Underestimated pyridoxine consumption and neurotoxicity: a novel manifestation with rheumatologic relevance - a case-based review

Case 1

A 36-year-old female patient was referred to a rheumatology clinic due to joint pain in both hands and paresthesia in the upper limbs. On rheumatological examination the only abnormality was tenderness of the carpometacarpal I (CMC I) joints bilaterally, without signs of inflammation. Ultrasound examination confirmed the presence of minor degenerative changes in the CMC I joints bilaterally, with no inflammation. No signs of peripheral nerve compression syndromes were visible. The result of the neurophysiological examination was normal. In medical history, the patient declared adherence to a healthy diet, rich in nuts and oats. Additionally, due to involvement in numerous sport activities, the patient consumed supplements for athletes. Based on this information, the level of B vitamins was determined, revealing high concentration of vitamin B6 (117 ug/l, N: 5–30 ug/l). The levels of other vitamins, including B12, were normal. The patient was recommended to limit the consumption of products rich in B vitamins and to discontinue the use of additional supplements. A control test after 3 months showed normalization of the vitamin B6 level (19.4 ug/l) and clinical resolution of the symptoms. Due to the complete subsidence of symptoms, rheumatological observation was terminated one year after the first visit.

Case 2

A 46-year-old man, previously healthy, was referred to the rheumatology clinic due to suspected systemic lupus erythematosus (SLE). Neurological diagnostics was initiated due to reported symptoms of memory and concentration deterioration. Patient’s complaints were objectified in the neuropsychological evaluation, with conclusion: “Among properly integrated cognitive functions, selective and mildly pronounced deficits in learning and memorizing verbal material become apparent; the performance profile in test tasks and clinical trials is not characteristic of any disease associated with central nervous system involvement”. During the diagnostic process, the presence of antinuclear antibodies in the serum was found at a titer of 1:320 speckled type. Immunoblot examination revealed antibodies against ribosomal protein P. Complement components C3 and C4 were normal. Concomitantly, the classical pathway activity (CH50) was lowered (35,5 U/ml; N: 41,69–95,06 U/ml) and C1q concentration was significantly elevated (284,90 mg/dl; N: 12,2–39,5 mg/dl). Magnetic resonance imaging of the head did not reveal any abnormalities. During rheumatological evaluation, no typical symptoms of rheumatological diseases, including SLE, were found. Despite the presence of antibodies, the patient did not meet the diagnostic criteria for any systemic connective tissue disease. In the search of other potential causes of the observed abnormalities, among others, the concentration of vitamins B was evaluated. The level of vitamin B1 and B6 exceeded the upper limit of the norm (137 ug/l (N: 38–85 ug/l) and 226.6 (N: 5–30 ug/l) respectively). Vitamin B12 concentration was normal. After a more in-depth medical interview, the patient admitted to daily consumption of large amounts of nuts. Cessation of this dietary habit was recommended. A control test after three months showed normalization of vitamin B6 level to 18,6 ug/l with concurrent significant improvement in memory function. Surprisingly, the previously noted abnormalities within complement system normalized with the C1q concentration at 21,9 mg/ml and CH50 at the level of 73,2 U/ml. Moreover, quantitative evaluation of antibodies against ribosomal protein P was within normal range (0,6 U/ml; N: <7 U/ml). The patient remains under rheumatological observation due to immunological abnormalities detected at the beginning, however after a year of observation no new symptoms have appeared.

