Biotin
Summary
Water-soluble biotin is an essential cofactor for enzymes in intermediary metabolism and a key regulator of gene expression. (More information)
Both parenteral nutrition devoid of biotin and prolonged consumption of raw egg white have been associated with symptoms of frank biotin deficiency, including hair loss, dermatitis, and rash, ataxia, seizures, and other neurological dysfunctions.
Biotinidase deficiency is a hereditary disorder that impairs the absorption and recycling of biotin, resulting in a secondary biotin deficiency. (More information)
The recommended adequate intake (AI) of biotin is established at 30 micrograms (μg) / day in adults. The biotin requirements are more likely to increase during pregnancy and lactation period.
Studies in animals have shown that biotin sufficiency is essential for normal fetal development. If the marginal biotin deficiency during pregnancy increases the risk of congenital anomalies in humans, it is an area of current concern and research.
Biotin is used in the treatment of a hereditary disorder of thiamine transport, called basal ganglia disease sensitive to biotin, and is currently being tested in trials to limit or reverse functional disabilities in people with multiple sclerosis. (More information)
The definitive evidence that establishes whether biotin supplementation improves the homeostasis of glucose and lipids in individuals with type 2 diabetes mellitus is currently scarce, but suggestive observations have been published.
Biotin can not be synthesized by mammalian cells and must be obtained from exogenous sources. Biotin is widely found in foods, and good dietary sources including egg yolks, liver, whole grain cereals, and some vegetables.
Long-term anticonvulsant (anti-seizure) therapy may increase the biotin dietary requirement because anticonvulsants may interfere with intestinal absorption and renal reabsorption of biotin and probably also increase the degradation of biotin to inactive metabolites.
Biotin is a water-soluble vitamin that is generally classified as a B-complex vitamin. After its initial discovery in 1927, it took nearly 40 years of research to unequivocally establish biotin as a vitamin (1). Biotin is required by all organisms but can be synthesized by some strains of bacteria, yeast, fungi, algae, and some plant species (2).
Function
Biotinylation
Biotin functions as a covalently linked cofactor required for the biological activity of the five biotin-dependent carboxylase enzymes of mammals (see below). Such a non-protein cofactor is known as a "prosthetic group." The covalent attachment of biotin to apocarboxylase (ie, a catalytically inactive carboxylase) is catalyzed by the enzyme, holocarboxylase synthetase (HCS). The term "biotinylation" refers to the covalent addition of biotin to any molecule, including apocarboxylases and histones. HCS catalyzes the posttranslational biotinylation of the epsilon amino group of a lysine residue at the active site of each apocarboxylase, converting the inactive apocarboxylase into a fully active holocarboxylase (Figure 1a). Particularly the lysine residues within the N-terminus of specific histones, which help to package the DNA in the eukaryotic nucleus, can also be biotinylated (3). Biotinidase is the enzyme that catalyzes the release of biotin from biotinylated histones and the peptide products of holocarboxylase degradation (Figure 1b).
Enzyme cofactor
Five mammalian carboxylases that catalyze essential metabolic reactions:
Both acetyl-Coenzyme A (CoA) carboxylase 1 (ACC1) and acetyl-CoA carboxylase 2 (ACC2) catalyze the conversion of acetyl-CoA to malonyl-CoA using bicarbonate and ATP; malonyl CoA generated via ACC1 is a limiting substrate for the synthesis of fatty acids in the cytosol, and malonyl CoA generated via ACC2 inhibits CPT1, an enzyme of the outer mitochondrial membrane important in the oxidation of fatty acids (Figure 2). ACC1 is found in all tissues and is particularly active in lipogenic tissues (ie, liver, white adipose tissue, and mammary glands), the heart, and pancreatic islets. ACC2 is especially abundant in the skeletal muscle and heart (4).
Pyruvate carboxylase is a critical enzyme in gluconeogenesis - the formation of glucose from sources other than carbohydrates, such as pyruvate, lactate, glycerol, and glucogenic amino acids. Pyruvate carboxylase catalyzes the ATP-dependent incorporation of bicarbonate into pyruvate, producing oxaloacetate; hence, pyruvate carboxylase is anaplerotic for the citric acid cycle (Figure 3). The oxaloacetate can then be converted to phosphoenolpyruvate and eventually to glucose.
