High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study.

BACKGROUND: We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept. METHODS: Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables. RESULTS: The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product. CONCLUSIONS: Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

Biotin induced biochemical hyperthyroidism: a case report and review of the literature.

BACKGROUND: Biotin is a commonly used supplement for hair, nail, and skin. Recent literature suggests that high-dose biotin therapy for neurological diseases like Multiple sclerosis can interfere with lab results that use biotin/streptavidin immunoassay, called biotin interference. Biotin interference can affect thyroid lab results, giving biochemical hyperthyroidism. CASE PRESENTATION: Our patient, a 64-year-old white man with a known history of multiple sclerosis, presented with elevated free T3, free T4, and low TSH that resembled hyperthyroidism. He had no symptoms of hyperthyroidism except some fatigue and tachycardia on the first encounter. He was started on anti-thyroid medications. He was then re-evaluated since his lab results remained the same after two months of anti-thyroid medications. It was found that he was on biotin, 10000mcg/day, for his multiple sclerosis. Biotin was discontinued, and five days later his lab results returned to normal values. CONCLUSION: The lack of knowledge of biotin use by patients can lead to misdiagnosis of patients' thyroid lab results and improper management. Awareness about biotin interference and abnormal thyroid lab values should be a priority among clinicians and the public. If the biotin is discontinued on time, such misdiagnosis can be avoided.

Elevated free thyroxine and free triiodothyronine probably caused by high-dose biotin intake in a patient with Graves' disease: a case report.

Biotin is a water-soluble vitamin that acts as a cofactor for carboxylase, and is often used as a component in several immunoassays. We present a case of a 46-year-old male with Graves' disease (GD) who revealed elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels after high-dose biotin intake. Levels of these hormones had been within the reference range when he was on thiamazole 5 mg/day for 7 years; however, the levels increased from 1.04 to 2.20 ng/dL and from 3.05 to 9.84 pg/mL for FT4 and FT3, respectively, after he started taking biotin 72 mg/day. Despite these high levels, his symptoms and the other laboratory results, including the thyroid-stimulating hormone level, did not suggest GD relapse. His thyroid hormone data was decreased and returned within the reference range immediately after the laboratory assays for FT3 and FT4 had been coincidentally changed from those containing streptavidin-biotin complexes to biotin-free ones. Biotin interference, which is caused by high-dose biotin intake and immunoassays using some form of streptavidin-biotin complex, is sometimes clinically problematic, giving high or low results. To our knowledge, this is the first case report of a patient with GD on high-dose biotin receiving high thyroid hormone level results that were initially misunderstood as an aggravation of the disease; there are some reports of misdiagnosis of hyperthyroidism due to biotin administration. Unexpected fluctuations in thyroid function test results in patients with GD should be checked for biotin intake, immunoassays and the limiting concentration of biotin to avoid misdiagnosis of relapse.

Twin Premature Infants With Riboflavin and Biotin Deficiency Presenting With Refractory Lactic Acidosis, Rash, and Multiorgan Failure During Prolonged Parenteral Nutrition.

We are reporting monochorionic, diamniotic twin premature infants born at 25 weeks and 6 days gestation with riboflavin (vitamin B2) and biotin (vitamin B7) deficiency, while on prolonged total parenteral nutrition (TPN) during vitamin shortage. They presented initially with skin rash, lactic acidosis, and thrombocytopenia. Both twins progressed to severe respiratory failure, severe lactic acidosis, with refractory vasodilatory shock, pancytopenia, ischemic bowel injury, acute kidney injury, liver injury, and capillary leak syndrome leading to death of twin A. The surviving twin B was diagnosed with riboflavin and biotin deficiency that presented with abnormal metabolic work up suggestive of maple syrup urine disease, glutaric acidemia type 2, and X-linked adrenoleukodystrophy. Twin B was started on riboflavin and biotin supplementation at 41 days of life, with rapid improvement in clinical findings and laboratory abnormalities within days of starting biotin and riboflavin supplementation. He was discharged home in stable condition at 49 weeks of postmenstrual age.

Biotin alleviates hepatic and intestinal inflammation and apoptosis induced by high dietary carbohydrate in juvenile turbot (Scophthalmus maximus L.).