Case 3

A 65-year-old female patient with a confirmed diagnosis of Sjögren disease (SjD), based on the presence of anti-SSA antibodies and presence of typical infiltrations in a minor salivary gland (Focus score = 1,3), was evaluated because of persistent symptoms of peripheral neuropathy. Until this point, in the treatment of the underlying disease, due to the lack of signs of organ involvement, only symptomatic treatment of sicca symptoms was used. The patient had previously been diagnosed with unilateral carpal tunnel syndrome based on the results of electroneurography and ultrasonography. Due to the persistence of symptoms despite surgical treatment, a 3-month supplementation of B vitamins was prescribed by neurologist with a product containing 200 mg of pyridoxine in one tablet. Due to the initial improvement in symptoms, the prescription was extended by the general practitioner (GP) for another couple of months. The patient then continued supplementation with OTC drugs. After about a year of supplementation, symmetrical neuropathic pain appeared in the upper limbs. Neurophysiological and ultrasound examinations did not reveal any new changes, apart from post-operative changes in the area of the previously operated carpal tunnel syndrome on the right side. Vitamin B12 deficiency was ruled out. During routine visits to the attending rheumatologist, the patient did not report chronic supplementation with B vitamins on her regular medication list, considering it a supplement. During one of the subsequent rheumatology visits, due to the persistence of symptoms typical of peripheral neuropathy, after a thorough interview, the patient admitted to supplementing with B vitamins. The level of vitamin B6 was determined to be 254.8 ug/l (N 5–30 ug/l). The patient was recommended to immediately discontinue supplementation. A follow-up assessment after three months showed a decrease in the level of vitamin B6 to 163,1 ug/l with improvement in symptoms, with further decrease at 6 months to the level of 27.4 ug/l coupled with complete disappearance of neuropathic symptoms.

Search strategy

A comprehensive literature search according to CABARET guidelines [6] was conducted in PubMed, Scopus and Web of Science to identify studies related to vitamin B6 (pyridoxine) toxicity and its effects on the nervous system. Both the Medical Subject Headings (MeSH) and free-text terms were utilized in the search strategy and included: ‘vitamin B6’, ‘pyridoxine’, ‘pyridoxine toxicity’, ‘overdose’, ‘neuropathy’, ‘central nervous system’. Appropriate Bollean operators (AND, OR) were used. Detailed search strings for each of the databases are included in Supplementary Material 1. Reviews, original papers and case reports were included in the review. Work published between 1983 (the first report of vitamin B6 neurotoxicity) and 2025 were scanned with the last literature search being conducted on the 10^th May 2025. Non-English articles were excluded. A total of 88 results were retrieved, with 77 after removal of duplicates. Two independent reviewers screened titles and abstracts for eligibility as well as quality and risk of bias, excluding 15 papers on these bases. The remaining 62 articles were subject to full-text reading by two independent researchers. Discrepancies were resolved through discussion. Consequently, 50 studies were included in the final analysis.

Potential role of vitamin B6 in the development of central nervous system abnormalities

The first reports suggesting potential neurotoxicity of excessive vitamin B6 consumption come from the work by Schaumburg published in 1983 [13]. Following that publication, over the years, the neurotoxicity of vitamin B6 has been described in numerous case reports [19, 22, 23]. Newer sources highlight more widespread consequences of pyridoxine toxicity, including dysautonomia [24], impaired coagulation [25] and symptoms mimicking CNS abnormalities [26].

A systematic review by Muhamad et al., published in 2023, quoted six studies focusing on the topic of mechanism behind pyridoxine toxicity [10]. One of the trials involved sural nerve biopsy, revealing axonal degeneration and reduction in the density of myelinated fibers [17]. However, another study did not confirm the correlation between increased vitamin B6 concentration and neuropathic symptoms [27]. Vrolijk et al. investigated the toxicity of vitamin B6 forms in vitro [28]. According to their findings, elevated pyridoxin levels led to cell death and axonopathy in the neuronal cell line but not in the intestinal cells. As of today’s knowledge, pyridoxine cannot cross the brain-blood barrier. Nevertheless, its metabolites are involved in the development of pyridoxine-dependent seizures in newborns, allowing the speculation of interplay between the CNS and pyridoxine also later in life. Due to lack of sufficient data on the pathomechanisms of pyridoxine-induced neuropathy at the level of CNS, below we discuss some of those known from peripheral neuropathy which seem feasible in the development of CNS abnormalities.

As mentioned above, the CNS has not been described as affected by vitamin B6 toxicity. In the case of our patient, other potential factors contributing to such symptoms, such as rheumatological and neurological conditions, structural abnormalities and other nutritional deficiencies have been excluded. Moreover, the patient improved significantly along with the lowering of serum pyridoxine concentration. This drew our attention to potential mechanisms involved in the pathogenesis of such a phenomenon.

