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New Considerations for Biotin Use in Hair Disorders

New Considerations for Biotin Use in Hair Disorders

alopecia

Figure 1. Central Centrifugal Cicatricial Alopecia.

Biotin has been highly commercialized in the past decade, with consumer sales steadily increasing from July 2014 to June 2017.1,2 Its increased popularity is likely due to media attention promoting its use (still mostly unsubstantiated) in hair and nail growth, as well as its documented health benefits in biotinidase deficiency, propionic acidemia, diabetes, lipid disorders, diabetic peripheral neuropathy, and secondary, progressive multiple sclerosis (MS).3-11 

Regardless of whether individuals are using biotin for cosmetic or therapeutic purposes, the literature is clear that many of them are ingesting more than the daily value of 30 mcg4,12 set by the FDA in 2016.  The commercial availability of biotin in doses ranging from 30 to 10,000 mcg makes supraphysiologic dosing possible.1 Manufacturers are not required to list biotin on their label unless the product has been fortified with it, although the FDA will require all food products and dietary supplements to list the daily value for biotin on their labels by January 2020.

Currently, however, there is no recommended daily intake for biotin, nor a tolerable upper intake level, the maximum amount at which a supplement can be taken without any adverse health effects. However, according to the Office of Dietary Supplements website, “high biotin intakes, and potentially even intakes greater than the AI, [adequate intake] may pose another type of health risk.13 Supplementing with biotin beyond recommended intakes can cause clinically significant falsely high or falsely low laboratory test results.”

In November 2017, the FDA issued a statement cautioning the public on the harmful effects of high-dose biotin on laboratory testing.14,15 According to the report, serum biotin interferes with certain laboratory tests, causing falsely low- or high-test results; this poses a threat to patient safety. There has been at least 1 reported death as a consequence of biotin interference, in which falsely low troponin levels in a patient delayed care.14 

The prevalence of high-dose biotin use has dramatically increased over the past 3 years and will likely continue, placing patients at risk for erroneous endocrine (thyroid-stimulating hormone [TSH], human chorionic gonadotropin [HCG]) and cardiac (N-terminal prohormone of brain natriuretic peptide [NT-proBNP], troponin T) testing.5,16 The effect of biotin on laboratory results is a direct consequence of its interference in the biotin-streptavidin immunoassay employed by most reagent manufacturers. Clinicians should be aware of these effects in order to adequately evaluate inaccurate laboratory results in the setting of increased biotin use among the general population. 

Biotin: The Vitamin 

Biotin is a water-soluble B vitamin, also known as vitamin H, vitamin B7, and coenzyme R, that serves as a co-factor for 5 carboxylases.17-19 It is responsible for fatty acid metabolism, gluconeogenesis, and catabolism of branched chain amino acids.17-19 Intestinal bacteria synthesize biotin, thus providing an endogenous source. Biotin can also be found exogenously in soybeans, butter, peas, sunflower seeds, lentils, peanuts, walnuts, pecans, and eggs. 

Biotin is currently marketed as a supplement for hair and nail growth. It is sold in different formulations, from beauty supplements to multivitamins, and is available in stores and online. Most hair, nail, and skin supplements contain 5000 to 10,000 mcg of biotin, while multivitamins range in their dosing from 30 to over 300 mcg.1,4 

Biotin’s small molecular size and ability to attach to a variety of functional groups have proven useful in the in vitro diagnostic industry. Additionally, biotin’s affinity for streptavidin has been exploited for use as an immobilizing system in protein analysis. The biotin-streptavidin interaction has, and continues to be, used by most reagent manufacturers in immunoassays that measure TSH, HCG, NT-proBNP, and troponin T. 

alopecia

Figure 2.  Localized alopecia areata.

Use in Hair and Nail Disorders

Biotin has been purported to help in hair and nail disorders for decades; however, no randomized controlled trial has proven its efficacy in these conditions.20 A recent study reviewing its efficacy in hair and nail disorders found 18 reported cases.20 The cases were a combination of acquired and congenital biotin deficiencies, predominantly congenital type (eg, biotinidase or holocarboxylase synthetase deficiency). All 18 cases involved patients with underlying pathology for poor hair or nail growth—each of whom demonstrated improved clinical outcomes with biotin use.20 Each case varied in the time needed for clinical improvement and administered biotin dose.20 These findings suggest that biotin deficiency is relatively uncommon, or at least discordant with the number of consumers purchasing biotin supplements. 

