Peripheral Neuropathy and its Causes
Peripheral Neuropathy (PN) is a broader term that encompasses various neurological conditions that involve damage to the peripheral nervous system, impacting motor, sensory or autonomic nerves.1 Common causes of PN include diabetes, excessive alcohol intake, injury, autoimmune diseases, infections, and certain vitamin deficiencies, such as vitamin B6.2 In addition to a deficiency of vitamin B6, there is also a clear association between elevated vitamin B6 levels and the development of PN, predominately causing a dysfunction of sensory nerves resulting in symptoms of tingling, numbness and burning, usually in the hands or feet.3 When vitamin B6 toxicity is the cause of PN, studies have shown that symptoms often improve once serum vitamin B6 levels decline,4 with resolution of neurologic dysfunction typically occurring within six months.5
The Role and Importance of Vitamin B6
Vitamin B6 is an essential water-soluble vitamin vital for the health and functioning of the human body.6 It is naturally present in many foods, including meats, fish, poultry, whole grains, legumes, starchy vegetables, and non-citrus fruits, and is widely available as a dietary supplement.6 Vitamin B6 is made up of a group of six chemically related compounds; pyridoxine, pyridoxal, pyridoxamine and their 5’-phosphates, with pyridoxal-phosphate (PLP) being the biologically active form.7 Pyridoxine and pyridoxal are converted into the active form PLP and distributed around the body.8 PLP is an antioxidant that is involved in more than 140 biochemical reactions in the body, assisting with macronutrient metabolism, cellular signalling, neurotransmitter synthesis and nerve function.9 Whilst pyridoxine is readily excreted in the urine, PLP can be found in muscle tissue and the liver.9 The half-life elimination of vitamin B6 is approximately 15-20 days.10 Long-term daily supplementation of vitamin B6 may increase the half-life, leading to accumulation.11
Recommended Daily Intake and Potential Toxicity of Vitamin B6
In Australia, the recommended daily intake (RDI) for adult’s ranges between 1.3-2mg/day, with the upper level (UL) set at 50mg/day.8 Food consumption is estimated to provide up to 5mg/day of vitamin B6 in adults, with supplementation contributing up to 80% of daily intake.4 It is unlikely for an adult to exceed ULs through food sources only. Supplementation containing a high dose, at or above 50mg/day, of vitamin B6 increases the risk of toxicity.4
Hypothesised Mechanism of Vitamin B6-Induced Neuropathy
The mechanism through which vitamin B6 toxicity can lead to neuropathy is unclear, but it has been hypothesised to be a result of pyridoxine inhibiting pyridoxal kinase (PDXK) activity, thus reducing γ-aminobutyric acid (GABA) synthesis and decreasing GABA signalling within sensory neurons.11 As GABA is an inhibitory neurotransmitter,12 decreased GABA neurotransmission can damage sensory nerves.11
The Variance of Sensitivity to Vitamin B6 Toxicity
The Therapeutic Goods Administration (TGA) has reported that the risk of developing PN from vitamin B6 toxicity varies greatly between individuals; in some people, it occurs from doses less than 50mg/day.13 Plasma PLP is the most common measure of vitamin B6 status. PLP concentrations of more than 30 nmol/L have been traditional indicators of adequate vitamin B6 status in adults.15
Prevalence and Source of Vitamin B6 in Australian Medicines
In Australia, there are currently more than 1,500 medicines containing vitamin B6 including multivitamins, vitamin B complexes and magnesium and zinc supplements.13 PN appears to occur most commonly when people unknowingly take multiple products containing vitamin B6.13 Vrolijk et al., 2020 also reported that Pyridoxine, the most common form found in supplements, has a cytotoxic effect on neuronal cells, and this is considered more influential on the development of PN than vitamin B6 dosage.14
Regulatory Changes in Response to Vitamin B6 Induced PN
To address the rising prevalence of PN from elevated vitamin B6 levels, the TGA announced regulatory changes in March 2022. A warning label is to be added to products containing a daily dose of more than 10mg of vitamin B6, and the maximum daily dosage of vitamin B6 in a single product has been reduced from 200mg to 100mg for adults.16 Vitamin B6 is an important micronutrient required for various functions within the body. Adequate levels are crucial for optimal health, with PN a potential consequence in both deficient and toxic states.
The tightening of regulations by the TGA has increased the safety of supplementation. Although some people develop PN when supplementation is low dose, a much higher risk occurs when taking more than one supplement containing vitamin B6. Many reports suggest people are unaware of just how much vitamin B6 they are consuming via supplementation. Whilst there is no specific treatment for pyridoxine toxicity, cessation of supplements containing pyridoxine and individualised symptom management is crucial,4 with resolution of neurologic dysfunction typically occurring within six months. Both consumer and practitioner education to increase awareness is essential. Further research to investigate the relationship between vitamin B6 and PN, including individual differences and certain vitamer forms used in supplements, is warranted.
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