Vitamers B6 are vital at the fetal and neonatal stages for the nervous system development [29, 30]. Pyridoxine plays an important role in the synthesis of a number of neurotransmitters (dopamine, serotonin, gamma-aminobutyric acid (GABA), noradrenaline) [31]. GABA, with its primarily inhibitory function in the nervous system, is thought to indirectly serve a neuroprotective role. Therefore, it can be speculated that pyridoxine deficiency leads to nervous system damage through its effect on the glutamergic system. This role is not only limited to adults, as the significance of vitamin B6 and glutamergic system can already be observed at the fetal brain development [30].

Furthermore, in the case of mild vitamin B6 deficiency synthesis of GABA and serotonin is restricted, leading to sleep and behavior disturbances as well as cardiovascular and endocrinological disorders [32]. Symptoms from the CNS associated with pyridoxine deficiency include pyridoxine dependency seizures, impaired cognitive function, depression and premature neuron aging [33].

The role of pyridoxine is the synthesis of neurotransmitters is presented in Fig. 1. However, the role of vitamin B6 in the nervous system in not limited solely to these processes. It’s essential role in enzymatic activity affects, among others, energy supply to the CNS [31], myelin formation and homocysteine metabolism. The latter explains the impact of vitamin B6 on prevention of stroke [34] as well as development of neurodegenerative diseases [35].

All of the described roles of vitamin B6 undoubtedly explain the reasoning behind its supplementation and facilitate its usage in case of deficiency-based abnormalities. However, the influence of pyridoxine overdose on the CNS function observed by our team is speculative.

In the case of peripheral neuropathy, the competitive binding in enzymatic proteins of active and inactive forms (pyridoxal-5’-phosphate and pyridoxine respectively) has been suggested [28]. We hypothesize that the impact of excessive vitamin B6 consumption can serve a similar role in both peripheral nervous system (PNS) and CNS metabolism, leading to vitamin B6 overdose mimicking the symptoms of its deficiency.

Complement dysregulation in the course of vitamin B6 overdose

An issue that deserves a separate thread is the transient dysregulation of the complement system in the second of the presented cases, which was concomitant with a very high vitamin B6 concentration and eased upon normalization of neuropsychological status and restoring normal B6 levels. The results of laboratory analyses of the complement system may be perceived as inconclusive at first glance. Complement components C3 (0.88 g/l) and C4 (0.16 g/l) were within the normal range (0.8–1.57 and 0.13–0.39 g/l, respectively), the first component of the classical complement pathway C1q exceeded the normal range 7-fold (284.9 mg/dl vs. 12.2–39.5 mg/dl) but the total activity of the classical pathway (CH50) was low (35.5 U/ml vs. 41.5–95,5 U/ml). However, the bottleneck of the classical complement pathway is the C2 protein [36, 37], which is not routinely analyzed and acts between C1q and C3. While C2 is consumed due to an excessive supply of C1q, the overall pathway activity goes low, but the level of C3, the most abundant complement protein, may be affected minimally. Indeed, C3 and C4 levels were higher when the patient recovered (1.07 g/l and 0.22 g/l respectively), thus making such a scenario plausible. An unanswered question remains whether a high concentration of plasma C1q was directly linked to vitamin B6 levels. B6 is rather associated with anti-inflammatory conditions [38, 39] but on the other hand, C1q is an exceptional complement protein that is mainly produced by monocytes/macrophages and dendritic cells, unlike most complement proteins produced by liver hepatocytes [40, 41]. Therefore, the steering mechanisms of C1q production may be different. Moreover, C1q is not only a pathway- initiating molecule upon pathogen challenge but an important player in the scavenging of immune complexes and apoptotic cells, thus, its dysregulation may break homeostasis in several ways [42, 43]. Previously, we reported a case of 30-year-old patient with behavioral changes who also presented with complement abnormalities. Application of complement-targeting drug, eculizumab resolved unfavorable clinical picture [44]. Here, there is another evidence that complement dysregulation may coexist with neurological symptoms. Based on the available literature it is impossible to define whether increased concentration of C1q in the peripheral blood constitutes a factor stimulating microglia to further local production of this protein [45] or if it can directly affect the CNS. Even though more research in the area is required, our observation supports the idea of correlation between complement dysregulation and CNS abnormalities.

