Biotin in Human Nutrition

J EAN-PIERRE BONJ OUR

Department of Vitamin and Nutrition Research
F. Hoffmann-La Roche & Co. Ltd.
Bade. Switzerland
INTRODUCTION
Biotin serves as prosthetic group in a number of enzymes four of which occur in
animal and human tissues namely: pyruvate carboxylase (EC 6.4.1.1) (PC), acetyl-
CoA carboxylase (EC 6.4.1.2) (ACC), propionyl-CoA carboxylase (EC 6.4.1.3)
(PCC), and 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) (MCC).*2* Biotin is
linked in these enzymes covalently to the c amino group of a lysine residue in the
apoenzyme; the linkage is established by holoenzyme synthetase. This enzyme has a
high specificity for d-biotin and a broad one for the apoenzyme, suggesting that the
environment of the lysine residue to which the biotin is attached may be similar in the
various apoenzymes. All biotin-containing enzymes are concerned with the transfer of
a carbonyl group. The mechanism of these reactions has been el~cidated..~. The four
biotin-containing carboxylases are involved in carbon-chain elongation steps in mam-
malian metabolism: in gluconeogenesis (PC), fatty acid synthesis (ACC), propionate
metabolism (PCC), and in the catabolism of leucine (MCC).. The activities of these
carboxylases were found to decrease progressively in different tissues of animals when
fed a biotin-deficient diet, and to be rapidly restored on administration of biotin
although at different rates for the various tissues.. In humans biotin administration
enhanced PCC,6 MCCSV6 and also PC activities in leukocytes and after discontinua-
tion of biotin PCC and MCC activities returned to normal: whereas the ACC activity
remained unaffected.
The glycoprotein avidin, which is a component of raw egg white, strongly binds
biotin and also compounds structurally related to biotin containing an intact ureido
function in cis c~nfiguration.~. Feeding raw egg white induces biotin deficiency in most
animals. The animals cease to grow and start to develop characteristic pathological
symptoms affecting mainly the skin (seborrheic dermatitis) and the growth of hair
(alopecia) and on treatment with biotin all symptoms disappear.*-. Besides this
experimental egg white injury, spontaneous outbreaks of biotin deficiency which
respond to biotin treatment have occurred in animals under field conditions. Lesions
were similar to those produced under experimental conditions. The reason for these
outbreaks is not known but might be due to poor bioavailability of biotin in the feed
used. Furthermore, biotin-responsive disease conditions have been noted, such as the
Fatty Liver and Kidney Syndrome (FLKS) in broilers, which is due to a suboptimal
biotin content in the rations coupled with certain nutritional and environmental stress
factors..
OLDER FINDINGS
Seborrheic dermatitis of infancy, a self-limiting skin eruption of infants under six
months of age, closely resembles skin changes produced in rats fed a diet rich in egg
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98 ANNALS NEW YORK ACADEMY OF SCIENCES
white. A large number of reports9 have shown a beneficial effect of biotin treatment in
seborrheic dermatitis and in cases of Leiners disease, probably a generalized and
greatly intensified form of seborrheic dermatitis. Therefore, these skin changes have
been considered a sign of a biotin deficiency in infants.
When avidin, which strongly binds biotin rendering it thus unavailable for
nutritional purposes, was added to the diet of four volunteers a fine brawny desquama-
tion was observed in all subjects after 10 weeks on this diet. Furthermore, from the
fifth week onward mental changes such as mild depression progressing to extreme
lassitude were described. Besides this report of experimentally induced egg white
injury three further cases of an excessive intake of raw eggs have been observed. The
two adults and the boy showed skin changes and the boy also showed alopecia totalis.
The skin lesions in these patients and in the volunteers responded promptly to
administration of biotin; in the boy new hair began to grow. The observed mental
changes also disappeared on treatment with biotin. These findings confirm that biotin
deficiency leads to skin changes both in children and adults. In severe deficiencies
loss of hair can also occur.