Excessive dietary carbohydrate commonly impairs the functions of liver and intestine in carnivorous fish. In the present study, a 10-week feeding trial was carried out to explore the regulation of biotin on the hepatic and intestinal inflammation and apoptosis in turbot (Scophthalmus maximus L.) fed with high carbohydrate diets. Three isonitrogenous and isolipidic experimental diets were designed as follows: the CC diet with 18.6% of carbohydrate and 0.04 mg/kg of biotin, the HC diet with 26.9% of carbohydrate and 0.05 mg/kg of biotin, and the HCB diet with 26.9% of carbohydrate and 1.62 mg/kg of biotin. Results showed that high dietary carbohydrate (HC diet) impaired the morphology of liver and intestine, however, inclusion of dietary biotin (HCB diet) normalized their morphology. Inflammation-related gene expression of nuclear factor κB p65 (nf-κb p65), tumor necrosis factor α (tnf-α), interleukin-1ß (il-1ß), il-6 and il-8, and the protein expression of NF-κB p65 in the liver and intestine were significantly up-regulated in the HC group compared to those in the CC group (P < 0.05), the HCB diet decreased their expression compared to the HC group (P < 0.05). The gene expression of il-10 and transforming growth factor-ß (tgf-ß) in the liver and intestine were significantly decreased in the HC group compared to the CC group (P < 0.05), and inclusion of dietary biotin increased the il-10 and tgf-ß expression in the liver and intestine (P < 0.05). Moreover, compared to the CC group, the HC group had a stronger degree of DNA fragmentation and more TUNEL-positive cells in the liver and intestine, and the HCB group had a slighter degree of DNA fragmentation and fewer TUNEL-positive cells compared to the HC group. Meanwhile, the gene expression of B-cell lymphoma protein-2-associated X protein (bax) and executor apoptosis-related cysteine peptidase 3 (caspase-3) were significantly up-regulated and the gene expression of B-cell lymphoma-2 (bcl-2) was significantly down-regulated both in the liver and intestine in the HC group compared with those in the CC group (P < 0.05). Inclusion of dietary biotin significantly decreased the bax and caspase-3 mRNA levels and increased bcl-2 mRNA level in the liver and intestine (P < 0.05). In conclusion, high dietary carbohydrate (26.9% vs 18.6%) induced inflammation and apoptosis in liver and intestine. Supplementation of biotin (1.62 mg/kg vs 0.05 mg/kg) in diet can alleviate the high-dietary-carbohydrate-induced hepatic and intestinal inflammation as well as inhibit apoptosis in turbot. The present study provides basic data for the application of biotin into feed, especially the high-carbohydrate feed for turbot.

Thyroid disorders in elderly: A comprehensive review.

The approach to management of thyroid disorders in the elderly differs from that for younger individuals: it considers frailty of the population, coexisting medical illness and medications, clearance rate of medications and drug-drug interactions along with target organ sensitivity to the treatment. We present a comprehensive review of literature for the clinical presentation, pathophysiology, diagnostic evaluation, and management of thyroid disorders in the elderly.

Biotin-induced thyroid stimulating hormone aberrations in the setting of immunotherapy.

INTRODUCTION: Immune checkpoint inhibitors are associated with immune-mediated thyroid disease and other endocrinopathies. Biotin is an over-the-counter supplement known to interfere with lab assays, including thyroid function tests. Biotin-induced complications with lab monitoring during immunotherapy have not been previously reported. CASE REPORT: We present a case of a 68-year old woman with hypothyroidism after initiating immune checkpoint blockade therapy and abnormal laboratory monitoring values while concurrently taking biotin supplements.Management & outcome: The patient was initiated on levothyroxine with subsequent dose increases over a period of weeks with resolution of symptoms and normalization of free thyroxine levels. Thyroid stimulating hormone (TSH) levels appeared to remain elevated until biotin supplements were held and levels normalized. DISCUSSION: The purpose of this report is to provide the first known incidence of biotin complicating the routine monitoring of immune checkpoint inhibitors with elevated TSH levels and to alert providers to elicit accurate medication histories regarding over-the-counter supplements.

