Biotin Deficiency
Biotin Deficiency
Biotin Deficiency
Related terms:
Metabolic Pathway, Biotin, Avidin, Biotinidase, Inositol, Nested Gene, Urinary Ex-
cretion, Egg White
VITAMINS
TOM BRODY, in Nutritional Biochemistry (Second Edition), 1999
Biotin Deficiency
Biotin deficiency in humans is rare. The first indicator of human biotin deficiency
appears to be a drop in urinary biotin, with a maintenance of plasma levels of the
vitamin. The deficiency can result from a rare genetic deficiency in biotinidase. The
disease occurs in about 1 in 40,000 infants and results in a rash about the eyebrows
and cheeks and neurological symptoms, such as muscle pain, extreme tiredness,
and numbness. Biotin deficiency may occur in persons who consume raw eggs
(six per day) over many months. Egg white contains a protein called avidin, which
binds to biotin extremely tightly, though not via a covalent linkage. The physiological
function of the avidin in egg white is not clear. The protein tightly binds the biotin
released during the digestion of dietary protein and prevents its absorption. Avidin
is destroyed during cooking. The protein has proven useful in inducing experimental
biotin deficiency in studies in humans and animals. Biotin deficiency has occurred
during prolonged total parenteral nutrition, where biotin had been inadvertently
omitted from the liquid formula. Persons who are taking antibiotics or who have
had parts of their intestines surgically removed may be at risk for a deficiency.
Biotin deficiency in animals results in alopecia, a scaly dermatitis, anorexia, and
eventually death. Some of the biochemical changes occurring in rats consuming
a biotin-deficient diet containing raw egg white are illustrated in Figure 9.33. The
animals consumed the diet for up to 30 days. The activities of three biotin-requiring
enzymes were determined in the livers of rats killed at the indicated times. The
enzymes measured were acetyl-CoA carboxylase (●), propionyl-CoA carboxylase (○),
and pyruvate carboxylase (Δ).
Copyright © 1971
Studies with pregnant animals have revealed that biotin deficiency tends to leave the
mothers in a healthy state, while producing birth defects in the fetuses (Mock et al.
1997a).
Biotin
Amitava Dasgupta PhD, in Biotin and Other Interferences in Immunoassays, 2019
Nutritional Biotin Deficiency
Biotin deficiency is usually characterized by alopecia and scaly erythematous der-
matitis distributed around the body orifices, acidemia, aciduria, hearing and vision
problems, and developmental delay in children. Biotin deficiency may also cause
paresthesias, myalgias, and mild depression. Biotin deficiency may have adverse
effects on the immune system and lipid metabolism. Frank biotin deficiency is rare.
However, as discussed earlier, prolonged consumption of raw eggs may cause biotin
deficiency because raw egg white contains an antimicrobial protein known as avidin
that tightly binds biotin and prevents its absorption. In adults and adolescents who
chronically consume raw egg white the following symptoms may develop due to egg
white injury syndrome33:
Pregnancy may cause subclinical biotin deficiency in healthy women because rapidly
dividing cells of the developing fetus require biotin for synthesis of essential bi-
otin-dependent carboxylases and also for histone biotinylation. Approximately 50%
of pregnant women have an abnormally increased urinary excretion of 3-hydrox-
yisovaleric acid, which probably reflects decreased activity of the biotin-dependent
enzyme 3-methycrotonyl-CoA carboxylase. Mock et al. compared concentrations of
biotin and its metabolites as well as 3-hydroxyiosvaleric acid in 13 urine specimens
obtained from pregnant women (during both early and late pregnancy) with those in
urine specimens obtained from 12 nonpregnant women and observed that during
early pregnancy, biotin excretion was not significantly different from controls but
excretion of 3-hydroxyvaleric acid was increased relative to controls. From early to
late pregnancy, biotin excretion decreased in 10 out of 13 women; by late preg-
nancy, biotin excretion was less than normal in 6 women. During late pregnancy,
3-hydroxisovaleric acid levels remained significantly elevated in the urine of
pregnant women compared with controls. Although serum biotin concentrations
were significantly greater than those of controls during early pregnancy, serum
biotin levels in pregnant women decreased in each woman studied from early to late
pregnancy. The authors concluded that biotin status decreases during pregnancy.43
Case Report: A 54–year-old woman with short bowel syndrome was supported with
home parenteral nutrition. Six months after receiving 2200 kcal/day of balanced
home parenteral nutrition without biotin, she developed biotin deficiency as evi-
denced by complete hair loss, eczematous dermatitis with waxy pallor, lethargy, and
hyperesthesias. Her serum biotin level was 332 pg/mL and urine biotin level was
5.22 ng/mg of creatinine indicating biotin deficiency. The same parenteral nutrition
was continued with addition of 10 mg/day oral biotin supplementation. After 3 weeks
of intervention, serum (650 pg/mL) and urine (35.6 ng/mg of creatinine) biotin
concentrations returned to normal levels. New hair growth was evident and all of
her other symptoms resolved. Intravenous biotin was then provided (5 mg/day) for
a month after which serum biotin level was increased to 1316 pg/mL and urine
biotin level to 178 ng/mg of creatinine. Later the patient had been subsequently
maintained on an intravenous multivitamin product containing only 60 μg of biotin
