Biotin (vitamin H or vitamin B7) is a B-complex vitamin that acts as an essential coenzyme for five carboxylases: pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase, and coenzyme for acetyl-CoA carboxylases 1 and 2. These carboxylases help in several chemical processes in the cell, including gluconeogenesis, amino acid metabolism, and fatty acid synthesis. The Food and Nutrition Board of the Institute of Medicine recommends a daily dietary intake of 30 mcg/day to maintain good health. Biotin deficiency is very rare in those who take in a normal balanced diet. Mammals obtain biotin from food. Foods rich in biotin are egg yolk, liver, cereals (wheat, oats), vegetables (spinach, mushrooms), and rice. Dairy items and breast milk also contain biotin.
Nominal biotin deficiency has been noted in pregnant and lactating women, but its clinical significance is unknown. Biotin supplements are available in the market for improvement in nail, hair, and skin health, but there is no robust evidence available. Taking biotin supplements can interfere with some laboratory tests resulting in false-positive and false-negative results. There are studies reporting the efficacy of high-dose biotin in some neurological conditions, such as multiple sclerosis; however, the underlying mechanism is uncertain.
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There are many causes of biotin deficiency. It can occur in rare inborn errors of metabolism, namely holocarboxylase synthetase deficiency or biotinidase deficiency. Biotinidase deficiency is an autosomal recessive disorder. It can present as severe biotin deficiency with both neurological and dermatological features. It affects endogenous recycling and failure in releasing biotin from dietary protein. This affects the activity of 5 carboxylases that depends on biotin. Gastrointestinal tract bacterial imbalances resulting from broad-spectrum antibiotics or inflammatory bowel disease can affect biotin synthesis in the intestine and thus lead to biotin deficiency.
Biotin deficiency can also occur in patients on parenteral nutrition without added biotin. Therefore, recommended daily dose of biotin must be added to total parental nutrition (TPN), particularly if TPN therapy is likely to be given for more than a week. Currently, all hospital pharmacies add biotin to TPN preparations.
Low Biotin levels can occur in patients on antiepileptics such as carbamazepine, phenytoin, and phenobarbital. Possible underlying mechanisms include impaired biotin uptake across the intestinal mucosa, exaggerated biotin catabolism, and inhibition of renal reabsorption. Therefore, patients who are likely to be on anticonvulsants for long periods should receive biotin supplementation.
Prolonged use of oral antibiotics may also lead to biotin deficiency. The most likely underlying mechanism is the inhibition of intestinal flora, leading to reduced biotin production. Another possible explanation is the antibiotic-driven overgrowth of biotin-consuming bacteria.
Likewise, low biotin levels can occur in patients on isotretinoin for acne treatment, elderly individuals, people with alcohol use disorder, and smokers (particularly women). Some studies have found biotin deficiency in a large percentage of pregnant and lactating women. Some experts argue that there can be teratogenic effects of decreased biotin levels, and a higher intake of biotin should be advised to pregnant women.
Reports exist of biotin deficiency in severely malnourished children in developing countries and through the intake of modified milk without biotin supplementation. Biotin deficiency has been observed in infants consuming hypoallergenic formulas.
Consuming large amounts of raw egg whites can lead to acquired biotin deficiency. Raw egg contains the glycoprotein avidin. Avidin binds to biotin in the gastrointestinal tract and prevents biotin absorption, also known as “egg white injury.”
Suboptimal biotin level is common in pregnancy. Despite a normal dietary biotin intake, about half of the pregnant women in the US are marginally biotin deficient. According to the worldwide neonatal screening survey, the incidence of profound biotin deficiency is one in 112,271, and the incidence of partial deficiency is one in 129,282. The combined incidence of profound and partial deficiency is one in 60089 live births. Biotinidase deficiency has been diagnosed more commonly in children of the White race. Research has observed a higher incidence of biotin deficiency in Brazil, Turkey, and Saudi Arabia. People who excessively consume alcohol have a relatively higher incidence of low biotin levels compared to the general population.