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As this case series demonstrates, there is limited data on the benefits of biotin use on hair and nail disorders. Congenital biotin deficiency is cited in the literature but acquired biotin deficiency is rare as most individuals meet the necessary biotin requirements through their diet. The most common presentation for acquired biotin deficiency is secondary to raw egg consumption. Avidin, a protein found in raw egg whites, has a strong affinity for biotin—but only if uncooked.21 When uncooked, avidin binds to biotin and prevents its absorption in the intestine.21 Once cooked, avidin becomes denatured and is unable to bind to biotin.21 Aside from pregnancy, malnutrition, adverse effects of medications, biotinidase deficiency, and holocarboxylase synthetase deficiency, there are few studies on low biotin levels. Thus, there is insufficient evidence to support supplemental biotin use in patients without known deficiencies.20,22

How Biotin Interferes with Immunoassays 

Immunoassays are a scientific reconstruction of a naturally-occurring phenomenon—known as cellular immunity. The design uses antibodies as analytical reagents to measure enzymes, tumor markers, lipoproteins, vitamins, and other metabolites.23 The ability of biotin to interfere in laboratory results depends on the assay type. Immunoassays, which are most susceptible to biotin interference, employ soluble or free biotinylated analogues or biotinylated antibodies.4 

The literature cites 2 assays which are commonly affected by high-dose biotin intake. The first is known as the competitive assay which includes free T3 (FT3), free T4 (FT4), thyroid stimulating hormone receptor antibody (TRAb), estradiol, testosterone, cortisol, vitamin B12, and folate.5,6 The second is known as the “sandwich” immunometric assay and involves troponin, NT-proBNP, TSH, HCG, sex hormone-binding globulin, insulin, luteinizing hormone, and follicle-stimulating hormone.5,6,16 

Both assay types employ similar methods for the separation phase. Each relies on the streptavidin-biotin interaction to separate the reagent antibody from the reaction. Therefore, any substance that interferes with this process will affect both assay subtypes. Excess biotin in the blood sample interferes with this process, thus causing erroneous laboratory results. In competitive assays, the excess biotin in the sample will compete with the biotinylated analog for binding sites which results in falsely elevated laboratory values.25 While in the “sandwich” assays, the excess biotin in the sample displaces biotinylated antibodies, resulting in falsely low laboratory values.25,26 

The Cases

The literature shows that the following laboratory values: TSH, FT4, FT3, HCG, NT-proBNP, and troponin may be affected by elevated serum biotin levels.4,16,25,27 A recent study reviewed the literature for cases of immunoassay interference secondary to daily biotin use.25 The study found 8 reported cases of interference with daily biotin doses ranging from 10 to 300 mg. All 8 cases demonstrated erroneous lab results secondary to the patient’s biotin use. Each patient was taking supplemental biotin for therapeutic care (eg, restless leg syndrome in end-stage renal disease [ESRD],8,28,29 MS, history of organic acidosis in a newborn, propionic acidemia, X-linked adrenoleukodystrophy).

High-dose biotin has been associated with improved clinical outcomes in patients with progressive MS.3,11 Three of the 8 cases investigated biotin interference among MS patients on 300 mg of daily biotin.25 There were significant effects on TSH, FT4, FT3, and TRAb results when comparing biotin-dependent assays to alternative methods. TSH was falsely low (<0.01 mUI/L, 0.02 mUI/L), while FT4 (99 pmol/L, 100.4 pmol/L, >100 pmol/L), FT3 (12.3 pmol/L, 11.6 pmol/L), and TRAb (36 IU/L, > 40 U/L) were falsely elevated.25 

Similar findings were found in the cases involving organic acidemia (10 mg/day, 30 mg/day), X-linked adrenoleukodystrophy (300 mg/day), and propionic acidemia (40 mg/day). The case of restless leg syndrome in an ESRD patient on 10 mg of daily biotin demonstrated falsely low parathyroid hormone (48 pg/mL).25 Many of these cases had no clinical consequences24; however, in the newborn with organic acidemia and the ESRD patient, the laboratory error led to delayed care, specifically delayed diagnosis of congenital hypothyroidism and severe secondary hyperparathyroidism, respectively. In most of these cases, the effect of biotin on the immunoassay resolved after at least 25 hours.25 Naturally, in the ESRD patient, the effect of biotin lingered—resolving after 15 days.25 

Another study evaluated the prevalence of biotin use by quantifying serum biotin levels among emergency department patients. Each patient’s residual plasma sample was analyzed for serum biotin concentration; 10 ng/mL was set as the threshold for presumed interference based on the assay manufacturer’s guidelines. The study showed 7.4% of patients (107 patients in total) had concentrations at or above 10 ng/mL, with the majority having a biotin concentration between 10 and 29 ng/mL.4 Only 2 of the 107 patients had biotin listed in their medical record, while 33 had multivitamins listed. All 107 patients were at risk of biotin interference to troponin, NT-proBNP, TSH, and HCG testing.4 