Over-the-counter supplementation

With broad access to social media and popular-science texts published mainly online, the general understanding of the importance of proper nutrition is on the rise. However, mass-media oftentimes share incomplete or even completely inaccurate information, with poor or no scientific evidence to support it. This frequently leads to excessive supplement consumption with concurrent nutritional mistakes. In the USA alone, it is estimated that approximately 70% of the country’s population consumes some form of dietary supplements, leading to an industry worthy of 28 billion USD [46]. A major difference between a medication prescribed by healthcare professionals and a dietary supplement is the lack of pharmaceutical control over the latter– it requires neither clinical trials nor careful analysis upon market launching. Therefore, the dosage of specific products is impossible to establish and monitor, hence the impact it has on the patients’ health is difficult to predict. Cases of vitamin B6 intoxication from OTC products resulting in neuropathy are known in the literature [19, 47, 48]. This was also the case in one of the patients presented herein, who consumed an OTC vitamin B after a period of supplementation recommended by the physician. Undoubtedly, the role of prescription prolongation, without providing the patient with information about potential toxicity of B6, played a significant role in the process. The cessation of that product alone was sufficient to lower the serum pyridoxine level and improve neurological symptoms.

It is not uncommon in most countries worldwide to facilitate micronutrients consumption through fortified foods. In the case of zinc, iron, and vitamin D such a strategy has brought considerable benefit to public health. The concept of fortified food is to supply the population with a quantity high enough to avoid deficiencies, but not too abundant in order to prevent potential toxicity. In the case of presented patients, however, a mixture of fortified foods proved sufficient to cause high serum levels of pyridoxine with concomitant neurological symptoms.

Iatrogenic vitamin B6 overdose

Vitamins B are commonly prescribed in case of steroid-induced diabetes, peripheral neuropathy, discopathy or post/long COVID syndrome. In rheumatological practice, vitamin B is frequently used in the management of, to name a few, inflammatory polyneuropathy or entrapment syndromes. In SjD patients, the latter, manifesting as the carpal tunnel syndrome, is much more common than in the general population with unclear pathogenesis of the phenomenon [49–51] However, oftentimes instructions regarding timing of such supplementation are not clearly stated. Consequently, patients tend to prolong the medication with their GPs or turn to OTC products. The complexity of managing multimorbidity patients in the GPs office has been raised in multiple studies [52]. With intricate and dynamically changing guidelines regarding supplementation in highly specialistic fields, and limited time during visits at the GPs offices, it seems reasonable that the specialist initializing the supplementation should be responsible for specification of dosage and timing as well as potential future laboratory controls. Many healthcare systems struggle with fragmentation of patient care, leading to unsatisfactory management of symptoms, polypharmacy and difficulties in access to specialistic care in case of complications. Clear guidelines from specialists and effective communication with GPs seem to constitute the basis for more patient-focused healthcare.

Disclosure

Presented clinical data constituted a part of conference presentation during 25^th Congress of the Polish Society for Rheumatology (Potential vitamin B6 toxicity from a rheumatologist’s perspective; Kinga Grochowalska, Marta Magdalena Jaskólska, Iga Kościńska-Shukla, Michał Chmielewski; Reumatologia 2024;62 (Suppl 1)(XXV KONGRES POLSKIEGO TOWARZYSTWA REUMATOLOGICZNEGO):80–81; DOI: 10.5114/reum/193276). The review has not been previously published neither in part nor as a full text. The article meets the criteria for publication under the Springer Open Choice Programme.

Conflict of interest

Iga Kościńska-Shukla gave two lectures sponsored by Woerwag Pharma on the safety of treatment with group B vitamins formulations. This cooperation did not influence the results published in this article.