Biotin deficiency

Biotin deficiency

Biotin deficiency also known as vitamin B7 deficiency, is rare and may occur from nutritional causes, but more commonly results from deficiencies of enzymes involved in biotin homeostasis (e.g. biotinidase deficiency). Severe biotin deficiency in healthy individuals eating a normal mixed diet has never been reported 1. People with biotin deficiency can present with abnormal skin and hair changes, metabolic and neurologic abnormalities 2. The clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails and the central nervous system. Seizures, hypotonia, ataxia, optic atrophy, visual deficits, sensorineural deafness and developmental delay (in children) are some of the neurological manifestations. Metabolic abnormalities may include organic aciduria, lactic acidosis and hyperammonemia. Supplementation with biotin leads to clinical improvement in most cases. In severe cases, without treatment, coma and death may ensue 2. Early detection and treatment with pharmacologic doses of biotin are important to prevent the development of irreversible complications. Marginal biotin deficiency has been demonstrated in pregnancy and lactation, but the clinical significance is uncertain. Biotin supplements have been promoted to improve skin, hair and nail health; however robust evidence for their efficacy is lacking. It is important to be aware that intake of biotin supplements may lead to interference with certain laboratory tests leading to false positive or false negative results. High-dose biotin has been found to be helpful in certain neurological conditions (e.g. multiple sclerosis); however, the mechanism of action is uncertain 2.

Biotin physiology

Biotin (vitamin B7) is a water-soluble vitamin is a cofactor for five carboxylases (propionyl-CoA carboxylase, pyruvate carboxylase, methylcrotonyl-CoA carboxylase, acetyl-CoA carboxylase 1, and acetyl-CoA carboxylase 2) that catalyze critical steps in the metabolism of fatty acids, glucose, and amino acids 3. Biotin (vitamin B7) also plays key roles in histone modifications, gene regulation (by modifying the activity of transcription factors), and cell signaling 4.

Most biotin in foods is bound to protein, although some dietary biotin is in the free form 5. Gastrointestinal proteases and peptidases break down the protein-bound forms of ingested biotin into biocytin and biotin-oligopeptides, which undergo further processing by biotinidase, an enzyme, in the intestinal lumen to release free biotin 5. The free biotin is then absorbed in the small intestine, and most biotin is stored in the liver 4.

A limited number of reliable indicators of biotin status is available 6. In healthy adults, the concentration of biotin is 133–329 pmol/L in serum and 18–127 nmol/24 hours in urine 3. Abnormally low urinary excretion of biotin is an indicator of biotin deficiency, as is abnormally high excretion of 3-hydroxyisovaleric acid (higher than 3.3 mmol/mol creatinine) or 3-hydroxyisovalerylcarnitine (higher than 0.06 mmol/mol creatinine) resulting from reduced activity of methylcrotonyl-CoA carboxylase 7. The most reliable individual markers of biotin status, including deficiency and sufficiency, are biotinylated methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase in white blood cells 7. Oral administration of large doses of biotin increases serum concentrations of biotin and its metabolites 8. However, serum concentrations of biotin and its catabolites are not good indicators of marginal biotin deficiency because they do not decrease sufficiently in people with marginal biotin deficiency for these changes to be detectable with existing tests 4.

Table 1: Adequate intakes for Biotin

AgeMaleFemalePregnancyLactation
Birth to 6 months5 mcg5 mcg
7–12 months6 mcg6 mcg
1–3 years8 mcg8 mcg
4–8 years12 mcg12 mcg
9–13 years20 mcg20 mcg
14–18 years25 mcg25 mcg30 mcg35 mcg
19+ years30 mcg30 mcg30 mcg35 mcg

Footnote: Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an recommended dietary allowance.

Sources of biotin

Food

Many foods contain some biotin. Foods that contain the most biotin include organ meats, eggs, fish, meat, seeds, nuts, and certain vegetables (such as sweet potatoes) 9. The biotin content of food can vary; for example, plant variety and season can affect the biotin content of cereal grains, and certain processing techniques (e.g., canning) can reduce the biotin content of foods 9.