Methylcrotonyl-CoA carboxylase catalyses an essential step in the catabolism of leucine, an essential branched-chain amino acid. This enzyme containing biotin catalyses the production of 3-methylglutaconyl-CoA from methylcrotonyl-CoA (Figure 4a).
Propionyl-CoA carboxylase produces D-malonylmalonyl-CoA from propionyl-CoA, a product derived from the β-oxidation of fatty acids with an odd number of carbon atoms (Figure 4a). The conversion of propionyl-CoA to D-malonylmalonyl-CoA is also required in the catabolic pathways of two branched-chain amino acids (isoleucine and valine), methionine, threonine, and cholesterol side chain (Figure 4a and 4b) .
Regulation of chromatin structure and gene expression
In eukaryotic nuclei, DNA is packaged into compact structures to form nucleosomes - fundamental units of chromatin. Each nucleosome is composed of 147 DNA base pairs wrapped around eight histones (histone pairing: H2A, H2B, H3, and H4). Another histone, called H1 linker, is located on the outside surface of each nucleosome and serves as an anchor to fix the DNA around the nucleus of the histone. The compact packaging of the chromatin should be relaxed from time to time to allow biological processes, such as DNA replication and transcription. Chemical modifications of DNA and histones affect the folding of chromatin, increasing or reducing the accessibility of DNA to factors involved in the previously mentioned processes. Together with DNA methylation, a number of chemical modifications within the N-terminal end of the nucleus histones modify their electrical charges and structures, thereby changing the conformation of the chromatin and the transcriptional activity of the genes.
The various modifications of histone tails, including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, carbonylation, deimination, hydroxylation, and biotinylation, have different regulatory functions. Several biotinylation sites have been identified in the histones H2A, H3, and H4 (5). Among them, the biotinylation of histone H4 in lysine (K) 12 (designated H4K12bio) appears to be enriched in heterochromatin, a tightly condensed chromatin associated with repeat regions in the (peri) centromeres and telomeres, and with known transposable elements as long terminal repeats (3). In addition, biotinylation tags are co-localized with well-known repression marks of genes such as lysine 9 methylated on histone H3 (H3K9me) on transcriptionally competent chromatin (6). For example, H4K12bio can be found in the promoter of the SLC5A6 gene that codes for the transporter of the biotin assimilation mediation in cells, the human sodium-dependent multivitamin transporter (hSMVT). When biotin is abundant, HCS can biotinylate the histone H4 in the promoter of SLC5A6, which stops the synthesis of hSMVT and reduces the assimilation of biotin. Conversely, in the biotin-deficient cells, the biotinylation marks in the LC5A6 promoter are removed in such a way that gene expression can occur, allowing the synthesis of hSMVT and subsequently increasing the assimilation of biotin (7).
Deficiency
Although evident biotin deficiency is quite rare, the human biotin dietary requirement has been demonstrated in three different situations: prolonged intravenous (parenteral) feeding without biotin supplementation, infants fed an elemental formula lacking in biotin, and consumption of clear of raw egg for a prolonged period (from several weeks to several years) (8). Raw egg white contains an antimicrobial protein known as avidin that can bind to biotin and prevent its absorption. Cooking egg white denatures avidin, making it susceptible to digestion and therefore unable to prevent the absorption of biotin dietary (5).
Signs and symptoms of biotin deficiency
Signs of obvious biotin deficiency include hair loss (alopecia) and a reddish scaly rash around the eyes, nose, mouth, and genital area. Neurological symptoms in adults have included depression, lethargy, hallucinations, and numbness and tingling of the limbs, ataxia, and seizures. Characteristic facial eruptions, along with the unusual distribution of facial fat, have been called "biotin-lacking traits" by some researchers (1). Individuals with inherited disorders of biotin metabolism (see Congenital Metabolic Disorders) that result in functional biotin deficiency often have similar physical findings, as well as seizures and evidence of impaired function of the immune system and increased susceptibility to bacterial and fungal infections (9, 10).