per day and the patient remained symptom free indicating no biotin deficiency.48
When an infant is weaning from breast and feeding formula, biotin deficiency is
rarely observed. However, a 5-month-old Japanese infant who had been diagnosed
during neonatal period with dyspepsia, developed typical skin lesions after feeding
with amino acid formula that did not contain biotin. Urinary excretion levels of 3-hy-
droxyisovaleric acid, 3-methylcrotonylglycine, and methylcitric acid were elevated
confirming biotin deficiency in the infant. Oral supplement of 1 mg biotin daily
corrected biotin deficiency in the infant and organic aciduria was also resolved.49
Amino acid formula and hydrolyzed formulas given to infants in Japan with milk
allergies theoretically contain little if any biotin or carnitine. Hayashi et al. reported
cases of six infants with milk allergies who were fed amino acid formula and/or hy-
drolyzed formula who showed elevated urinary levels of 3-hydroxyisovaleric acid and
lower serum concentrations of free carnitine compared with age-matched infants
who were fed breast milk or standard infant formulas, indicating biotin and carnitine
deficiency in infants fed with amino acid/hydrolyzed formula. Supplementation with
biotin and l-carnitine corrected such deficiency. The authors concluded that care
should be taken to avoid biotin and carnitine deficiency in allergic infants fed with
amino acid or hydrolyzed formulas.50 There is a report of biotin deficiency in a
girl with type 1B glycogen storage disease caused by an exclusive feeding of a
glucose-containing glycogen storage disease formula.51 A Japanese study involving
46 preterm infants indicates that chronic biotin deficiency may be observed in
preterm infants despite feeding maternal milk and/or standard infant formula.52
Some clinical and biochemical manifestations of biotin deficiency may also occur
in severe protein-energy malnutrition. In one study the authors reported that the
average plasma biotin concentrations were lower in 16 malnourished children than
in 31 controls.53 Therefore malnourished children from developing countries are at
higher risk of biotin deficiency.
Biotinidase is the enzyme responsible for liberating the vitamin biotin from biocytin
and dietary protein–bound vitamin. Individuals lacking biotinidase activity become
biotin deficient. Because the liver is the major source of plasma biotinidase, chronic
liver diseases may decrease serum biotinidase activity and cause biotin deficiency.
In one study, using a spectrophotometric method the authors measured serum
biotinidase activities in sera from 62 children with chronic liver diseases and from
27 healthy controls. The authors observed normal serum biotinidase activity in
patients with noncirrhotic chronic liver diseases (chronic viral hepatitis, prehepatic
portal hypertension, glycogen storage disease, Gaucher disease). However, serum
biotinidase activities in patients with cirrhosis and Wilson disease were significantly
less than those of the control group. The lowest enzyme activities were detected
in patients with fulminant hepatitis. The authors concluded that serum biotinidase
activity was significantly lower in patients with cirrhosis, particularly in the patients
with decompensated cirrhosis and fulminant hepatitis but these patients exhibited
no clinical symptoms related to biotin deficiency. However, decreased serum bio-
tinidase activity in chronic liver diseases was associated with severe impairment of
hepatocellular function.54
Marginal biotin deficiency may occur in women smokers owing to the increased
catabolism of biotin by cigarette smoke.55 Chronic alcohol consumption in humans
may cause reduction in plasma biotin levels.56 This finding has also been reproduced
in chronically alcohol fed rats. Inhibition of intestinal biotin absorption by chronic
alcohol feeding has been demonstrated in rat model.57 Moreover, malnutrition and
deficiencies of multiple vitamins have been widely reported in alcoholics.58
Ketogenic diet (low carbohydrate and high fat) has been reported to cause biotin
deficiency in mice. Ketogenic diet increases biotin bioavailability and consumption
and hence it promotes energy production by gluconeogenesis and branched-chain
amino acid metabolism, which results in biotin deficiency. Therefore biotin sup-
plementation is important for mice after feeding with ketogenic diet.59 There is a
case report of concurrent nonketotic hyperglycinemia and propionic acidemia in
an 8-year-old boy who was placed on a ketogenic diet. At 2 years of age, he was
diagnosed with nonketotic hyperglycinemia by observing elevated glycine levels and
mutations in the GLDC gene. At 8 years of age, after having been placed on ketogenic
diet, he became lethargic and had severe metabolic acidosis with ketonuria. Urine
organic acid analysis and plasma acylcarnitine profile were consistent with propionic
acidemia. He was found to have an apparently homozygous mutation in the PCCB
gene: c.49C>A; p.Leu17Met. The patient was treated with natural protein restric-
tion, carnitine, biotin, and thiamine, which resulted in subjective and biochemical
improvement.60 As mentioned earlier, prolonged treatment with anticonvulsants
may cause biotin depletion in serum. Patients taking antibiotic for a long time
theoretically may experience biotin deficiency because antibiotics may cause al-
teration of gut flora that produce biotin. Biotin is reabsorbed by the kidney, so
studies have addressed potential biotin deficiency in patients suffering from chronic
renal failure. However, no biotin deficiency has been reported in such patients.
