Continuing Education Activity

This activity describes the toxicity associated with vitamin B6 at higher doses. It explains in detail the pathophysiology and toxicokinetics of vitamin B6 toxicity and patient symptoms. This activity reviews the evaluation and treatment of vitamin B6 toxicity and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of vitamin B6 toxicity.
• Outline an appropriate evaluation for suspected vitamin B6 toxicity.
• Review a reasonable differential diagnosis for patients presenting with signs and symptoms of pyridoxine toxicity.
• Select the treatment and management options available to the healthcare team for vitamin B6 toxicity.

Introduction

Vitamin B6 is a micronutrient required by the body. Vitamin B6 refers to multiple chemically similar compounds, of which pyridoxine is the most common and is the compound found in commercially available vitamin supplements. The body uses vitamin B6 in numerous enzymatic reactions, including neurotransmitter production, amino acid metabolism, glucose metabolism, lipid metabolism, hemoglobin synthesis and function, and gene expression.[1] In the United States, vitamin B6 intake from food averages about 1.9 mg/day.[2] Intake of food-based sources of pyridoxine will not cause toxicity. The only reported cases of vitamin B6 toxicity are from supratherapeutic dosing of supplements or iatrogenic.

Etiology

Almost all cases of vitamin B6 toxicity are from supratherapeutic dosing, either iatrogenic or laypersons self-treating with over-the-counter supplements. Daily dietary intake will not provide enough pyridoxine to cause toxicity. The daily dietary intake of vitamin B6 is approximately 1.9 mg/day in the United States.[2] Additionally, typical pyridoxine doses used for co-treatment with isoniazid are 10 to 25 mg/day. Pyridoxine toxicity typically manifests as neurologic symptoms, including paresthesias in the extremities and, in severe cases, difficulty with ambulation. This sensory neuropathy usually develops at doses of pyridoxine above 1000 mg per day. There are some case reports of sensory neuropathies at doses of less than 500 mg per day in patients taking supplements for months. However, none of the studies had sensory nerve damage at a daily intake below 200 mg of pyridoxine per day.[3] A rare cause of vitamin B toxicity is hypophosphatasia.[4]

Epidemiology

Vitamin B6 supplementation is a therapeutic option for a variety of medical conditions. Pyridoxine is used in supratherapeutic doses as an antidote to treat seizures from isoniazid toxicity.[5] It is used in therapeutic doses for hyperemesis gravidarum and isoniazid.[6][7] It is used as a nutritional supplement by the lay public for a variety of perceived health benefits, including morning sickness, cardiovascular disease, premenstrual syndrome, depression, and carpal tunnel syndrome. Evidence for efficacy for many of these uses is mixed.

Over-the-counter supplements are the most likely culprit for patients taking a pyridoxine level above the safe recommended upper limit. Often patients are unaware that high-dose pyridoxine could be harmful. One illustrative case report describes a patient presenting to a healthcare facility with peripheral neuropathy, and he reported taking vitamin B-complex supplements at fifty times the daily suggested allowance for ten years.[8]

According to the 2017 U.S. poison center data, there were 566 reports of using pyridoxine therapeutically as an antidote.[9] Additionally, 377 pyridoxine exposure cases were reported, including eight cases with only minor or moderate clinical effects.  There were no serious outcomes or deaths reported.

Pathophysiology

Paradoxically the most common symptoms associated with vitamin B6 toxicity are similar to those with vitamin B6 deficiency. A patient will experience peripheral sensory neuropathy. Most commonly, this causes numbness in a stocking-glove distribution over the extremities. In addition to peripheral neuropathy, patients can experience ataxia and disequilibrium as well.[10] One large study found that patients also could experience hyperesthesia, bone pains, muscle weakness, numbness, and fasciculations.[11]

One study examined the role of pyridoxine toxicity on human cells to examine the neurotoxic effects further. They found that pyridoxine induced cell death in a concentration-dependent fashion and inhibited pyridoxal-5-phosphate dependent enzymes.[12] Thus it appears that the inactive form of B6, pyridoxine, competitively inhibits the active vitamin B6 form, pyridoxal-5’-phosphate causing the symptoms of vitamin B6 toxicity to mimic the symptoms of vitamin B6 deficiency.

