this time. Data
currently available suggest that the daily need in childhood is 0.5 to 1.5 mg and in
adolescence is 1.5 to 2 mg. The requirement in infancy is clearly related to protein
in-take and is 20g/gm of dietary protein. Requirements of a few individuals will undoubtedly be higher than the estimates
for the normal population. Some of these patients will manifest frank biochemical
and clinical signs of deficiency which will
usually be promptly reversed by adminis-tration of small additional amounts of
pyri-doxine. Another group of patients will re-quire large amounts of the vitamin to
bal-ance the heritable alteration in binding
properties of a specific apoenzyme requi.r-ing pyridoxal phosphate for normal activity.
It would appear that most infants, chil-dren, and adults will have little difficulty in
achieving an adequate intake of vitamin B6
if they receive what is considered to be in other respects an adequate diet.
COMMITTEE ON NUTRITION
CHARLES U. Lowi, M.D., Chairman
DAVID B. COURSIN, M.D.
GEORGE N. DONNELL, M.D.
FELIX HEALD, M.D.
MALCOLM A. HOLLIDAY, M.D.
ROBERT KAYE, M.D.
DONOUGH O’BRIEN, M.D.
GEORGE M. OWEN, M.D.
Howi.im A. PEA1ISON, M.D.
CHARLES ScmviR, M .D.
MICHAEL
J.
SWEENEY, M.D. L.J.
FILER, M.D., Consultant0. L. KLINE, M.D., Consultant
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metabo-1078 LETFERS TO THE EDITOR
1076 VITAMIN B6 REQUIREMENTS
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ing and limitations and hopes to make the re-sults of this study available to the membership next spring.
Those who attended the Annual Meeting this October will recall that a panel discussion on various aspects of pediatric practice took place, and more such programs are planned for the future.
Finally, the Council welcomes comments and suggestions from the Fellowship regarding possible ways in which it can be of further
assistance to our members.
CARL C. FISCHER, M.D.
Chairman
battered child. It takes no great amount of diagnostic acumen to make a diagnosis of the battered child. It is, therefore, most important that the physicians and pediatricians be alert and conscious of signs diagnostic of the mal-treatment syndrome. Only in this way can a battered child possibly be saved from lethal
inflicted injuries. Prevention by proper recog-nition of these more insidious symptoms will
lead to the ultimate decreased incidence and eradication of this life-threatening disease.
