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Submitted URL:
https://www.cureus.com/articles/199499-vitamin-b6-toxicity-secondary-to-daily-multivitamin-use-a-case-report#!/
Effective URL:
https://www.cureus.com/articles/199499-vitamin-b6-toxicity-secondary-to-daily-multivitamin-use-a-case-report
Submission: On February 02 via manual (February 2nd 2024, 5:06:32 am UTC) from US — Scanned from US

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VITAMIN B6 TOXICITY SECONDARY TO DAILY MULTIVITAMIN USE: A CASE REPORT

Alexander Paluszny • Shuhao Qiu



Alexander Paluszny • Shuhao Qiu

Published: November 14, 2023

DOI: 10.7759/cureus.48792

Peer-Reviewed

Cite this article as: Paluszny A, Qiu S (November 14, 2023) Vitamin B6 Toxicity
Secondary to Daily Multivitamin Use: A Case Report. Cureus 15(11): e48792.
doi:10.7759/cureus.48792


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ABSTRACT

Vitamin B6 is a water-soluble vitamin that is an important cofactor in various
metabolic processes. Although rare, its consumption can sometimes result in
toxicity, which typically presents with peripheral neuropathy in the early
stage. While vitamin B6 toxicity is most often associated with supplemental
mega-doses of more than 50 mg/day, more recent studies have shown that toxicity
can occur in cases of much smaller doses as well. We present a case of a
73-year-old male with a three-year history of progressive peripheral neuropathy
who was found to have a serum vitamin B6 level of 259.9 nmol/L (reference range:
20-125 nmol/L) but only reported taking a daily multivitamin containing 6 mg of
vitamin B6. This case of toxicity in the setting of a daily intake lower than
the European Food Safety Administration's (EFSA) newly established Tolerable
Upper Intake Level (UL) of 12 mg/day highlights the need for further research
into the effects of relatively low-dose vitamin B6 supplementation.


INTRODUCTION

Vitamin B6 is a water-soluble vitamin that plays a role in multiple enzymatic
reactions critical for the metabolism of carbohydrates, lipids, and amino acids.
The recommended daily intake of vitamin B6 is between 1.3-2.0 mg/day, which can
be found in foods such as poultry, fish, potatoes, fortified grains, and fruit
[1]. As an essential nutrient, vitamin B6 is also found in dietary supplements,
such as multivitamins, although dietary deficiency is rare. Intake of food-based
sources of vitamin B6 will not cause toxicity, but the use of supplements
containing the nutrient potentially can, classically presenting with peripheral
neuropathy [2]. The less commonly reported symptoms include ataxia, muscle
weakness, disequilibrium, and dermatosis [3]. As one of the rarer causes of
peripheral neuropathy, vitamin B6 toxicity can often be overlooked, leading to a
delay in diagnosis. We present a patient with a three-year history of peripheral
neuropathy secondary to vitamin B6 toxicity due to daily multivitamin use.


CASE PRESENTATION

A 73-year-old male presented to his primary care physician for a wellness visit
with a three-year history of peripheral neuropathy. He initially reported
numbness in the bilateral lower extremity, usually only at night. The patient
denied any back pain or weakness in his legs. The physical exam showed normal
pulses, strength, reflexes, gait, and mental status with decreased vibratory
sense on the left ankle and decreased monofilament sensation bilaterally.
Preliminary laboratory evaluation revealed vitamin B12, thyroid levels, HbA1C,
and antinuclear antibodies to be within the reference range. A previous
peripheral neuropathy workup from 2020 was also unremarkable.

The patient was seen in the clinic again eight months later with similar
complaints of progressive bilateral numbness and tingling in the lower
extremities with occasional involvement of his fingertips. The physical exam
again showed normal pulses, strength, reflexes, gait, and mental status with
decreased vibratory sense bilaterally. The patient was referred
for electromyography at this time, which showed bilateral sensory neuropathy of
unknown etiology with early signs of progression to motor fibers. The patient
was instructed to follow up with his primary care physician for further
evaluation.