Dietary avidin, a glycoprotein in raw egg whites, binds tightly to dietary biotin and prevents biotin’s absorption in the gastrointestinal tract [13,14]. Cooking denatures avidin, making it unable to interfere with biotin absorption 1.

Several food sources of biotin are listed in Table 2.

Table 2: Selected Food Sources of Biotin

Foodmcg per
serving
Beef liver, cooked, 3 ounces30.8
Egg, whole, cooked10.0
Salmon, pink, canned in water, 3 ounces5.0
Pork chop, cooked, 3 ounces3.8
Hamburger patty, cooked, 3 ounces3.8
Sunflower seeds, roasted, ¼ cup2.6
Sweet potato, cooked, ½ cup2.4
Almonds, roasted, ¼ cup1.5
Tuna, canned in water, 3 ounces0.6
Spinach, boiled, ½ cup0.5
Broccoli, fresh, ½ cup0.4
Cheddar cheese, mild, 1 ounce0.4
Milk, 2%, 1 cup0.3
Plain yogurt, 1 cup0.2
Oatmeal, 1 cup0.2
Banana, ½ cup0.2
Whole wheat bread, 1 slice0.0
Apple, ½ cup0.0
[Source 10 ]

Dietary supplements

Biotin is available in dietary supplements containing biotin only, in supplements containing combinations of B-complex vitamins, and in some multivitamin/multimineral products 11. The absorption rate of oral, free biotin is 100%, even when people consume pharmacologic doses of up to 20 mg/day biotin 12.

Biotin deficiency causes

Biotin or viatmin B7, a water-soluble B vitamin, is an essential nutrient that plays key roles in the metabolism of glucose, amino acids, and fatty acids. Recent studies support a role for biotin in cell proliferation, DNA repair, epigenetic gene regulation as well as normal immune function 13.

Biotin is available from various food sources (meats, dairy, vegetables, seeds, and nuts) and is also synthesized by intestinal bacteria; hence dietary deficiency is uncommon. In addition, a substantial proportion of individuals may consume biotin containing dietary supplements 14. Chronic alcoholics and those on long-term anticonvulsants could develop biotin deficiency because of impaired intestinal uptake of the vitamin. Avidin, a protein found in egg whites, binds strongly to biotin, impairing the absorption of the vitamin, leading to severe biotin deficiency in those who consume excessive amounts of raw eggs. Patients affected by certain genetic defects affecting biotin metabolism present with a clinical picture of biotin deficiency.

Excessive consumption of raw egg whites

Avidin in raw egg whites has a high affinity for biotin, making it unavailable for absorption. Heat destroys the avidin, so those who eat cooked eggs are not at risk of biotin deficiency. Raw egg whites lead to biotin deficiency only when eaten in excessive amounts (perhaps a dozen or more a day) 15.

Total parenteral nutrition without biotin supplementation

Several cases of biotin deficiency in patients receiving prolonged total parenteral nutrition (TPN) therapy without added biotin have been reported 16. Therefore, all patients receiving TPN must also receive biotin at the recommended daily dose, especially if TPN therapy is expected to last more than 1 week. All hospital pharmacies currently include biotin in TPN preparations 17.

Use of infant formulas with inadequate biotin

Biotin deficiency has been reported in infants receiving hypoallergenic formulas 18.

Chronic anticonvulsant therapy

Prolonged use of the anticonvulsants, phenobarbital, phenytoin, primidone, and carbamazepine, have been linked to biotin deficiency. Possible mechanisms include inhibition of biotin uptake across the intestinal mucosa, accelerated biotin catabolism and impaired renal reabsorption of biotin. Therefore, supplemental biotin has been suggested for patients who are treated with anticonvulsants that have been linked to biotin deficiency 19.