Worldwide profound biotinidase deficiency is reported to be 1 in 137401; partial biotinidase deficiency is estimated to be 1 in 109,921, and the comprehensive incidence is 1 in 61067. In countries with higher rates of consanguinity, such as Saudi Arabia and Turkey, the prevalence is higher. Neto et al. reported an incidence of 1 per 9,000 population in Brazil. In the US, biotin deficiency is observed to be greater in people of Hispanic origin and lesser in African American population.
Holocarboxylase synthetase deficiency is observed to be 1 in 87,000.
Biotin (B7) has a key role in cellular energy metabolism, including ATP production and regulation of oxidative stress, since it is a crucial cofactor for five carboxylases that works for mitochondrial metabolism of glucose, fatty acids, and amino acids. Holocarboxylase synthetase plays a vital role in protein biotinylation, and protein biotinidase is essential for the release of biotin from biotinylated peptides.
Current evidence shows a vital role of biotin in gene expression and chromatin structure. Approximately 2000 genes have been identified so far that are biotin-dependent. Biotin is attached to histones, and this histone biotinylation appears to work in transcriptional repression of genes and thus maintain genome stability.
Biotin also regulates immunological and inflammatory functions. Patients with multiple carboxylase deficiency, which has links with biotin deficiency, have shown defects in B-cell and T-cell immunity. Biotin plays a key role in the function of natural killer (NK) lymphocytes and the generation of cytotoxic T lymphocytes. It shows a role in the maturation and responsiveness of immune cells. Evidence shows increasing interleukin-1-beta (IL-1-beta) and proinflammatory cytokines TNF-alpha in biotin deficiency. Biotin levels also affect transcriptional factors, such as NF-kappa B.
In addition to the role biotin plays as a cofactor in various carboxylation reactions, recently, it has been observed that biotin plays important roles in gene expression and immune mechanisms.
- Pyruvate carboxylase (PC) - catalyzes an important step in the gluconeogenesis, TCA cycle, and lipogenesis
- Propionyl-CoA carboxylase (PCC) - important in the metabolism of amino acids and odd-chain fatty acids
- 3-Methylcrotonoyl-CoA carboxylase (MCC) - carries out the catabolism of leucine
- Acetyl-CoA carboxylase 1 (ACC 1) - converts acetyl CoA to malonyl CoA, which is a significant step in lipid synthesis
- Acetyl-CoA carboxylase 2 (ACC 2) - has a regulatory function in fatty acid oxidation
Biotin deficiency can also manifest clinically due to genetic disorders leading to a lack of the enzyme holocarboxylase synthetase, or the individual carboxylase enzymes can be deficient. Biotinylation of histones may have an important role in gene expression. Biotin has also been observed to affect gene expression via other mechanisms. Many biotin-dependent genes have been studied in human cells. Some of these genes encode enzymes involved in glucose metabolism, cytokines like interleukin-2 and insulin receptors. Biotin has been reported to have a role in antibody production, differentiation of T and B lymphocytes, macrophage function, and the normal functioning of natural killer cells. Recurrent infections, particularly fungal, are commonly seen in patients with biotin deficiency.
History and Physical
Biotin deficiency leads to variable clinical presentations, mainly neurological and dermal abnormalities. Biotinidase deficiency is the commonest etiology; in many countries, including the US, screening for biotinidase deficiency is a part of the newborn screening program. Therefore the condition is identified in many individuals before symptoms develop. History includes recognizing risk factors for biotin deficiency, such as history related to gastrointestinal disease or inflammatory bowel disease. Any history of drug intake that interferes with biotin metabolism or uptake is significant, e.g., antiepileptics, antibiotics, or isotretinoin. Dermal abnormalities in biotin deficiency are due to impaired fatty acid metabolism. These include hair loss (alopecia) and periorificial dermatitis; scaly, red rash around the orifices, i.e., eyes, nose, and mouth (also called “biotin-deficient face”). The rash is similar to that of zinc deficiency. Patients may also develop conjunctivitis and skin infections.