Toxicokinetics

After oral ingestion of pyridoxine, peak plasma levels are achieved in approximately one hour.[11] In the liver and other tissues, absorbed vitamin B6 forms are converted by the liver to pyridoxal 5’-phosphate (PLP) and transported in the serum bound to albumin.[13] Oral doses of 100 mg of pyridoxine, pyridoxal, and pyridoxamine, the majority are excreted unchanged in the urine.[14]

Several drugs have interactions with vitamin B6 and can interfere with their levels. These medications typically lower the level of pyridoxine and leave to vitamin B6 deficiency and not toxicity. Isoniazid, cycloserine, penicillamine, and L-dopa all form complexes with vitamin B6, limiting its bioavailability. Oral contraceptives are associated with lower pyridoxine phosphate levels in a subset of women.[15] High doses of pyridoxine may decrease the blood levels of phenytoin and phenobarbital.[3]

History and Physical

History and physical exams are essential for identifying patients with vitamin B6 toxicity. Most patients will have neurologic symptoms and be seeking an evaluation for sensory neuropathy. A detailed medication reconciliation, including over-the-counter supplements, is needed. Since many over-the-counter supplements can have different doses of pyridoxine, having patients bring in medication and supplement bottles can be beneficial to ascertain the exact dosage of vitamins in a particular product.

The physical examination should include a thorough neurologic exam, including sensory, motor, gait, reflexes, cranial nerve testing, and muscle strength. Patients will typically present with bilateral sensory or motor changes, although a unilateral presentation is possible if there has been previous trauma or neurologic injury to an extremity.

Evaluation

Serum pyridoxine levels are typically less than 30 mcg/L. Patients with signs or symptoms of neuropathy should receive a referral to neurology or other specialists that can perform nerve conduction velocity studies. The diagnostic evaluation will typically start with the patient reporting signs and symptoms of peripheral sensory neuropathy. The workup of peripheral neuropathy is important to evaluate and rule out other etiologies of neuropathy.

Treatment / Management

There is no specific treatment or antidote for pyridoxine toxicity. Treatment involves cessation of supplemental pyridoxine promptly following diagnosis, symptomatic management, and supportive care for any continued or irreversible symptoms. This could include physical therapy when appropriate.

Also, the recommended daily allowance for different age groups should be kept in mind while prescribing B-6:

• 0.5 to 1 mg in children
• 1.3 mg daily for young adults
• 1.7 mg daily for men older than 50 years
• 0.5 mg daily for women older than 50 years

Differential Diagnosis

The differential diagnosis of vitamin B6 toxicity is broad and includes deficiency or toxicity of other vitamins, including vitamin B12 as the symptoms are similar. Other causes of peripheral neuropathy merit consideration include diabetes mellitus, autoimmune disorders (lupus), chronic liver disease, end-stage liver disease, HIV/AIDS, hypothyroidism, Lyme disease, lymphoma, monoclonal gammopathy, syphilis, porphyria, drugs (amiodarone, digoxin, lithium, isoniazid), and toxins (heavy metals, ethanol, organophosphates). Exposure history and the temporal course will help differentiate many of these etiologies.  Additional laboratory testing and nerve conduction velocity studies may also be helpful.

• Diabetes mellitus
• Autoimmune disorders (lupus)
• Chronic liver disease
• HIV/AIDS
• Hypothyroidism
• Lyme disease
• Lymphoma
• Monoclonal gammopathy
• Syphilis
• Porphyria
• Drugs
• Toxins, including other vitamins

Prognosis

Prognosis is usually favorable, with symptoms resolving or decreasing when supratherapeutic pyridoxine has been discovered and stopped. Neuropathy from massive exposures can cause long-term disability or death. Neurologic dysfunction improves following discontinuation of vitamin B supplementation and usually resolves within six months. Some patients do not recover.

Complications

Patients typically experience symptoms of peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea with long-term intake of dosages above 250 mg/day. Additional morbidity would include ataxia and dysesthesias.

Deterrence and Patient Education

Patients should receive education regarding vitamins and minerals derived from their daily diet. Counseling should be provided to patients interested in supplementing pyridoxine and discussing risk with higher-end dosing. Medical professionals employing pyridoxine as therapy will typically use smaller doses.

Pearls and Other Issues

• Vitamin B6 is used to treat multiple medical conditions and is available as a supplement over the counter.
• Vitamin B6 toxicity symptoms mimic vitamin B6 deficiency.
• The classic presentation of pyridoxine toxicity is peripheral sensory neuropathy.
• It is helpful to obtain a thorough history and ask about supplements and dosages.
• Vitamin B6 toxicity is seen with vitamin supplements but not from dietary intake of foodstuffs.
• Symptoms generally improve after discontinuing supplementation.

Enhancing Healthcare Team Outcomes

Healthcare is a team enterprise consisting of multiple medical professions, and various interactions within this process influence patient care and outcomes. The most crucial factor for pyridoxine toxicity is to recognize peripheral neuropathy as a critical feature. This will trigger a comprehensive interview to get additional information on past medical history, medications, supplements, and occupational and environmental exposure history.  Allied health professionals can assist in patient care outcomes by completing the medical history and current medications and supplements. Obtaining a detailed vitamin supplement history, including drug names, dosages, and length of time a patient has been taking medication, can be key aspects in identifying vitamin B6 toxicity.