Prolonged oral antibiotic therapy

Prolonged use of oral antibiotics has been associated with biotin deficiency. Inhibition of intestinal flora that produces biotin is presumed to be the basis for biotin deficiency. Another possible mechanism could be antibiotic-induced overgrowth of bacteria that consume biotin 20.

Smoking and Chronic alcoholism

Studies have shown that smoking may accelerate biotin catabolism, especially in women. Chronic alcoholism may cause intestinal malabsorption of biotin 21.

Short gut syndrome and inflammatory bowel disease

Individuals with short bowel syndrome and inflammatory bowel disease are also at risk of biotin deficiency as a result of intestinal malabsorption of biotin.

Marginal biotin deficiency during pregnancy and lactation

Recent studies have shown decreased biotin levels in a significant proportion of pregnant and lactating women. There are concerns that marginal biotin deficiency during pregnancy might be teratogenic and some experts have recommended a higher intake of biotin by pregnant women 13.

Certain inborn errors of biotin metabolism may also lead to the manifestation of biotin deficiency

Biotinidase deficiency is the most common cause of biotin deficiency; in most developed countries including the US. Biotinidase deficiency is inherited in an autosomal recessive fashion and occurs at a frequency of approximately 1 in 60,000 live births.; an estimated 1 in 120 individuals are heterozygous for the condition. Biotinidase deficiency is the most common cause of biotin deficiency; in most developed countries including the US. In individuals homozygous for the disorder, biotinidase levels are < 30% normal leading to biotin deficiency from insufficient free biotin release due to diminished biotin recycling. Symptoms of biotinidase deficiency typically develop between 1 week and 1 year of age. The severity of the enzyme deficiency may vary. Those with profound biotinidase deficiency have biotinidase deficiency levels less than 10% normal, while those with partial biotinidase deficiency have enzyme levels between 10-30% normal. In the US and many other countries, newborn screening includes tests for biotinidase deficiency deficiency. Approximately 150 mutations in the biotinidase deficiency gene have been reported to cause biotinidase deficiency. The biotinidase deficiency gene is located on chromosome 3p25. A mouse model of biotinidase deficiency has been developed to study various aspects of the disorder 22.

Holocarboxylase Synthetase deficiency is also an autosomal recessive disorder and can be diagnosed prenatally. The enzyme holocarboxylase synthetase is required for the biotinylation of the apocarboxylase enzymes into the active holocarboxylase forms; therefore deficiency leads to multiple carboxylase deficiency. Infants with this disorder present in the first few months of life with acidosis, hyperammonemia, hypotonia, seizures and developmental delay. Mutations in the HCLS gene cause holocarboxylase synthetase deficiency.

Because both biotinidase and holocarboxylase synthetase deficiency leads to decreased levels of the biotin-dependent carboxylases, the two conditions have also been classified as multiple carboxylase deficiency. Profound biotinidase deficiency was previously known as early-onset multiple carboxylase deficiency, partial biotinidase deficiency as late-onset or juvenile-onset multiple carboxylase deficiency and holocarboxylase synthetase deficiency as neonatal or early-onset multiple carboxylase deficiency 23.

Rarely, isolated deficiencies of each of the five individual biotin-dependent carboxylases may also occur.

Biotin deficiency due to a defect in biotin transport has also been described 24.

Regardless of the cause of biotin deficiency, clinical manifestations are similar. However, the age of onset, rates of symptom development and the sequence in which symptoms appear can greatly differ. All of the mechanisms responsible for the development of the manifestations have not been established.

Groups at risk of biotin deficiency

The following groups are among those most likely to have inadequate biotin status.

Individuals with biotinidase deficiency

Biotinidase deficiency is a rare autosomal recessive disorder that prevents the body from releasing free biotin, leading to biotin deficiency despite normal intake. Without treatment, biotinidase deficiency produces neurological and cutaneous symptoms, and profound biotinidase deficiency can lead to coma or death 25. Because treatment with oral biotin starting at birth (or before symptoms develop) and continuing for the rest of the person’s life can prevent these symptoms, all newborns in the United States and many other countries are screened for this disorder 26.