In this same study, surveys were administered to patients in a clinical setting to evaluate the prevalence of biotin use among this patient population. Nearly 2000 surveys were completed, and the results showed nearly 7.7% of patients reported a history of biotin use.4 Of those patients, 41% reported taking supplements with biotin dose of 1000 to 10,000 mcg—more than 30-fold the daily recommended dose. Most surprisingly, 29.5% of the total participants could not recall their biotin dose.4 These results highlight the need to investigate biotin use among patients in clinical practice, especially if there is a need for cardiac or endocrine lab testing. 

alopecia

Figure 3. Diffuse alopecia areata.

Next Steps for Clinicians

The National Health and Nutritional Examination Survey estimates that the prevalence of biotin use is as high as 32%, including doses without significant risk for interference.2 This estimate, along with the fact that retail sales of biotin have been steadily increasing over the past 3 years, suggest that high-dose biotin intake will continue to have harmful effects on laboratory results. Therefore, clinicians should be prepared to critically evaluate laboratory results and correlate their findings with the clinical picture. 

Moreover, there is a need for patient-directed initiatives. Questionnaires can be made available in the clinical setting, thus allowing insight into patient’s supplement use, and should ask directly about biotin. This will also provide clinicians with an opportunity to discuss the presumed need for biotin and potential harm this practice may have on laboratory results. Calling or emailing patients before scheduled lab work can help remind patients to stop taking biotin at least 72 hours beforehand,2,30 as it takes at least 48 hours to clear the system. Less urgent laboratory tests can be put off until patients stop this supplement.

Laboratories can also be involved in mitigating risk by implementing biotin-depletion protocols (ie, immunoassays that bind biotin differently),31,32 referring to other laboratories, or contacting providers if they suspect interference. 

Another possibility is manufacturers producing immunoassays that are less susceptible to interference. Perhaps the popularity of patients taking this supplement will compel them to develop alternative assays or redesign current ones to mitigate the risk of biotin interference. There are already assays in existence which are less prone to biotin interference.2 Additionally, there are biotin-based assays designed with biotin pre-bound to streptavidin, which theoretically should preclude the effects of biotin.2 There are also immunoassays that use anti-animal antibodies instead of biotinylated antibodies, however, these assays are not commonly used in most laboratories. 

For now, the best strategy is communication. Strengthening the communication between providers and patients and educating patients on the risk biotin poses to laboratory results is critical to any potential initiative. Moreover, interdisciplinary involvement is necessary for any future success in this matter.

Dr De Souza is a clinical research fellow in the dermatology department at Wake Forest Baptist Medical Center in Winston-Salem, NC.

Dr McMichael, Hair and Scalp Section Editor, is professor and chair of the department of dermatology at Wake Forest Baptist Medical Center in Winston-Salem, NC.

Disclosures: Dr De Souza reports no relevant financial relationships. 

Dr McMichael has received grants from Allergan and Proctor & Gamble. She is a consultant for Aclaris, Allergan, Bioniz, Cassiopea, Covance, eResearch Technology, Inc, Galderma, Guthey Renker, Incyte, Johnson & Johnson, Merck & Co, Inc, Merz Pharmaceuticals, Pfizer, Proctor & Gamble, and Samumed. She receives royalties from Informa Healthcare and UpToDate and also has conducted research for Cassiopea and Samumed.

References

1. Roche Diagnostics. Understand the potential for interference. https://biotinfacts.roche.com/understand/. Accessed November 26, 2018.

2. Kirkwood J. Meeting the biotin challenge. American Association for Clinical Chemistry. https://www.aacc.org/publications/cln/articles/2018/janfeb/meeting-the-biotin-challenge. Published January 1, 2018. Accessed November 26, 2018.

3. Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: A pilot study. Mult Scler Relat Disord. 2015;4(2):159-169.

4. Katzman BM, Lueke, AJ, Donato LJ, Jaffe AS, Baumann NA. Prevalence of biotin supplement usage in outpatients and plasma biotin concentrations in patient presenting to the emergency department. Clin Biochem. 2018;60:11-16.

5. Elston MS, Sehgal S, Du Toit S, Yarndley T, Conaglen JV. Factitious Graves’ disease due to biotin immunoassay interference—a case and review of the literature. J Clin Endocrinol Metab. 2016;101(9):3251-3255.

