Biotin Deficiency


Article Author:
Fatima Saleem


Article Editor:
Michael Soos


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/25/2019 1:20:17 PM

Introduction

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.[1][2][3][4] These carboxylases help in several chemical processes in the cell, including gluconeogenesis, amino acid metabolism, and fatty acid synthesis.[1][3] The Food and Nutrition Board of the Institute of Medicine recommends a daily dietary intake of 30 mcg/day, for the maintenance of 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.

Besides, gut micro bacteria can produce biotin. The average dietary intake of biotin in the western population is approximately 35 to 70 mcg/day.[2][3][5]

Etiology

There are many causes of Biotin deficiency. It can occur in rare inborn errors of metabolism, namely holocarboxylase synthetase deficiency or biotinidase deficiency.[5][3] Biotinidase deficiency is an autosomal recessive disorder. It can represent as severe biotin deficiency with the neurological and dermatological presentation. It affects endogenous recycling and failure in the release of biotin from dietary protein. Thus affects the activity of 5 carboxylases that depends on biotin.[6][7] Gastrointestinal tract bacterial imbalances such as due to the use of 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.[5][1]

Low Biotin levels can occur in patients on antiepileptics such as carbamazepine, Phenytoin, Phenobarbitol. Likewise, low Biotin levels can occur in patients on isotretinoin for acne treatment, elderly individuals, excessive alcohol consumption, smokers (particularly women). Reports exist of biotin deficiency in severely malnourished children in developing countries and through the intake of modified milk without biotin supplementation. 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, which is also known as “egg white injury.”[1][3][5][8]

Epidemiology

Suboptimal biotin level is common in pregnancy. In spite of a normal dietary biotin intake, about half of the pregnant women in the U.S. are marginally biotin deficient. According to the worldwide neonatal screening survey, the incidence of profound biotin deficiency is one in 112271, and the incidence of partial deficiency is one in 129282. 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.[9][6] People who excessively consume alcohol have a relatively higher incidence of low biotin levels as compared to the general population.[5]

Pathophysiology

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.[1][2][10]

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 works in transcriptional repression of genes and thus maintain genome stability.[1][8][9]

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 generation of cytotoxic T lymphocytes. It shows a role for the maturation and responsiveness of immune cells. Evidence show increasing levels of 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.[1][10]

History and Physical

Biotin deficiency leads to many clinical abnormalities, mainly neurological and dermal abnormalities. 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 biotin deficiency presentations include ketolactic 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 characteristic cutaneous lesion of biotin deficiency. In human adults, after 3 to 4 weeks of having a raw egg diet, a 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 face, particularly malar prominences which may resemble dermatitis rash due to soaps.

Evaluation

The diagnostic tests for biotin deficiency are urinary 3-hydroxyisovaleric acid and biotin, and the status of propionyl-CoA carboxylase in lymphocytes.[8][9] Biotin-dependent carboxylases in human lymphocytes are reliable markers for determining biotin status. Decreased activity of beta-methylcrotonyl-CoA carboxylase 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 who are receiving biotin-free total parenteral nutrition. Therefore, serum biotin levels are not reliable indicators of marginal biotin deficiency.[5][8] 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.[6][7]

Treatment / Management

Biotin deficiency management essentially means treating the cause. Oral biotin supplements have high bioavailability. Usually, a dose of 5 mg/day is given regardless of the etiology of biotin deficiency.[5] 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 [8]. 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 symptoms of biotinidase deficiency.[7][9]

Differential Diagnosis

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.[11] Biotin deficiency can present with a clinical picture similar to that of 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.[3] The clinician can differentiate zinc deficiency skin rash from biotin deficiency rash as zinc deficiency causes bullous, scaly (scald like) lesions on facial orifices as well as friction areas of the body. Zinc deficiency causes angular cheilitis, alopecia, and paronychia.[12]

Prognosis

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 can lead to developmental delay and autistic behavior.[6][7][9] 

Complications

Since biotin plays a crucial role in maintaining the 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-tests 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.[8][9][13][14]

Deterrence and Patient Education

Marginal biotin deficiency is common in pregnancy and may be due to an increased demand for biotin. Likewise, lactation can lead to an increased demand for biotin.[8] Clinical data shows that patients of multiple sclerosis, when treated with daily biotin doses of up to 300 mg, responds positively, with a reversal in disease progression as well as reduce chronic disability.[1][2] The likely mechanism is due to increased myelin production leading to increased axonal remyelination. Biotin may also increase energy production and hence decrease axonal hypoxia in multiple sclerosis.[2]

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.[7][9] Management of the disorder is optimally by a pediatrician, endocrinologist, and a geneticist. Both 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 V]