Risk factors of biotin deficiency
Apart from prolonged consumption of raw egg white or total intravenous nutritional support lacking in biotin, other conditions may increase the risk of biotin depletion. Smoking has been associated with an increase in the catabolism of biotin (11). Rapidly dividing cells of the developing fetus require biotin for the synthesis of essential carboxylases and for the biotinylation of histones; therefore, the biotin requirement is prone to increase during pregnancy. Research suggests that a substantial number of women develop a marginal or subclinical deficiency during normal pregnancy (see also Disease Prevention) (8, 12, 13). In addition, certain types of liver diseases can decrease the activity of biotinidase and theoretically increase the biotin requirement. A study of 62 children with chronic liver disease and 27 healthy controls found that the activity of serum biotinidase was abnormally low in those with a severely impaired function due to cirrhosis (14). However, this study did not provide evidence of biotin deficiency. In addition, anticonvulsant medications, used to prevent seizures in individuals with epilepsy, increased the risk of a biotin depletion (for more information about biotin and anticonvulsants, see Drug / Drug Interaction).
Congenital metabolic disorders
Biotinidase deficiency
There are several ways in which hereditary disorder, biotinidase deficiency, leads to a secondary deficiency of biotin. Intestinal absorption is diminished because a shortage of biotinidase prevents the release of biotin from dietary proteins (15). The recycling of our own biotin bound to the carboxylase and histone is also altered, and the urinary loss of biocytin (N-biotinyl-lysine) and biotin is increased (see Figure 1 above) (5). The biotinidase deficiency uniformly responds to the supplemental biotin. Oral supplementation with up to 5 to 10 milligrams (mg) of biotin daily is sometimes required, although smaller doses are often sufficient (reviewed in 16).
Holocarboxylase synthetase (HCS) deficiency
Some forms of HCS deficiency respond to supplementation with pharmacological doses of biotin. HCS deficiency results in decreased formation of all holocarboxylases at physiological blood concentrations of biotin; thus, high-dose biotin supplementation (10-80 mg biotin daily is required (10).
The prognosis of these two disorders is usually good if biotin therapy is introduced early (childhood or childhood) and continues for life (10).
Deficiency of biotin transport
There has been a case report of a child with biotin transport deficiency who responded to a high-dose biotin supplementation (17). It should be noted that the presence of a defective human sodium-dependent multivitamin transporter (hSMVT) was discarded as the cause of biotin transport deficiency.
Phenylketonuria (FCU)
Abnormally high concentrations of the amino acid, phenylalanine, in the blood of individuals affected with FCU can inhibit the activity of biotinidase. Schulpis et al. he speculated that seborrheic dermatitis associated with low biotinidase activity in these patients would be resolved by compliance with a special diet low in protein but not with biotin supplementation (18).
Markers of biotin status
Four measures of marginal biotin deficiency have been validated as indicators of the status of biotin: (1) reduced urinary excretion of biotin and some of its catabolites; (2) the high urinary excretion of an organic acid, 3-hydroxyisovaleric acid, and its derivative, carnityl-3-hydroxyisovaleric acid, both of which reflect the decreased activity of the biotin-dependent methylcrotonyl-CoA carboxylase; (3) the reduced activity of propionyl-CoA carboxylase in peripheral blood lymphocytes (5); and (4) reduced levels of holo-methylcrotonyl-CoA carboxylase and holo-propionyl-CoA carboxylase in lymphocytes - the most reliable indicators of biotin status (19). These markers have only been validated in non-pregnant men and women, and may not accurately reflect the status of biotin in pregnant women and lactating women (12).
Adequate Intake (AI)
Sufficient scientific evidence is scarce to estimate the dietary requirement for biotin; therefore, a Recommended Daily Intake (IDR) for biotin has not been established. Instead, the Board of Nutrition and Food (JNA) of the Institute of Medicine (IOM) established recommendations for Adequate Intake (IA, Table 1). The AI for adults (30 micrograms [μg] / day) was extrapolated from the AI for infants exclusively fed with human milk and is expected to overestimate the dietary requirement for biotin in adults. Dietary intakes of generally healthy adults have been estimated to be between 40-60 μg / day of biotin (1). The requirement for biotin in pregnancy can be increased (20).