Besides these cases no reports on biotin deficiency symptoms in humans have
appeared in the literature. This absence of reports could be due to the fact that
biotin-containing foods are numerous, although the absolute amount of biotin present
in even the richest dietary sources is very Rich dietary sources for biotin are
liver (100 pg biotin/100 g), egg yolk (52 pg/lOO g), and cooked whole cereals (20-30
pg/ 100 g). But not all of the dietary biotin seems to be bioavailable. While in corn all of
the microbiologically determined biotin was available, in oats, milo, and barley only
2630% and in wheat none was found to be available to the
Another possible source of biotin for man could be the enteric synthesis of this
vitamin by the microflora. During the 1940s several investigators noted that the
amount of biotin excreted in urine and feces together is higher than the dietary biotin
intake: changes i n dietary biotin intake were clearly affecting urinary biotin excretion,
whereas fecal excretion remained more or less unaffected. Trying to elucidate the
contribution of the intestinally synthesized biotin to the total biotin requirement,
patients were given sulfa drugs or antibiotics to destroy the microflora. But these
experiments were inconclusive: Two studies reported no changes in urinary biotin
concentration, suggesting that enterically synthesized biotin does not contribute to the
biotin requirements. Two other studies observed a decrease in urinary biotin excretion,
but this effect may have been due to the avidin included in the diet or to changes in
absorption of dietary biotin caused by the high dosis of antibiotics administered. When
measured, a reduction in fecal biotin content was noted? The uncertainty about human
biotin requirements is expressed in the various dietary recommendations for this
vitamin in different co~ntri es.~ For the first time estimated safe and adequate daily
dietary intakes for biotin were recently established for the United state^.'^Recom-
mended daily intakes increase from 35wg for neonates to 100-200 fig for adults.
Intestinal absorption of biotin has been shown to occur in the first third to half of
the rat small intestine with the molecule diffusing intact through the intestinal all.^.^
Other studies using hamster small intestine suggest a sodium activated transport
mechanism with a minor diffusional component in biotin intestinal ~ptake. ~ Further
investigations are needed to establish the exact mechanism for biotin absorption. Very
little information is available on the metabolism of biotin in humans: it is only known
that biotin is absorbed more extensively when given orally than instilled directly into
the colon.16 Furthermore, biotin levels rapidly increase both in plasma and red blood
cells when biotin is given intravenously, but 24 h later the levels returned to starting
values and 100% of the dose was found to be excreted in urine.I7 In human urine large
amounts of free biotin and very small quantities of biotin metabolites were determined
BONJOUR: BIOTIN IN HUMAN NUTRITION 99
by microbiological analysis. Bioautographic procedures revealed d-biotinsulfoxide and
another unidentified metabolite in human urine, but no degradation of the cyclic urea
ring of biotin.18 Recent investigations have shown that orally applied biotin is absorbed
rapidly and that the amount of biotin metabolites excreted in normal urine is as large
as that of unchanged biotin2; in these urines no d-biotinsulfoxide or -sulfone could be
detected.20
The occurrence of biotin deficiency due to dietary restrictions is very rare.
Nevertheless, population groups may be detected in which a state of marginal
deficiency exists without apparent clinical manifestation. The assessment of biotin
levels in body fluids may identify such groups. But any determination of biotin
concentrations as well as investigations into the metabolism of biotin in animals and
humans are complicated by the analytical procedures to be used for biotin. Biotin is
present in only very small quantities in body fluids. Moreover, depending on the
analytical method some of the biotin metabolites are estimated as biotin. For the
assessment of biotin microorganisms are used which require biotin as growth factor,
such as Lactobacillus plantarum or Ochromonas danica2 These microorganisms
utilize biotin and its metabolites to different extents and, therefore, the results of
analyses will differ accordingly. When biotin concentrations are determined using an
isotope dilution assay with avidin, any compound containing the cyclic ureido group of
biotin will be estimated as biotin.2 Colorimetric, gas chromatographic and polaro-
graphic methods have also been proposed for the determination of biotin.2 In any
method used bound biotin has to be released from the test material by acid hydrolysis
with sulfuric acid or by digestion with papain. I t is therefore not surprising that-using
these different methods for the analysis of biotin-mean biotin concentrations have
been reported ranging from 25 to 150 nmol/l in urine and from 0.5 to 7 nmol/l in
bl ~od. ~. ~ But even so, segments of the population were detected in which the biotin
status was reduced compared with a control population and using the same method of
analysis. Such groups were: children with seborrheic dermatitis and Leiners di sea~e, ~. ~
children with burns and scalds? pregnant and lactating women,2*9*2 athlete^,^.^the
el derl ~, ~. ~ alcoholics,22 and patients with a~hl orhydri a.~.~ Low biotin concentrations
were recently found also in epileptic^.^.^^The clinical significance of reduced levels of
biotin in humans is not yet clear.
RECENT DEVELOPMENTS
A defect in the degradative metabolism of branched-chain amino acids and in the
propionate-methylmalonate pathway is associated with the accumulation of small
molecular weight organic acids in blood and/or in urine. Some patients with organic
acidemias and acidurias suffer from an inborn error of metabolism of the biotin-
dependent carbo~yl ases. ~~~~~ Children with such an inborn error of metabolism of the
biotin-containing carboxylases can be divided into two groups: one affected by an
isolated defect of either of the carboxylases and the other group by a combined
deficiency of the three mitochondria1 biotin-dependent carboxylases. Isolated defects
have been observed for PCC and PC leading to propionic acidemia and to lactic
acidosis, respectively. The cases reported up to now with an isolated defect of MCC
resulting in 3-methylcrotonyl glycinuria have not included sufficiently extensive
enzymatic investigations to exclude a combined carboxylase deficiency. No isolated
defect has been observed for the cytosolic ACC.