Therefore there is no reason for a regular biotin supplementation in patients with
chronic renal failure.61 However, biotin may be effective in the management of
uremic neurologic disorders. In one study the authors supplemented nine patients
undergoing chronic hemodialysis for 2–10 years and suffering from encephalopathy
(dialysis dementia) and peripheral neuropathy with 10 mg of biotin/day for 1–4 years.
Within 3 months, there was a marked improvement in all patients in respect to
disorientation, speech disorders, memory failure, myoclonic jerks, flapping tremor,
restless legs, paresthesia, and difficulties in walking.62 The various causes of biotin
deficiency are summarized in Table 2.6.
BIOTIN | Physiology
J. Zempleni, D.M. Mock, in Encyclopedia of Food Sciences and Nutrition (Second
Edition), 2003
Biotin status may be reduced during human pregnancy. In the majority of pregnant
women, excretion of 3-hydroxyisovaleric acid is significantly greater than the
upper limit of normal. The serum concentration of biotin commonly decreases
significantly from early to late pregnancy and reaches values that are below the
lower limit of normal in some individuals. Likewise, the urinary excretion rates of
biotin and bisnorbiotin are often significantly less in late pregnancy than in early
pregnancy.
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Biotin
Biotin deficiency occurs rarely; the recommendation for the AI for biotin has been
set at 30 μg day−1 for all adults independent of age but there are hardly any data
about elderly adults (Garry et al., 1982). The lack of data is mainly due to the result
of the lack of analytical tools to quantitate biotin in body fluids.
Biotin Insufficiency
The symptoms of nutritional biotin deficiency include dry skin, seborrheic dermati-
tis, fungal infections, skin rashes, brittle hair, alopecia, and hyperglycemia. If left
untreated, neurological symptoms may develop: depression, altered mental status,
myalgia, hyperesthesia, and paresthesia. The inherited defects of biotin metabolism
give rise to similar clinical signs and symptoms. Biotin deficiency can be simply
treated with a pharmacological dose of biotin which will ameliorate the clinical
symptoms.
Nutritional deficiency of biotin is rare and case reports in the literature almost
exclusively relate to inborn errors of biotin metabolism and transport, long-term use
of parenteral nutrition,33, 34 chronic anticonvulsant therapy,35–37 or excessive inges-
tion of egg whites. Suboptimal biotin status has also been reported in pregnancy,
alcoholism, smoking, inflammatory bowel disease, children with severe burns, and
in patients with seborrheic dermatitis and Leiner’s disease. Adherence to a vegetarian
diet is not thought to affect biotin status.
Avidin
Avidin is a glycoprotein found in egg white which binds biotin very tightly and
specifically and is resistant to pancreatic enzymes. Thus dietary avidin binds to
dietary biotin, inhibiting its absorption and if exposure is prolonged, deficient states
can result.38
Since then, two separate defects in the cycle of biotin utilization have been described:
HLCS deficiency and biotinidase deficiency.41 Both disorders are autosomal reces-
sive and have incidences of 1 in 87,000 and 1 in 60,000 live births, respectively.42,
43 Deficiency of either enzyme results in multiple carboxylase deficiency (MCD),
Biotin
Amitava Dasgupta PhD, in Biotin and Other Interferences in Immunoassays, 2019
Using five healthy adult volunteers who consumed 0.75 mg of biotin supplement
per day for 14 days, Zempleni et al. showed that such supplementation resulted in
a significant decrease in mitogen-stimulated peripheral blood mononuclear cell
(PBMC) proliferation. Moreover, secretion of cytokines such as interleukin (IL)-1
and IL-2 decreased by 65% and 45%, respectively, following biotin supplementation.