Disease Prevention
Congenital anomalies
Current research indicates that at least one third of women develop marginal biotin deficiency during pregnancy (8), but it is not known if this could increase the risk of congenital anomalies. Studies based on small observation in pregnant women have reported an abnormally high urinary excretion of 3-hydroxyisovaleric acid both early and late in pregnancy, suggesting a decreased activity of methylcrotonyl-CoA carboxylase dependent on biotin (21,22). In a randomized, single-blind intervention study in 26 pregnant women, supplementation with 300 μg / day of biotin for two weeks limited the excretion of 3-hydroxyisovaleric acid compared to placebo, confirming that the increased excretion of 3-hydroxyisovaleric acid in effect it reflected marginal biotin deficiency in pregnancy (23). A small cross-sectional study in 22 pregnant women reported an incidence of low activity of lymphocyte propionyl-CoA carboxylase (another marker of biotin deficiency) greater than 80% (13). Although the level of biotin deficiency is not associated with overt signs of deficiency in pregnant women, such observations are sources of concern because subclinical biotin deficiency has been shown to cause cleft palate and hypoplasia of limbs in several animal species (reviewed in 13). In addition, biotin depletion has been found to suppress the expression of biotin-dependent carboxylases, remove biotin tags from histones, and decrease proliferation in cultured human embryonic mesenchymal stem cells (24). The altered activity of carboxylases may result in alterations in lipid metabolism, which has been linked to cleft palate and skeletal abnormalities in animals. In addition, the biotin deficiency leading to the reduction of histone biotinylation at specific loci in the genome could possibly increase genomic instability and result in chromosomal abnormalities and fetal malformations (13).
While pregnant women are advised to consume supplemental folic acid before and during pregnancy to prevent neural tube defects (see Folate), it would also be prudent to ensure adequate intake of biotin during pregnancy. The current AI for pregnant women is 30 μg / day of biotin, and no toxicity has been reported at this level of intake (see Safety).
Treatment of Diseases
Biotin-sensitive basal ganglia disease
Biotin-sensitive basal ganglia disease, also called thiamin metabolism dysfunction syndrome-2, is caused by mutations in the gene encoding the thiamin type 2 transporter (THTR-2). Clinical features appear around three to four years of age and include subacute encephalopathy (confusion, drowsiness and altered level of consciousness), ataxia, and seizures. A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia was recently conducted. The data showed that monotherapy with biotin (5-10 mg / kg / day) efficiently suppressed the clinical manifestations of the disease, although one third of patients suffered from recurrent acute crises. Often associated with poor outcomes, acute seizures were not observed after thiamin supplementation started (300-400 mg / day) and during a five-year follow-up period. An early diagnosis and immediate treatment with biotin and thiamin led to positive results (25). The mechanism for the beneficial effect of biotin supplementation has not yet been elucidated.
Multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease characterized by progressive damage to the myelin sheath surrounding the nerve fibers (axons) and neuronal loss in the brain and spinal cord of affected individuals. The progression of neurological disabilities in patients with MS is often assessed by the Expanded Disability Status Scale (EDSS) with scores from 1 to 10, starting with minimal signs of motor dysfunction (score of 1) to death by EM (score of 10). ATP deficiency due to mitochondrial dysfunction and increased oxidative stress may be partially responsible for the progressive degeneration of neurons in MS (26). Given its role in the intermediary metabolism and in the synthesis of fatty acids (required for the formation of myelin) (see Function), it has been postulated that biotin could exert beneficial effects that would limit or reverse functional alterations associated with MS (26) .
A non-randomized, uncontrolled pilot study in 23 patients with progressive MS found that high doses of biotin (100-600 mg / day) were associated with sustained clinical improvements in 5 (out of 5) patients with progressive visual loss and in 16 (from 18) patients with partial paralysis of the extremities after a mean follow-up period of three months after the start of treatment (27). In addition, preliminary results from the multicenter, randomized, placebo-controlled trial in 154 subjects with progressive MS indicated that 13 of 103 patients who randomly received daily oral biotin (300 mg) for 48 weeks achieved a composite functional endpoint that included a decrease in the scores of the EDSS. In comparison, none of the 51 patients randomly assigned to the placebo group showed significant clinical improvements (28). Two ongoing trials are evaluating the effect of high-dose biotin supplementation in the treatment of MS (see trials NCT02220933 and NCT02220244 at www.clinicaltrials.gov).