Clinically, children suffering from a defect of biotin-dependent carboxylases
present similarly with poor feeding, persistent vomiting, muscular hypotonia, lack of
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ANNALS NEW YORK ACADEMY OF SCIENCES
responsiveness, lethargy and coma, often ketoacidosis, and developmental retardation
in older children. Differential diagnosis can therefore be established only after
extensive biochemical investigations of organic acids in blood and urine suspected to
occur in isolated deficiencies. It has been proposed2 that the main diagnostic
metabolites in urine for 3-methylcrotonyl glycinuria are 3-methylcrotonic acid and/or
3-methylcrotonylglycine; methylcitric and 3-hydroxypropionic acids in urine and
propionic acid in blood for propionic acidemia; and lactic acid in blood and urine for
lactic acidosis. Measurements of activities in cultured fibroblasts or leukocytes of all
the biotin-dependent carboxylases must be included. These extensive biochemical
investigations allow the identification of the defective enzyme and also of cases with a
combined enzyme deficiency which in the past have often been wrongly classified as
suffering from an isolated defi~iency.~ The nature of the molecular defect in isolated
carboxylase deficiencies is not yet known. But the lack of definite biotin responsiveness
suggests that the defect involves the apoenzyme and is not dependent on the
metabolism of biotin.**
Infants affected by a combiried deficiency of the biotin-dependent carbo~ylases~~
present clinically with the symptoms of organic acidemia and aciduria and most
prominently also with skin rash and mostly alopecia. Biochemically each of the
above-mentioned short-chain organic acids of an isolated enzyme defect can be found
in blood and urine of such patients. Enzyme activities in cultured fibroblasts were
noted to be reduced in some affected children and normal in others. But only this
combined carboxylase defect has been shown unequivocally to be biotin-responsive in
v i m and in vivo. This finding indicates that the basic genetic defect results either from
an abnormality in absorption, transport, and/or metabolism of biotin or from a defect
in the holocarboxylase synthetase, which covalently binds biotin to the apoenzymes.
Such a holocarboxylase defect has been demonstrated in some ~hi l dren.~~*~ Recently, a
reduced biotinidase activity in serum of three children with typical symptoms of
combined carboxylase deficiency has been reported and confirmed in further
patient^.'^.'' Such a deficient biotinidase activity prevents the liberation of biotin from
biotin-containing compounds in the circulation and leads to the excretion of biocytin
(r-N-biotinyl-lysine) in the urine of affected children.20
I n a boy with a dietary defic:iency of biotin caused by excessive intake of raw eggs,
metabolic consequences similar to those observed in combined carboxylase deficiency
were describedz9: elevated excretion in urine of 3-methylcrotonylglycine, of 3-
hydroxyisovaleric, 3-hydroxypropionic, methylcitric, and 3-hydroxybutyric acids.
Activities of PCC and MCC in cultured fibroblasts were found to be reduced as were
the biotin concentrations in blood and urine. Clinically, the 1 1-year-old mentally
retarded boy presented with alopecia totalis and generalized erythematous, scaly
eruptions most prominently on his face. Treatment with biotin and the omission of raw
eggs from the diet led to a reversal of all the metabolic manifestations observed; the
skin began to improve within days and there was hair growth within two weeks.
Skin lesions and loss of hair have also been reported in ~hildren~ and adults3G36
receiving long-term total parenteral nutrition without biotin. When measured, biotin
concentration^^^"*'^in blood and urine were found to be reduced and in urine elevated
excretion of abnormal organic acids (i .e. 3-methylcrotonylglycine, 3-hydroxypro-
pionic, methylcitric, and lactic acids) were noted. On treatment with biotin or on
switching to a multivitamin preparation containing biotin, skin lesions healed and the
hair began to regrow in all patients. Patients on total parenteral nutrition are known to
develop depressive episodes which were thought not to be related to their alimentation.