6. Wijeratne NG, Doery JC, Lu ZX. Positive and negative interference in immunoassays following biotin ingestion: a pharmacokinetic study. Pathology. 2012;44(7):674-675.

7. Li D, Radulescu A, Shrestha RT, et al. Association of biotin ingestion with performance of hormone and nonhormone assays in healthy adults. JAMA. 2017;318(2):1150-1160.

8. Koutsikos D, Agroyannis B, Tzanatos-Exarchou H. Biotin for diabetic peripheral neuropathy. Biomed Pharmacother. 1990;44(10):511-514.

9. Fernandez-Mejia C. Pharmacological effects of biotin. TJ Nutr Biochem. 2005;16(7):424-427.

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11. Tourbah A, Got O, Vighetto A, et al. MD1003 (high-dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: A randomized, double-blind, placebo-controlled study. CNS Drugs. 2018;32(7):661-672.

12. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington DC: National Academies Press; 1998.

13. Office of Dietary Supplements. Biotin. https://ods.od.nih.gov/factsheets/Biotin-HealthProfessional. Updated September 17, 2018. Accessed November 27, 2018.

14. FDA. The FDA warns that biotin may interfere with lab tests: FDA Safety Communication. https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm586505.htm. Published November 28, 2017. Accessed November 26, 2018. 

15. Lipner SR. Rethinking biotin therapy for hair, nail, and skin disorders. J Am Acad Dermatol. 2018;78(6):1236-1238.

16.  Willeman T, Casez O, Faure P, Gauchez AS. Evaluation of biotin interference on immunoassays: new data for troponin I, digoxin, NT-Pro-BNP, and progesterone. Clin Chem Lab Med. 2017;55(10):e226-e229.

17. Zempleni J, Suttie JW, Gregory JF III, Stover PJ, eds. Handbook of Vitamins. 5th ed. Boca Raton, FL: CRC Press;  2013: 397-412.

18. Mock DM. Biotin: from nutrition to therapeutics. J Nutri. 2017;147(8):1487-1492.

19. McMahon RJ. Biotin in metabolism and molecular biology. Annu Rev Nutr. 2002;22:221-239.

20. Patel DP, Swink SM, Castelo-Soccio L. A review of the use of biotin for hair loss. Skin Appendage Disord. 2017;3(3):166-169.

21. Mock DM. Skin manifestations of biotin deficiency. Semin Dermatol. 1991;10(4):296-302.

22. Said HM. Biotin: the forgotten vitamin. Am J Clin Nutr. 2002;75(2):179-180.

23. Trüeb RM. Serum biotin levels in women complaining of hair loss. Int J Trichology. 2016;8(2):73-77. 

24. Diamandis EP, Christopoulos TK. The biotin-(strept)avidin system: principles and applications in biotechnology. Clin Chem. 1991;37(5):625-636.

25. PikettyML, Polak M, Flechtner I, Gonzales-Briceno L, Souberbielle JC. False biochemical diagnosis of hyperthyroidism in streptavidin-biotin-based immunoassays: the problem of biotin intake and related interferences. Clin Chem Lab Med. 2017;55(6):780-788.

26. Minkovsky A, Lee MN, Dowlatshahi M, et al. High-dose biotin treatment for secondary progressive multiple sclerosis may interfere with thyroid assays. AACE Clin Case Rep. 2016;2(4):e370-e373.

27. Kwok JS, Chan IH, Chan MH. Biotin interference on TSH and free thyroid hormone measurement. Pathology. 2012;44(3):278-280. 

28. Yatzidis H, Koutsicos D, Agroyannis B, Papastephanidis C, Francos-Plemenos M, Delatola Z. Biotin in the management of uremic neurologic disorders. Nephron. 1984;36(3):183-186.

29. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev. 2006;11(4):294-329. 

30. Grimsey P, Frey N, Bendig G, et al. Population pharmacokinetics of exogenous biotin and the relationship between biotin serum levels and in vitro immunoassay interference. Int J Pharmacokinet. 2017;2:247-256.  

31. Rulander NJ, Cardamone D, Senior M, Snyder PJ, Master SR. Interference from anti-streptavidin antibody. Arch Pathol Lab Med. 2013;137(8):1141-1146.

32. Trambas C, Lu Z, Yen T, Sikaris K. Depletion of biotin using streptavidin-coated microparticles: a validated solution to the problem of biotin interference in streptavidin–biotin immunoassays. Ann Clin Biochem. 2018;55(2):216-226. 

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