Mellitus diabetes
It has been shown that biotin deficiency manifests affects glucose utilization in mice (29) and causes fatal hypoglycemia in chickens. The biotin deficiency manifested probably also causes abnormalities in the regulation of glucose in humans (see Function). An early study in humans reported lower concentrations of serum biotin in 43 patients with type 2 diabetes mellitus compared to 64 non-diabetic control subjects, as well as an inverse relationship between fasting glucose and blood biotin concentrations (30). In a randomized, placebo-controlled intervention study in 28 patients with type 2 diabetes, daily supplementation with 9 milligrams (mg) of biotin for one month resulted in an average 45% decrease in fasting blood glucose levels (30 ). Nevertheless, another small study in 10 patients with type 2 diabetes and 7 non-diabetic controls found no effect of biotin supplementation (15 mg / day) for 28 days on fasting blood glucose concentrations in both groups ( 31). A more recent double-blind, placebo-controlled study by the same research group showed that the same biotin regimen decreased plasma triglyceride concentrations in both diabetic and non-diabetic patients with hypertriglyceridemia (32). In this study, the administration of biotin did not affect blood glucose concentrations in both groups of patients. Additionally, a few studies have shown that co-supplementation with biotin and chromium picolinate may be a beneficial adjunctive therapy for patients with type 2 diabetes (33-36). However, it has been shown that the administration of chromium picolinate alone improves glycemic control in diabetic subjects (see article in Chromium) (37).
As a cofactor of carboxylases required for the synthesis of fatty acids, biotin can increase the utilization of glucose for fat synthesis. It has been found that biotin stimulates glucokinase, a liver enzyme that increases the synthesis of glycogen, the stored form of glucose. Biotin also appears to trigger insulin secretion in the rat pancreas and improve glucose homeostasis (38). However, the reduced activity of ACC1 and ACC2 would be expected to reduce the synthesis of fatty acids and increase the oxidation of fatty acids, respectively. Not surprisingly, it is currently unclear whether biotin pharmacological doses could benefit the management of hyperglycemia in patients with impaired glucose tolerance. On the other hand, it remains to be proven whether supplemental biotin decreases the risk of cardiovascular complications in diabetic patients by reducing triglycerides and serum LDL cholesterol (32-34).
Brittle nails (onychorhexis)
The discovery that biotin supplements were effective in the treatment of hoof abnormalities in ungulate animals suggested that biotin might also be beneficial in strengthening brittle nails in humans (39-41). Three uncontrolled trials that examined the effects of biotin supplementation (2.5 mg / day for several months) in women with brittle nails have been published (42-44). In two of the trials, subjective evidence of clinical improvement was reported in 67% -91% of the participants available for follow-up at the end of the treatment period (42, 43). One trial that used scanning electron microscopy to evaluate the fragility of the nails reported less cracking of the nails and an increase in the thickness of 25% of the nail plate in patients supplemented with biotin for 6 to 15 months (44). It was also found that biotin supplementation (5 mg / day) was effective in controlling unruly hair and nail cracking in two young children with inheritable hereditary hair syndrome (45). Although preliminary evidence suggests that biotin supplementation may help strengthen fragile nails, larger placebo-controlled trials are needed to evaluate the efficacy of high-dose biotin supplementation for the treatment of brittle nails.
Hair loss (alopecia)
It was found that the administration of biotin reverses alopecia in children treated with the anticonvulsant, valproic acid (see Interaction with drugs / drugs). However, although hair loss is a symptom of severe biotin deficiency (see Deficiency), there are no published scientific studies supporting the claim that high-dose biotin supplements are effective in preventing or treating loss. of hair in men and women (46).