Biotin supplements are readily available in the market. It is routinely given as a nutritional supplement for the treatment of hair loss and brittle nails. Evidence demonstrates the effectiveness of biotin supplements in splitting brittle nails (onychoschizia, onychoschisis). However, not much evidence favors the use of biotin supplementation in hair loss unless it is due to hereditary abnormalities of biotin metabolism or acquired biotin deficiency.[5] 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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Biotin Deficiency - Questions

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A 60-year-old woman, with a past medical history of inflammatory bowel disease and epilepsy, presents to the clinic with dermatitis and a red scaly erythematous rash around her eyes, nose, and mouth. She also complaints of hair loss. She takes carbamazepine for epilepsy. She is on broad-spectrum antibiotics for 2 months for cellulitis. Labs reveal severe biotin deficiency. Which of the following is the most appropriate management?



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A 22-year-old medical student wants to add muscle mass. His diet plan includes drinking 6 raw eggs per day. 8 weeks later he starts losing hair and develops a red scaly rash around his nose, mouth, and eyes. Investigations show biotin deficiency. What is the expected reason for his biotin deficiency?



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A 16-month-old male is brought to the emergency department due to intractable seizures. On further evaluation, he is seen to have ataxia, hypotonia, and developmental delay. He also has hearing and visual problems. On examination, there are dermal abnormalities seen, including hair loss and a red scaly rash around the nose, mouth, and eyes. His seizures have been intractable to standard antiepileptic medications, including vitamin B6 supplementation. Emergency department clinicians give the patient a vitamin supplement which subsequently halts the seizures. Which inborn error of metabolism is the child most likely having?



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A 30-year-old female presents to the clinician with a history of remitting and relapsing multiple sclerosis. She is recommended biotin in high doses for the treatment of her symptoms. Which of the following mechanisms may be involved?



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A 65-year-old man on total parenteral nutrition develops an erythematous rash around his mouth and nose. On examination, he has red eyes and increased tearing consistent with conjunctivitis. Neurological examination shows ataxia and hypotonia. He is lethargic and depressed. Which of the following tests will confirm the nutrient deficiency?



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A 65-year-old woman presents to her healthcare practitioner with a history of brittle nails that break easily. On examination, there is a splitting of the distal nail plate. She shows improvement after taking a supplement prescribed by her provider. What supplement might have improved her symptoms?



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Biotin Deficiency - References

References

Agrawal S,Agrawal A,Said HM, Biotin deficiency enhances the inflammatory response of human dendritic cells. American journal of physiology. Cell physiology. 2016 Sep 1;     [PubMed]
Sedel F,Bernard D,Mock DM,Tourbah A, Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016 Nov;     [PubMed]
Ogawa Y,Kinoshita M,Sato T,Shimada S,Kawamura T, Biotin Is Required for the Zinc Homeostasis in the Skin. Nutrients. 2019 Apr 24;     [PubMed]
Mock DM, Skin manifestations of biotin deficiency. Seminars in dermatology. 1991 Dec;     [PubMed]
Trüeb RM, Serum Biotin Levels in Women Complaining of Hair Loss. International journal of trichology. 2016 Apr-Jun;     [PubMed]
Hsu RH,Chien YH,Hwu WL,Chang IF,Ho HC,Chou SP,Huang TM,Lee NC, Genotypic and phenotypic correlations of biotinidase deficiency in the Chinese population. Orphanet journal of rare diseases. 2019 Jan 7;     [PubMed]
Strovel ET,Cowan TM,Scott AI,Wolf B, ERRATUM: Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genetics in medicine : official journal of the American College of Medical Genetics. 2018 Feb;     [PubMed]
Zempleni J,Wijeratne SS,Hassan YI, Biotin. BioFactors (Oxford, England). 2009 Jan-Feb;     [PubMed]
Zempleni J,Hassan YI,Wijeratne SS, Biotin and biotinidase deficiency. Expert review of endocrinology     [PubMed]
Kuroishi T, Regulation of immunological and inflammatory functions by biotin. Canadian journal of physiology and pharmacology. 2015 Dec;     [PubMed]
Schwantje M,de Sain-van der Velden M,Jans J,van Gassen K,Dorrepaal C,Koop K,Visser G, Genetic defect of the sodium-dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency. JIMD reports. 2019 Jul;     [PubMed]
Maxfield L,Crane JS, Zinc Deficiency . 2019 Jan     [PubMed]
Misir R,Blair R,Doige CE, Development of a system for clinical evaluation of the biotin status of sows. The Canadian veterinary journal = La revue veterinaire canadienne. 1986 Jan     [PubMed]
BROWN A, The effect of egg white and crystalline biotin methyl ester on a skin lesion in three infants. Glasgow medical journal. 1948 Sep     [PubMed]

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