Neurological symptoms include hypotonia, seizures, ataxia, numbness and tingling of the extremities, mental retardation, and developmental delay in children. The patient may show depression, lethargy, and a history of hallucinations. Other neurological abnormalities include optic atrophy and sensorineural hearing loss if the condition is left untreated.
Intestinal symptoms may also develop in patients with biotin deficiency, such as nausea, vomiting, and anorexia.
Other biotin deficiency presentations include ketoacidosis, lactic acidosis, and organic aciduria. Individuals with hereditary disorders of biotin deficiency such as biotinidase deficiency may also show impaired immune system function leading to increased susceptibility to infections, e.g., Candida. Biotinidase deficiency typically shows symptoms at the age of 1 week to more than one year and may have additional symptoms like hearing loss and optic atrophy.
As observed in swine, initial clinical symptoms of acquired biotin deficiency include gradual onset of hair loss, dry skin, and lesions on the feet and legs after six months of biotin deficiency. After nine months, the clinical picture resembles a characteristic cutaneous lesion of biotin deficiency. After 3 to 4 weeks of having a raw egg diet in adult humans, desquamative dermatitis was observed. After five weeks, anorexia, lethargy, and hyperaesthesia developed. Administration of biotin relieved symptoms in 5 days. Infants may initially show mild scaly erythema and dermatitis on the face, particularly malar prominences, which may resemble dermatitis rash due to soaps. Holocarboxylase synthetase deficiency can present very early in fetal life in the form of abnormal CNS findings and intrauterine growth retardation.
Once biotin deficiency is confirmed, a physical exam should be carried out focusing on the extent of the disease and must include a thorough neurological exam, developmental assessment (age-appropriate), hearing evaluation, and visual assessment.
The diagnostic tests for biotin deficiency are urinary 3-hydroxyisovaleric acid and biotin and the status of propionyl-CoA carboxylase in lymphocytes. Biotin-dependent carboxylases in human lymphocytes are reliable markers for determining biotin status. Decreased beta-methylcrotonyl-CoA carboxylase activity shunts the catabolism to alternative pathways, leading to the elevated formation of 3-hydroxyisovaleric acid. The most reliable marker of biotin deficiency is increased excretion of 3-hydroxyisovaleric acid in the urine (over 195 micromol/24 hours). Evidence shows that serum biotin concentration does not decrease in biotin deficiency patients receiving biotin-free total parenteral nutrition. Therefore, serum biotin levels are not reliable indicators of marginal biotin deficiency. If biotin deficiency is suspected, it warrants a thorough neurological examination and other investigations, including vision and hearing testing.
Biotinidase deficiency confirmation is done by DNA analysis, either allele-targeted methods or full-gene sequencing. Currently, all newborn screening programs in the U.S. and more than 30 other countries carry out screening for biotinidase deficiency.
- Low cerebral volume
- Widened extracerebral cerebrospinal fluid spaces
A complete reversal of these findings occurred with biotin use in two patients.
Treatment / Management
Biotin deficiency management essentially means treating the cause. Lifelong treatment with biotin supplements is required in patients with genetic disorders disrupting biotin metabolism, such as holocarboxylase synthetase deficiency and biotinidase deficiency. If the deficiency is related to excess consumption of raw eggs, it should be stopped, and biotin replacement should ensue. Change anticonvulsants if the deficiency is because of the use of a particular anticonvulsant. Similarly, those on prolonged oral antibiotic therapy may benefit from biotin supplementation.
Oral biotin supplements have high bioavailability. Usually, a dose of 5 mg/day is given regardless of the etiology of biotin deficiency. The Food and Nutrition Board of the National Research Council recommends a range of 5 mcg/day in newborn infants to 35 mcg/day in lactating women.
Practitioners should be aware that biotin requirements may increase during anticonvulsant therapy. In biotinidase deficiency, patient therapy typically consists of lifelong doses of biotin. Biotin doses in the range of 5 to 20 mg can treat and prevent clinical signs and biotinidase deficiency symptoms.