Nevertheless, mental changes have been reported in volunteers with experimentally
induced biotin deficiency, and irritability is often mentioned in children with an
inborn error of biotin-dependent enzymes.* Treatment with biotin in these cases and in
BONJOUR BIOTIN IN HUMAN NUTRITION 101
children and adults on total parenteral n~tri ti on~~* improved their mental status. In
a patient under psychiatric therapy receiving total parenteral nutrition without biotin,
and who showed only slight skin changes, treatment with biotin relieved his depres-
~i on.~
I n epileptics treated with anticonvulsants other than sodium valproate reduced
biotin levels in plasma have been noted and elevated concentrations of abnormal
organic acid in urine and of lactic acid in plasma have been found in contrast to
epileptics treated with valproate or to controls.23
CONCLUSIONS
A reduction in the activity of the biotin-dependent carboxylases leads to the
excretion of small molecular weight organic acids in ~r i ne. ~~. ~ The nature of these
metabolites depends on the metabolic step that is blocked in each case of an isolated
carboxylase deficiency. In a combined carboxylase deficiency, where the activities of at
least the three mitochondria1 biotin-dependent carboxylases are deficient and in some
cases also of the cytosolic ACC, most of the abnormal metabolites identified in an
isolated enzyme deficiency have been detected in the urine of affected patients. As the
activity of these carboxylases is dependent on biotin c~ncentration,~**~ a reduction of
circulating biotin levels, due to excessive intake of raw eggs,29 to total parenteral
nutrition without biotin3G32 or to treatment with specific anti conv~l sants,~~ also leads
to excretion of these abnormal organic acids in urine. Whether these abnormal
metabolites are equally found in segments of the population in which reduced
circulating biotin levels have been noted, remains to be investigated. And further
studies are necessary to demonstrate whether the appearance of these abnormal
organic acids in urine can be used as a functional parameter to define the requirement
of biotin.
Patients suffering from a combined deficiency of the biotin-dependent carboxyl-
ases present clinically with the symptoms of organic acidemia and aciduria and
prominently also with skin rash and mostly alopecia. Skin lesions and loss of hair have
been reported in patients with egg white i nj ~ry~* * ~ and in patients receiving total
parenteral n~tri ti on,~ ~ skin lesions only in volunteers on a biotin-deficient diet.9 In
humans-as in animals-biotin deficiency therefore provokes skin lesions and loss of
hair, and the seborrheic dermatitis of infancy, often reported in the older literature: is
then a true biotin-deficiency symptom.
Two basic genetic defects have been found to cause combined deficienc of the
biotin-dependent carboxylases: a defect of the holocarboxylase synthetaseV2 and
recently a deficient biotinidase activity.28 Such a biotinidase deficiency leads to the
appearance of biocytin in the urine of affected children, a compound that is not
normally excreted.20 These findings indicate that in healthy persons biotin is cleaved
from biocytin derived either from the catabolism of the biotin-containing carboxylases
or from bound biotin in food. Whether biotin exists in food free or bound to lysine
cannot be estimated as all determinations of biotin contents in food23*2 have been
based on microbiological assays that include an acid hydrolysis step. Such hydrolysis
liberates at least part of the bound biotin, which may not be wholly bioavailable as
indicated by the reduced availability of biotin in cereals in the chicken growth test.
Biocytin derived from the catabolism of carboxylases will be cleaved by the biotinidase
occurring in blood and the biotin liberated. Biotin is thus recycled in healthy humans.
Whether biotin circulates bound to a biotin-binding protein remains to be
elucidated. Certain findings seem to indicate that such a biotin-binding protein
102 ANNALS NEW YORK ACADEMY OF SCIENCES
exists: (1) the incomplete elimination of biotin from human and fetal calf serum by
extensive dialysis or by treatment with avidin, (2) the lower biotin concentrations
found in plasma when levels were determined by an avidin binding method compared
with the microbiological assay, which includes digestion with papain (J. Bausch,
unpublished results), and (3) by the older observation of an accumulation of biotin in
the a-globulin and albumin fractions of human plasma. This biotin-binding protein
might be biotinidase, as in patients with a deficiency of this particular enzyme an
elevated biotin clearance has been noted. However, the increased renal loss of biotin
could also be due to biocytin present in these patients.19 In the urine of healthy persons
only biotin metabolites and excess biotin are excreted.
This endogenous recycling of biotin-and not the intestinal synthesis-may then
be the reason why biotin deficiency symptoms take a long time to develop and are only
rarely seen in healthy humans.
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104 ANNALS NEW YORK ACADEMY OF SCIENCES
DISCUSSION OF THE PAPER
L. MACHLI N (Hoffmann-Lo Roche, Nufl ey, NJO7IIO): You mentioned that in the
elderly, in pregnant or lactating women, and I think in athletes the biotin levels were
low. In these cases is there any correlation with excessive organic acid excretion or any
other functional parameter or simply an observation that they are low?
J . P. BONJ OUR: It is only an Observation that biotin levels are low in these subjects.
Further investigations are necessary to show whether low circulating biotin levels lead
also in healthy persons to the excretion of abnormal organic acids.
H. N. BHAGAVAN: (Hoflmann-LaRoche, Nutley, NJ 071 10) Could you comment
on the optimum intake of biotin?
BONJ OUR: I think the American Medical Association has stipulated 60 p g per day
in total parenteral nutrition. The 1JS Food and Nutrition Board state in the last edition
of the Recommended Dietary Allowances that 100-300 pg biotin daily will meet the
needs of practically all healthy adults.