Individuals with chronic alcohol exposure

Chronic exposure to alcohol inhibits the absorption of biotin 27. Plasma biotin concentrations are low in 15% of people with chronic alcoholism 9.

Pregnant and breastfeeding women

At least a third of pregnant women develop marginal biotin deficiency in spite of normal biotin intakes; plasma and breastmilk concentrations of biotin decrease in lactating women, even when their dietary biotin intakes exceed the adequate intake 28. Additional research is needed to understand the clinical significance of these findings.

Biotin deficiency signs and symptoms

The signs and symptoms of biotin deficiency typically appear gradually and can include thinning hair with progression to loss of all hair on the body; scaly, red rash around body openings (eyes, nose, mouth, and perineum); conjunctivitis; ketolactic acidosis (which occurs when lactate production exceeds lactate clearance) and aciduria (abnormal amounts of acid in urine); seizures; skin infection; brittle nails; neurological findings (e.g., depression, lethargy, hallucinations, and paresthesias of the extremities) in adults; and hypotonia, lethargy, and developmental delay in infants 3. The rash and unusual distribution of facial fat in people with biotin deficiency is known as “biotin deficiency facies” 1.

Biotinidase deficiency is the most common cause of biotin deficiency in most developed countries including the US, newborn screening includes tests for biotinidase deficiency and the condition, therefore, is identified in a majority of individuals even before symptoms develop.

Impaired growth, skin, and hair changes and neurological problems are common in individuals with profound biotinidase deficiency (< 10% normal serum biotinidase activity) who are diagnosed late or are untreated. Individuals with partial biotinidase deficiency (10-30% of normal serum biotinidase activity) usually become symptomatic only during periods of stress, such as an infection.

Most individuals with untreated profound biotinidase deficiency develop symptoms in early infancy (mean age 3.5 months); however some may develop it as early as one week of life, and others may remain asymptomatic until adolescence. Some individuals present with a single finding and others present with multiple findings.

The first symptoms are usually associated with the skin and hair 29 and may include:

  • Dry skin
  • Conjunctivitis
  • Seborrheic dermatitis
  • Fungal infections, especially candidiasis.
  • Scaly, red rash, around eyes, nose, mouth, and perineum
  • Fine and brittle hair
  • Brittle nails
  • Hair loss or total alopecia

If undiagnosed and left untreated neurologic symptoms begin to develop 30. The most common neurologic findings include the following:

  • Hypotonia, motor, weakness, and lethargy
  • Ataxia and developmental delay
  • Mild depression, which may progress to profound lassitude and, eventually, to somnolence and coma
  • Changes in mental status
  • Generalized muscular pains (myalgias)
  • Hallucinations
  • Hyperesthesias and paresthesias
  • Seizures (commonly myoclonic, grand mal and focal seizures as well as infantile spasms)
  • Progressive spastic paresis and myelopathy
  • Optic atrophy
  • Sensorineural hearing loss may develop in 75% of untreated infants with profound biotinidase deficiency 23.

Intestinal tract symptoms also develop and most commonly include the following:

  • Nausea, occasionally severe
  • Vomiting
  • Anorexia

Respiratory symptoms include stridor, apnea and hyperventilation.

Metabolic problems include organic aciduria, ketolactic acidosis, and mild hyperammonemia 31. In severe cases, especially with profound untreated biotinidase deficiency, coma and death may ensue.

Holocarboxylase synthetase deficiency may present as early as during fetal life with intrauterine growth retardation and abnormal central nervous system (CNS) findings 32.

Biotin deficiency complications

Irreversible complications that may develop if treatment is delayed or inadequate include vision problems, sensory-neural hearing loss, ataxia, cognitive impairment, and developmental delay 33.

Biotin deficiency diagnosis

Profound and partial biotinidase deficiency are identified by newborn screening; however, newborn screening became available in developed countries only in the eighties, and is not routinely available in many developing nations 34.