In the cases of holocarboxylase synthetase deficiency detected antenatally, antenatal biotin treatment has been found to be very useful.
The significant differential includes the inborn error of metabolism, such as sodium-dependent multivitamin transporter defect. Sodium-dependent multivitamin transporter defect can cause a metabolic disorder similar to biotinidase deficiency. There is a deficiency of biotin, pantothenic acid, and lipoate. Biotin deficiency can have a clinical picture similar to acrodermatitis enteropathica (a disorder of zinc metabolism).
Biotin deficiency can present with symptoms similar to zinc deficiency. Biotin is necessary for zinc homeostasis in the skin; the precise nature of this association between zinc and biotin is unknown. The clinician can differentiate zinc deficiency skin rash from biotin deficiency rash as zinc deficiency causes bullous, scaly (scald-like) lesions on facial orifices and friction areas of the body. Zinc deficiency causes angular cheilitis, alopecia, and paronychia.
Biotin deficiency is rare and has a relatively good prognosis. Children diagnosed with biotinidase deficiency require early intervention and life-long biotin treatment. Children who quit therapy develop symptoms again within weeks to months. When neonates diagnosed by neonatal screening receive biotin, they develop normally without having any symptoms, and those with symptoms respond quickly to biotin treatment. Failure to evaluate and manage biotinidase deficiency at an early stage can cause irreversible neurodevelopmental abnormalities and lead to developmental delay and autistic behavior.
Since biotin plays a crucial role in maintaining cell-mediated and humoral immunity, biotin deficiency due to inborn errors of metabolism can cause candidiasis of the skin in infants and children. There may be IgA deficiency and low percentages of T lymphocytes. They may have absent delayed-hypersensitivity skin-test responses.
Biotin deficiency can cause encephalopathies. Patients usually respond well to large doses of biotin. Evidence shows that a lack of biotin is teratogenic in animal models. Strains of mice with biotin deficiency developed fetal malformations, most commonly cleft palate, micrognathia, and micromelia.
Deterrence and Patient Education
Marginal biotin deficiency is common in pregnancy and could be attributable to an increased demand for biotin. Likewise, lactation can lead to an increased demand for biotin. Clinical data shows that patients with multiple sclerosis, when treated with daily biotin doses of up to 300 mg, respond positively, with a reversal in disease progression and reducing chronic disability. The likely mechanism is due to increased myelin production leading to increased axonal remyelination. Biotin may also increase energy production and decrease axonal hypoxia in multiple sclerosis.
Enhancing Healthcare Team Outcomes
Biotin deficiency occurs in severely malnourished children in the developed world, thus creating a global public health problem. Biotinidase screening should be part of the workup of infants or children showing clinical features of the disease; it is a routine part of neonatal screening in many countries. Management of the disorder is optimally done by a pediatrician, endocrinologist, and geneticist. Nursing and pharmacists should educate parents about the appropriate dosage and the need for compliance and not stop taking supplemental biotin unless they are told to stop by their clinician. A dietician or nutritionist may also be part of the management team in the rare instances where dietary insufficiency is the etiology. All these disciplines need to function as an interprofessional healthcare team to manage biotin deficiency and guide the patient to an optimal outcome. [Level 5]
Biotin supplements are readily available in the market. It is routinely given as a nutritional supplement to treat hair loss and brittle nails. Evidence demonstrates the effectiveness of biotin supplements in splitting brittle nails (onychoschizia, onychoschisis). However, not much evidence favors biotin supplementation in hair loss unless it is due to hereditary abnormalities of biotin metabolism or acquired biotin deficiency. Health professionals should take this information into account and educate the patients. A dietary consult is recommended as patients need to know the type of food rich in biotin.
The primary care clinicians need to follow these patients, as it often takes months to reverse the symptoms. For patients who remain compliant with treatment, the outcomes are good.
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