Pyridoxine toxicity among lung transplant recipients

The complications of pyridoxine (or vitamin B6) toxicity are well known among neurologists due to the prevalence of peripheral neuropathy among this group; however, they are less recognised within the transplantation cohort where treatment containing pyridoxine is prescribed to counteract hypomagnesaemia secondary to calcineurin inhibitors. One such treatment is a nutritional supplement (Supplement X) that is readily available over the counter and contains magnesium, pyridoxine, calcium, colecalciferol and manganese. In this article, we describe our experience with pyridoxine toxicity following lung transplantation (LTx). A 59-year-old male with HIV and suppressed viral load underwent bilateral sequential LTx for chronic obstructive airways disease. His medications included tacrolimus, mycophenolate, prednisolone, azithromycin, trimethoprim/sulfamethoxazole, abacavir, lamivudine and raltegravir. In addition, Supplement X at four tablets daily and magnesium aspartate were prescribed due to persistent hypomagnesaemia secondary to tacrolimus. Two years after LTx, he reported patchy sensory loss, paraesthesia and neuropathic pain affecting his hands and feet. Clinical examination was consistent with a large fibre length-dependent sensory neuropathy confirmed on nerve conduction studies (NCS). Results showed a significantly elevated pyridoxine level of >2000 nmol/L (normal range: 35–110 nmol/L) without any perceivable alternate cause for neuropathy. Following cessation of Supplement X, the patient's sensory symptoms improved within 3 months. This case prompted a retrospective review of LTx recipients prescribed Supplement X with elevated pyridoxine levels. From a cohort of approximately 250 LTx patients currently receiving Supplement X, we identified 11 patients with pyridoxine excess (Table 1). If available, examination findings and NCS were also recorded, as well as follow-up outcomes on improvement and ongoing therapy. Approximately half the patients identified were female (55%) with a median age of 65 years. All patients were being treated for hypomagnesaemia secondary to tacrolimus. Nine patients (82%) reported symptoms of neuropathy and time to symptom onset varied from 4 weeks to 12 years. Only four patients had follow-up NCS, of which three demonstrated length-dependent sensory neuropathy consistent with pyridoxine toxicity. Supplement X was reduced or withdrawn in all cases with improvement or resolution of neuropathic symptoms in eight patients. The causes for peripheral neuropathy are vast; a systematic and thorough review of history, medications and risk factors is crucial in the diagnosis and treatment of this condition. LTx recipients are particularly complex given the potential comorbidities that may be contributing to neuropathy including steroid-induced diabetes and drugs. However, the clinical features, elevated pyridoxine levels and improvement of symptoms after cessation of supplementation suggest that pyridoxine was likely the culprit in most cases. A major limitation of this review, however, is the lack of confirmatory NCS in symptomatic patients. Supplement X is very commonly prescribed in LTx recipients to counteract hypomagnesaemia from calcineurin inhibitor therapy. One tablet of Supplement X, while containing 301.5 mg magnesium, also includes 41.1 mg pyridoxine. When prescribed at a dose of four tablets daily to treat hypomagnesaemia, this well exceeds the recommended daily pyridoxine intake of 100 mg.1 It should be noted that these supplements are available for purchase over the counter, and while there is no indicated maximum safe dose, an arbitrary limit of four tablets per day has been historically used at our centre based on previous Therapeutic Goods Association (TGA) guidelines suggesting a maximum daily dose of 200 mg of pyridoxine is considered acceptable.2 The symptomatic improvement seen among most of our patients following Supplement X withdrawal is supported by other study findings that pyridoxine toxicity-related peripheral neuropathy is potentially a reversible condition.3 At our centre, it has now become practice to restrict Supplement X to two tablets daily with caution; however, despite this, pyridoxine toxicity continues to prevail as seen in Table 1. A recent TGA statement reported 32 cases of pyridoxine-related adverse events, where 66% occurred at doses of 50 mg or less. It remains to be seen whether genetic factors influencing pyridoxine metabolism play a role in toxicity and the dose–response relationship.4 This represents a challenge in creating guidelines or recommendations about safe maximum daily dosing. We recommend that physicians involved in post-transplant care take caution in prescribing magnesium therapies containing additional supplements and particularly consider options that do not contain pyridoxine. The data that support the findings of this study are available from the corresponding author upon reasonable request.