At this follow-up visit, the patient reported new-onset lightheadedness and
dizziness. Repeat laboratory evaluations were completed, including serum vitamin
B6, which was found to be 259.9 nmol/L (reference range: 20-125 nmol/L). The
patient had been taking a daily multivitamin containing 6 mg of vitamin B6 for
more than 10 years, which he was instructed to discontinue at this time. When
asked about his diet, the patient reported eating a balanced diet and denied any
recent changes. He denied taking any additional vitamins, energy drinks, workout
supplements, or other items with known high amounts of vitamin B6.

One month after stopping the multivitamin, the patient reported relief from his
dizziness and a slight improvement in his numbness and tingling. He was advised
to continue to monitor his neuropathy symptoms and follow up with repeat serum
vitamin B6 in four months.


DISCUSSION

The Recommended Dietary Allowance (RDA) of vitamin B6 varies slightly depending
on age and gender. The RDA is 1.0 mg/day for children aged 9-13 years, 1.2
mg/day for girls aged 14-18 years, and 1.3 mg/day for boys aged 14-18 years. For
adults, the RDA is 1.3 mg/day for those aged 19-50 years, 1.5 mg/day for women
older than 50 years, and 1.7 mg/day for men older than 50 years. The estimated
dietary intake in the US is 1.5 mg/day for women and 2.0 mg/day for men [1]. The
multivitamin that our patient reported taking daily contained 6 mg of vitamin
B6, more than 350% of the RDA for older men. However, this is still seen as a
relatively low dose of vitamin B6 supplementation as products such as energy
drinks can have up to 40 mg of vitamin B6, 2300% of the RDA for older men [4].

The mechanism of vitamin B6 toxicity is not fully understood currently; however,
recent studies have offered valuable information. In a 2017 study, Vrolijk et
al. showed that vitamin B6 toxicity is related to which vitamer is found in
excess. Vitamin B6 constitutes a group of six vitamers: pyridoxine (PN),
pyridoxal (PL), and pyridoxamine (PM) along with their 5'-phosphate esters (PNP,
PLP, and PMP) [1]. PLP is the biologically active form while PN is the inactive
form, which is most often used in supplements. The study suggests that the
inactive PN can build up when taken in high doses and competitively inhibit the
active PLP, causing peripheral neuropathy. In contrast, other inactive vitamers,
such as PM, did not affect cellular viability [5].

In a follow-up study, Vrolijk et al. concluded that there are clear
inter-individual differences in the metabolism of PN, predisposing some to be
sensitive to toxicity [6]. This could begin to explain why this patient
experienced symptoms with a daily dose of 6 mg while vitamin B6 has previously
been reported as safe in doses up to 500 mg [3]. Additionally, in a 2021 paper,
Hadtstein and Vrolijk hypothesized that daily use for an extended period of time
can alter the normally rapid excretion of PN, causing an accumulation in the
system [7]. This hypothesis would be supported by the presentation seen in this
patient where a relatively small daily dose taken for more than 10 years
resulted in a clinically significant toxicity.

Peripheral neuropathy due to vitamin B6 toxicity in humans was first reported in
the early 1980s. These reports, however, occurred in the context of supplemental
vitamin B6 mega-doses of up to 6 g/day for extended periods [2]. Although there
is little evidence of their efficacy, mega-doses of 50-500 mg/day were used
empirically in the treatment of carpal tunnel syndrome, premenstrual syndrome,
and depression, among others [8]. Using these early studies, the US Institute of
Medicine set a Tolerable Upper Intake Level (UL) of 100 mg/day in 1998 [1].