Dietary supplements in dermatology: A review of the evidence for zinc, biotin, vitamin D, nicotinamide, and Polypodium.

Dietary supplements are commonly recommended by dermatologists in the treatment of skin, hair, and nail disorders. This review of oral over-the-counter supplement use in dermatology summarizes current evidence for the use of zinc, biotin, vitamin D, nicotinamide, and Polypodium in the management of common dermatologic disorders. Evidence for the safety and efficacy of these supplements is limited. Very few large-scale randomized controlled trials exist for these over-the-counter supplements, particularly biotin and Polypodium. The lack of standardized dosing and standardized outcome measures makes comparison across existing studies challenging, and the lack of adverse events reporting in the majority of studies limits analysis of supplement safety. The most promising evidence exists for the use of nicotinamide in preventing nonmelanoma skin cancers. There is some evidence for the role of vitamin D in decreasing melanoma risk and progression in some individuals and for the photoprotective role of Polypodium, although additional high-quality studies are needed to determine appropriate dosing. Current evidence is insufficient to recommend the use of biotin or zinc supplements in dermatology. Large-scale randomized controlled trials investigating safety and efficacy are needed before widespread incorporation of these oral supplements into the general practice of dermatology.

Unusual Presentation of Denys-Drash Syndrome in a Girl with Undisclosed Consumption of Biotin

We describe a 46,XX girl with Denys-Drash syndrome, showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and magnetic resonance imaging showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone was increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy. Histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were elevated four months after gonadectomy (157 ng/dL). Recent medical history revealed chronic daily comsumption of high dose biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry, was within reference intervals. Similar testosterone levels were detected on repeat immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should raise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. METHODS: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). FINDINGS: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. INTERPRETATION: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. FUNDING: MedDay Pharmaceuticals.

Bullous fixed drug eruption related to multivitamins.

Multivitamins are commonly consumed over-the-counter supplements. Drug reactions related to multivitamins are rare and very few cases have been reported. This is a case of a young woman who developed bullous fixed drug eruption to multivitamins.

When thyroid labs do not add up, physicians should ask patients about biotin supplements.

A 69-year-old woman with a remote history of Graves' disease treated with radioactive iodine ablation, who was maintained on a stable dose of levothyroxine for 15 years, presented with abnormal and fluctuating thyroid function tests which were confusing. After extensive evaluation, no diagnosis could be made, and it became difficult to optimise the levothyroxine dose, until we became aware of the recently recognised biotin-induced lab interference. It was then noticed that her medication list included biotin 10 mg two times per day. After holding the biotin and repeating the thyroid function tests, the labs made more sense, and the patient was easily made euthyroid with appropriate dose adjustment. We also investigated our own laboratory, and identified the thyroid labs that are performed with biotin-containing assays and developed strategies to increase the awareness about this lab artefact in our clinics.

Biotin interferences: Have we neglected the impact on serological markers?

BACKGROUND: Biotin has been reported to be a leading cause of interference on several immunoassay platforms using the streptavidin-biotin immobilization system. While biotin interferences have now been well characterized for several assays, only few data are available on their impact on serological markers of infectious viral diseases. METHODS: Overall, 10 healthy volunteers (HVs) received a single 100 mg dose of biotin to evaluate its effect on hepatitis B serological markers. Blood samples were taken several times before and after biotin intake. In addition, spiking experiments were applied to investigate biotin's impact on anti-HIV/p24 Ag and anti-HCV antibody levels. Several procedures designed to overcome this interference were evaluated. RESULTS: Biotin intake resulted in a false-negative anti-HBs immunological status (<10 mIU/mL) in 40.0% of cases. According to our anti-HBc and anti-HBe results, biotin intake was associated with 90.0% and 80.0% of false positive results, respectively. At the theoretical biotin peak concentration following a 100 mg intake, 50.0% and 66.6% of anti-HIV and anti-HCV results were false negatives, respectively. All the procedures evaluated to overcome the interference were proven effective. CONCLUSION: HBV, HCV, and HIV serological markers are likely to be highly sensitive to biotin. Our data confirm that the scope of biotin interference is broader than commonly described.