The authors concluded that administration of biotin for 14 days decreases PBMC
proliferation and synthesis of IL-1 and IL-2. Therefore biotin has an inhibitory
effect on PBMC proliferation and cytokine release..44 Using six healthy adult subjects
(one man and five women; age, 2–25 years) who took 2.15 mg of biotin daily for
5 days, Wiedmann observed that biotin supplementation increased expression of
both the genes encoding the cytokines IL-1 , interferon- , and IL-4 in human
PBMCs and the genes encoding 3-methylcrotonyl-CoA carboxylase ( -chain). The
increased expression of the gene encoding 3-methylcrotonyl-CoA carboxylase may
be associated with enhanced immune function. However, increased expression of
the genes encoding the cytokines such as IL-1 and interferon- is not necessarily
paralleled by increased levels of these cytokines in extracellular fluids. Biotin sup-
plementation causes increased synthesis of cytokine receptors, leading to increased
endocytosis and, thus, decreased extracellular accumulation of cytokines.45
Biotin deficiency in humans may increase the risk of infection due to compromised
immune system. Candida infections secondary to impaired immune function might
also contribute to the dermatitis due to biotin deficiency in infants and children.46
Pharmacogenomics of Antifungal
Agents
H.R. Ashbee, M.H. Gilleece, in Handbook of Pharmacogenomics and Stratified
Medicine, 2014
38.1.2 Triazoles
The first description of antifungal properties in azole compounds was in 1944 when
researchers studying biotin deficiency in animals noted that benzimidazole, which
is structurally similar to biotin, had activity against yeasts [8]. This finding was not
followed up at the time, but later groups routinely screened other azoles for anti-
fungal activity. Early agents to be developed in the group, including clotrimazole,
ketoconazole, and miconazole, are generally now confined to topical use because of
unfavorable safety profiles.
All classes of azoles are substrates and inhibitors of CYP450 enzymes, but the extent
to which they are metabolized by or inhibit the various CYP isoforms varies between
drugs [10–12]. Individual triazoles exhibit different properties, spectra of activity,
and therapeutic indications, and these are discussed next. Their pharmacokinetic
properties are summarized in Table 38.2.
38.1.2.1 Fluconazole
The first triazole antifungal to be marketed appeared in 1990. This was fluconazole,
a fluorinated bistriazole (i.e., with two triazole rings). Available in capsule and oral
solution, and as an intravenous preparation, it has activity against Cryptococcus,
most Candida species (except C. krusei and sometimes reduced activity against C.
glabrata), and some dimorphic fungi. It is generally considered to be fungistatic.
Because of its hydrophilic properties, it has excellent oral bioavailability (85–90%)
and its absorption is unaffected by gastric pH [9,13]. As fluconazole is largely excreted
via the kidneys, dose adjustment is required in patients with reduced creatinine
clearance, and it should be used with caution in patients with hepatic insufficiency,
although the data are limited. Fluconazole has a favorable safety profile and minimal
toxicity, although hepatotoxicity and prolongation of the QT interval in ECG have
been noted [3].
Fluconazole is a substrate of CYP3A4 and inhibits CYP 2C9, 2C19, and, to a lesser
extent, CYP3A4, an effect that may only occur at doses >200 mg/d [10]. It is also
a substrate of P-glycoprotein (P-gp), but not an inhibitor [14]. Drug interactions
mediated via the CYP450 enzymes are numerous and include those with alfentanil,
ciclosporin A, and midazolam mediated via interactions with CYP3A4; those with
amitriptyline, fluvastatin, and phenytoin are mediated via inhibition of CYP2C9 [15].
38.1.2.2 Itraconazole
Itraconazole is a lipophilic triazole, available as capsules, oral solution, and, in some
countries, a concentrate for parenteral administration. It has a broad spectrum
of activity, including Candida, Aspergillus, dimorphic fungi, and some melanized
fungi, but not Fusarium, Scedosporium, or the mucoraceous molds [16]. Its activity
may be either fungistatic or fungicidal depending on the fungal species [17]. Oral
bioavailability of itraconazole varies with formulation. Absorption of the capsules is
dependent on gastric pH, with increased absorption at acidic pH, while the solution
is best absorbed during fasting [9]. Itraconazole has nonlinear pharmacokinetics and
because of variable absorption, drug concentrations show significant variability in
individuals [18].