In healthy individuals, serum biotin ranges from 133-329 pmol/L and urinary excretion of biotin is 18-127 nmol/24 hours.

Decreased urinary excretion of biotin and its catabolites is an early indicator of biotin deficiency 35.

The levels of biotinylated methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase in white blood cells are considered to be one of the most reliable indicators of biotin status and are decreased in even those with marginal biotin deficiency. In contrast, serum biotin levels do not reliably indicate individuals with marginal biotin deficiency.

Individuals with profound biotinidase deficiency have serum enzyme activity of less than 10% of mean normal activity 36. Children with biotinidase deficiency commonly become symptomatic if caregivers do not administer biotin. Children who have partial biotinidase deficiency have 10-30% of mean normal serum biotinidase activity and usually develop clinical manifestations of biotinidase deficiency only during times of stress, such as infection or a systemic illness. False positive newborn screening tests for biotinidase deficiency may occur in premature infants 37 as well as neonates with jaundice 38.

When biotinidase deficiency has been identified, testing for the responsible mutation may be helpful 39. Dobrowolski et al 40 noted that, in the United States, the 4 mutations most commonly associated with complete biotinidase deficiency are c98:d7i3, Q456H, R538C, and the double mutation D444H:A171T. Partial biotinidase deficiency is almost universally attributed to the D444H mutation.

Prenatal testing and preimplantation genetic diagnosis are possible for biotinidase deficiency as well as holocarboxylase synthetase deficiency 32.

Nutritional biotin deficiency, biotinidase deficiency as well as holocarboxylase synthetase deficiency all respond to biotin treatment. However, isolated carboxylase deficiencies do not respond to biotin.

Once biotin deficiency has been established, further evaluation is recommended to determine the extent and severity of disease, and may include:

  • detailed neurologic exam, to look for hypotonia, ataxia, evaluate seizure activity, evaluation of psychomotor deficits
  • vision and hearing tests to evaluate for optic atrophy and sensorineural deafness.

Biotin deficiency treatment

The management of a patient with biotin deficiency must take the underlying cause into account. The most important aspects of the medical care in patients with biotin deficiency include the early recognition of the condition and the prompt institution of therapy with 5-10 mg per day of oral biotin. Some experts suggest increasing the dose to 15-20 mg per day at onset of puberty 31. Children with partial deficiency are usually treated with 1-5 mg per day 23.

Lifelong treatment with biotin is required in individuals diagnosed with genetic disorders affecting biotin metabolism (biotinidase deficiency and holocarboxylase synthetase deficiency).

If the deficiency is from excess consumption of raw eggs, the patient must stop consuming raw eggs and should be started on oral biotin therapy.

Ensure biotin containing vitamins are included in total parental nutrition (TPN) solutions if therapy is expected to last more than one week.

If the cause of biotin deficiency is anticonvulsant therapy, the anticonvulsant may be changed to another drug that does not interfere with biotin absorption. Alternatively, the patient may be started on supplemental biotin.

Similarly, those on prolonged oral antibiotic therapy may benefit from biotin supplementation.

Diet

The patient should eat a regular, well-balanced diet that contains adequate amounts of biotin. Fortunately, almost all foodstuffs contain significant quantities of biotin, and many widely consumed foods are relatively rich in biotin. No dietary restriction is needed.

Foods that are rich in biotin, include meats, especially liver, eggs, brewers yeast, fish, many cereals, especially oats, nuts, such as peanuts and walnuts, many vegetables such as cauliflower and peas, lentils and soybeans.

Biotin deficiency prognosis

With early detection and biotin therapy, many of the symptoms and signs of biotin deficiency are reversible. However, if left untreated, vision problems, hearing loss, and developmental delay can occur and these are usually irreversible 41. Dietary biotin deficiency, biotinidase deficiency, and holocarboxylase synthetase deficiency all respond to biotin treatment; however isolated carboxylase deficiencies are not biotin-responsive 23.

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