However, more recent studies have found evidence of vitamin B6 toxicity in the
absence of purposeful mega-doses [9]. Tynes et al. described a 30-year-old
post-bariatric surgery patient who developed peripheral neuropathy secondary to
vitamin B6 toxicity with their only reported intake being a daily multivitamin
containing 2 mg of vitamin B6 and two or three daily energy drinks which
contained 10-15 mg vitamin B6. Cessation of multivitamins and energy drinks led
to a complete reversal of the patient's symptoms [4]. In 2023, the European Food
Safety Administration (EFSA) was requested to deliver a scientific opinion on
the safety of vitamin B6, which led to the establishment of a new UL of 12
mg/day [10].

Similar to the case reported by Tynes et al., the peripheral neuropathy with
elevated serum vitamin B6 seen in our patient occurred in the context of
relatively low daily intake. While retrospective dietary information over the
span of three years is difficult to collect, the only reported vitamin B6
supplementation in this patient was in the form of a daily multivitamin
containing 6 mg of pyridoxine. With dietary intake in the US at approximately 2
mg/day for men, this would suggest an even lower daily intake than the newly
established EFSA UL of 12 mg/day.


CONCLUSIONS

Although significant additional intake from unreported or unknown sources cannot
be ruled out, this patient’s presentation suggests the need for more research
into the effects of long-term, low-dose pyridoxine supplementation.
Additionally, the case highlights the importance of obtaining a complete history
of over-the-counter supplement use by primary care physicians. This case also
serves as a reminder to keep vitamin B6 toxicity in the differentials for
peripheral neuropathy, especially if initial laboratory evaluations are
inconclusive. As with most patients with peripheral neuropathy due to vitamin B6
toxicity, this patient is expected to eventually have complete resolution of his
symptoms with a return to normal serum vitamin B6 levels.


REFERENCES

 1.  Institute of Medicine: Vitamin B6. Dietary Reference Intakes for Thiamin,
     Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid,
     Biotin, and Choline. The National Academies Press, Washington, DC; 1998.
     150-95. 10.17226/6015
 2.  Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown
     MJ: Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N
     Engl J Med. 1983, 309:445-8. 10.1056/NEJM198308253090801
 3.  Cohen M, Bendich A: Safety of pyridoxine — a review of human and animal
     studies. Toxico Lett. 1986, 34:129-39. 10.1016/0378-4274(86)90202-X
 4.  Tynes M, Hepprich M, Timper K: Regular intake of energy drinks and
     multivitamin supplements is associated with elevated plasma vitamin B6
     levels in post-bariatric patients. Sci Rep. 2021, 11:17830.
     10.1038/s41598-021-97205-7
 5.  Vrolijk MF, Opperhuizen A, Jansen EH, Hageman GJ, Bast A, Haenen GR: The
     vitamin B6 paradox: supplementation with high concentrations of pyridoxine
     leads to decreased vitamin B6 function. Toxicol In Vitro. 2017, 44:206-12.
     10.1016/j.tiv.2017.07.009
 6.  Vrolijk MF, Hageman GJ, van de Koppel S, van Hunsel F, Bast A:
     Inter-individual differences in pharmacokinetics of vitamin B6: a possible
     explanation of different sensitivity to its neuropathic effects.
     PharmaNutrition. 2020, 12:100188. 10.1016/j.phanu.2020.100188
 7.  Hadtstein F, Vrolijk M: Vitamin B-6-induced neuropathy: exploring the
     mechanisms of pyridoxine toxicity. Adv Nutr. 2021, 12:1911-29.
     10.1093/advances/nmab033
 8.  Bender DA: Non-nutritional uses of vitamin B6. Br J Nutr. 1999, 81:7-20.
     10.1017/S0007114599000082
 9.  van Hunsel F, van de Koppel S, van Puijenbroek E, Kant A: Vitamin B6 in
     health supplements and neuropathy: case series assessment of spontaneously
     reported cases. Drug Saf. 2018, 41:859-69. 10.1007/s40264-018-0664-0
 10. Turck D, Bohn T, Castenmiller J, et al.: Scientific opinion on the
     tolerable upper intake level for vitamin B6. EFSA J. 2023, 21:e08006.
     10.2903/j.efsa.2023.8006

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