Adverse events associated with itraconazole use include nausea and vomiting (par-
ticularly for the oral solution), hepatotoxicity, rash, and headache [18]. There is some
evidence that the occurrence of these toxicities correlates with the itraconazole
concentration in serum.
Itraconazole is a substrate and potent inhibitor of CYP 3A4, with many metabolites
also showing potent CYP3A4 inhibitory activity [19]. It is also an inhibitor of CYP 2C9
and P-gp [15]. These interactions form the basis for many drug interactions seen
with itraconazole. Interactions mediated via CYP3A4 include those with fluticasone,
lovastatin, phenytoin, rifampin, terfenadine, triazolam, and vincristine; those medi-
ated via P-gp include vincristine, cimetidine, and digoxin [15].
38.1.2.3 Voriconazole
Voriconazole is a second-generation triazole based chemically on fluconazole but
with a much broader spectrum of activity. It is active against Candida (including most
of the fluconazole-resistant species), Cryptococcus, and many species of Aspergillus; it
has some activity against Fusarium [16]. Voriconazole activity may be either fungicidal
or fungistatic depending on the fungal species [17]. It is the treatment of choice for
invasive aspergillosis and is used to treat infections due to Scedosporium or Fusarium.
Formulations of voriconazole include tablets, an oral suspension and an IV solution.
The suspension has good oral bioavailability, especially during fasting, but this is
reduced in the presence of high-fat meals [20]. The pharmacokinetics of voriconazole
are nonlinear in adults, meaning that relatively small changes in dosing can result in
unpredictable changes in drug exposure—being either much larger or smaller than
expected.
Toxicity associated with voriconazole includes visual disturbances, rash, and hepa-
totoxicity. Visual disturbances often decrease with continued use and may manifest
as photophobia, color changes, blurred vision, or flashes of light; they seem to
correlate with high drug concentrations [23]. Cutaneous adverse events are often
associated with sun exposure and usually resolve after discontinuation of the drug,
although an increased risk of squamous cell carcinoma has been reported with
voriconazole use in solid-organ transplant recipients [24]. Hepatotoxicity includes
elevated bilirubin, alkaline phosphatase, and transaminases, and correlates with
drug concentrations [25].
Voriconazole is both a substrate and an inhibitor for CYP2C19, 2C9, and 3A4, and is
also an inhibitor of 2B6 [26]. These properties underpin its multiple interactions with
drugs such as sirolimus, alfentanil, cyclosporine, diclofenac, methadone, efavirenz,
and midazolam [15].
38.1.2.4 Posaconazole
Posaconazole is the latest triazole to come to market. It was developed from itracona-
zole and is available only as an oral suspension, although a new tablet formulation
is currently under development [27]. Posaconazole has the broadest spectrum of
activity in vitro of all the azoles, with good activity against Candida, Cryptococcus,
Aspergillus, many dimorphic or melanized fungi, and several of the mucoraceous
molds [16]. It is fungicidal against Aspergillus, Cryptococcus, and Candida [28]. Oral
bioavailability is very dependent on gastric pH, with absorption maximized in the
presence of fatty foods [29]. As with itraconazole, absorption is improved by con-
comitant administration of acidic drinks, but it is saturated at a dose of 800 mg/d
and improved by dividing the dose. Drug concentrations achieved in serum vary
between patient groups and are known to be reduced in the presence of mucositis
and diarrhea, or with the use of proton pump inhibitors (PPIs) or H2 antagonists
[30].
Biotin
Biotin is also known as vitamin B7 or the anti-egg white injury factor. Biotin def-
iciency can be induced by feeding raw egg whites for prolonged periods. Deficiency
caused by raw egg white consumption is due to the presence of the glycoprotein
avidin, which binds biotin with high affinity. Biotin is comprised of an imidazole
ring that has two nitrogen atoms. The imidazole ring is fused to a thiophene ring
that in turn bears a 5-carbon valerate side chain. Biotin functions as a coenzyme
in reactions catalyzed by several carboxylase enzymes. The carboxyl group of the
valeryl side chain forms an amide linkage with an -amino group of a carboxylase
enzyme thereby covalently attaching the biotin molecule to the carboxylase enzyme.
In humans there are four carboxylases that utilize biotin. These enzymes involve
formation of an intermediate carboxybiotinyl enzyme in which the carbon from CO2
is temporarily bound to one of the nitrogen atoms of the imidazole ring before
transfer to its final destination. Biotin is found in many foods including egg yolk,
liver, and yeast. Biotin is also produced in the human gut by bacteria. The Food and
Nutrition Board recommends 30 micrograms (mcg) of biotin per day for adult intake
(Figure 5.2.8).