Sources
Food sources
Biotin is found in many foods, either as the free form that is directly taken by the enterocytes or as biotin bound to the dietary proteins. The yolk, liver, and yeast are rich sources of biotin. Estimates of the average daily biotin intakes from small studies ranged from 40 to 60 micrograms (μg) per day in adults (1). However, US national nutritional questionnaires have not yet been able to estimate the intake of biotin due to the scarcity and unreliability of the data with respect to the biotin content of the food. Food composition tables for biotin are incomplete so that daily intake can not be estimated reliably in humans. A study by Staggs et al. (47) used a high resolution liquid chromatography method instead of bioassays (48) and reported a relatively different biotin content for some of the selected foods. Table 2 lists some food sources of biotin, along with their content in μg.
Bacterial synthesis
Most bacteria that normally colonize the small intestine and the large intestine (colon) synthesize biotin (49). It remains unknown if biotin is released and absorbed by humans in significant quantities. Assimilation of free biotin in intestinal cells through the human sodium-dependent multivitamin transporter (hSMVT) has been identified in cultured cells derived from the lining of the small intestine and colon (50), suggesting that humans may be able to absorb biotin produced by enteric bacteria - a phenomenon documented in porcine.
Security
Toxicity
It is not known that biotin is toxic. In people without biotin metabolism disorders, doses of up to 5 mg / day for two years were not associated with adverse effects (52). Oral supplementation with biotin has been well tolerated in doses of up to 200 mg / day (almost 7,000 times the AI) in people with hereditary disorders of biotin metabolism (1). It was also found that daily supplementation with a highly concentrated formulation of biotin (100-600 mg) was well tolerated in individuals with progressive multiple sclerosis (27, 28). However, there is a case report of eosinophilic pleuropericardial effusion that endangers life in an elderly woman who took a combination of 10 mg / day of biotin and 300 mg / day of pantothenic acid (vitamin B5) for two months (53). Because reports of adverse events were scarce when the Dietary Reference Intakes (RDI) for biotin were established in 1998, the Institute of Medicine did not establish a maximum tolerable intake level (ML) for biotin (1).
Interaction with nutrients
Large doses of pantothenic acid (vitamin B5) have the potential to compete with biotin for intestinal and cellular uptake by the human sodium-dependent multivitamin transporter (hSMVT) (54, 55). Biotin also shares hSMVT with α-lipoic acid (56). It has been found that pharmacological (very high) doses of α-lipoic acid decrease the activity of biotin-dependent carboxylases in rats, but such an effect has not been demonstrated in humans (57).
Interaction with drugs
Individuals on long-term anticonvulsant (anti-seizure) therapy have reportedly reduced blood levels of biotin as well as increased urinary excretion of organic acids (eg 3-hydroxyisovaleric acid) indicating a decrease in the carboxylase activity (see Markers of biotin status) (5). The potential mechanisms of biotin depletion by anticonvulsants, primidone (Mysoline), phenytoin (Dilantin), and carbamazepine (Carbatrol, Tegretol), include inhibition of intestinal absorption and renal reabsorption of biotin, as well as catabolism increased biotin (51). The use of anticonvulsant valproic acid in children has resulted in hair loss reversed by biotin supplementation (58-61). Long-term treatment with antibacterial sulfonamide drugs (sulfa) or other antibiotics may decrease the bacterial synthesis of biotin. However, given that the extent to which bacterial synthesis contributes to the intake of biotin in humans is not known, the effects of antimicrobial drugs on the status of nutritional biotin remain uncertain (51).
Recommendation of the Linus Pauling Institute
Little is known about the amount of biotin dietary required to promote optimal health or prevent chronic diseases. The Linus Pauling Institute supports the recommendation made by the Institute of Medicine, which is 30 micrograms (μg) of biotin per day for adults. A varied diet should provide enough biotin for most people. However, following the recommendation of the Linus Pauling Institute to take a multivitamin-mineral supplement daily will generally provide an intake of at least 30 μg / day of biotin.
Older adults (> 50 years old)
Currently, there is no indication that older adults have an increased biotin requirement. If biotin dietary intake is not enough, a multivitamin-mineral supplement daily will generally provide an intake of at least 30 μg of biotin per day.