Continuing Education Activity

Water-soluble vitamin B6 is present in many foods, including meat, fish, nuts, beans, grains, fruits, and vegetables. As a coenzyme, vitamin B6 is a cofactor in over 100 enzymatic reactions. It contributes to neurotransmitter synthesis, interleukin-2 production, and hemoglobin formation. Vitamin B6 deficiency may present with seizures, mental status changes, anemia, rashes, and glossitis. This activity reviews the diagnosis, evaluation, and treatment of vitamin B6 deficiency and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the risk factors for developing vitamin B6 deficiency.
• Describe the pathophysiology of vitamin B6 deficiency.
• Describe signs and symptoms of vitamin B6 deficiency.
• Explain the importance of coordination among interprofessional team members to improve outcomes for patients with vitamin B6 deficiency.

Introduction

Vitamin B6 is a central molecule in the cells of living organisms. It is a water-soluble vitamin in many foods, including meat, fish, nuts, beans, grains, fruits, and vegetables.[1] Vitamin B6 is also an ingredient in multivitamin preparations for adults and children and is added to processed foods and nutritional powders as a supplement.

Six naturally occurring active compounds of vitamin B6, known as vitamers, exist in mammals. The most common are pyridoxine, pyridoxal, and pyridoxamine. Chemically, the latter differs from the first two by an amine group and a 2,5' phosphate ester. The two most significant esters are the active coenzyme forms, pyridoxal 5'phosphate (PLP) and pyridoxamine 5'phosphate (PMP). The primary forms of vitamin B6 in meats are esters, and the dominant plant source is pyridoxine, which is less bioavailable. Pyridoxine is the usual vitamer in multivitamin supplements. 

As a coenzyme, vitamin B6 is a co-factor in over 100 enzymatic reactions, including carbohydrate, amino acid, and lipid metabolism. It plays a role in gluconeogenesis and glycogenolysis. Vitamin B6 is critical in transamination and decarboxylation, the initial steps of porphyrin synthesis.[2] Pyridoxine influences cognitive development due to its involvement in neurotransmitter synthesis and immune function because of its role in interleukin-2 (IL-2) production. It is also essential in hemoglobin synthesis.

Fetal brain development requires adequate vitamin B6, and this continues throughout infancy. The recommended daily allowance (RDA) of vitamin B6 varies with age and life stage, with pregnant and breastfeeding women requiring higher amounts than others. [3][4][5][6]

Etiology

A varied, adequate diet will prevent vitamin B6 deficiency. Fish, organ meats, poultry, potatoes, grains, fortified cereals, soy products, legumes, and non-citrus fruits all are good sources of vitamin B6. 

Vitamin B6 deficiency is often associated with other vitamin B deficiencies, such as folic acid and vitamin B12. Low plasma levels of active vitamin B6 are found in individuals with chronic alcohol dependence, obesity, and protein-energy malnutrition. Pregnancy, preeclampsia and eclampsia, malabsorptive states such as celiac disease, inflammatory bowel disease, and bariatric surgery predispose to vitamin B12 deficiency.

Other at-risk groups with inadequate intake or increased metabolic requirements may become deficient in vitamin B6, including individuals with renal impairment and autoimmune disorders. Chronic renal failure patients, especially those on hemodialysis or peritoneal dialysis, often have low serum PLP concentrations and may exhibit signs and symptoms of vitamin B6 deficiency. Patients with autoimmune diseases such as rheumatoid arthritis have increased catabolism of vitamin B6. Both conditions require a higher recommended daily allowance (RDA) of vitamin B6.[7][8]

Drug interactions can result in vitamin B6 deficiency. In patients with tuberculosis, isoniazid (INH) competitively inhibits the action of pyridoxine, and routine supplementation is recommended.[9][10] Penicillamine and levodopa may also interfere with B6 metabolism. Some anticonvulsants, including valproic acid, carbamazepine, and phenytoin, can increase the catabolism of vitamin B6 and lead to a deficiency.[11][12][13][14][15][16] [National Institute of Health Vitamin B6 Health Professional Fact Sheet 2022]

Epidemiology

The Centers For Disease Control (CDC) have estimated that 10% of Americans may be deficient in vitamin B6, making it one of the most common nutrition deficiencies.[9] Overt symptomatic deficiency occurs less frequently than marginal deficiency. 

Risk factors for deficient vitamin B6 levels include inadequate intake, insufficient gastrointestinal (GI) absorption, hepatic and renal dysfunction, protein-energy malnutrition, and drug interactions.[6] Populations at risk for low dietary intake include those experiencing food insecurity or living in resource-limited countries. 

The human body cannot store water-soluble vitamin B6, and thus a daily intake is required. There appears to be a bioavailability preference for meat over plant sources. This may be clinically significant for adults and children consuming an exclusively plant-based diet who may benefit from supplementation. The usual vitamin B6 vitamer in multivitamin supplements is pyridoxine hydrochloride.

Pathophysiology

Vitamin B6 is primarily absorbed in the jejunum and is metabolized at the cellular level by the liver mitochondria and cytosol to the active form, pyridoxal 5'-phosphate (PLP). This phosphorylated form of the vitamin is converted to 4-pyridoxic acid and excreted by the kidneys.[17] 

Marginal vitamin B6 deficiency causes oral stomatitis, glossitis, and cheilosis. Irritability, confusion, and depression may also occur. Severely deficient adults may present with seborrheic dermatitis, microcytic anemia, and seizures.[18] Neonates and infants with an inborn error of pyridoxine metabolism may exhibit severe, refractory seizures that respond to pyridoxine administration. These are caused by a rare, autosomal recessive condition and usually resolve after administering pyridoxine or pyridoxal-5'-phosphate. There have also been sporadic reports of pyridoxine-dependent seizures in infants whose breast-feeding mothers suffer from malnutrition and vitamin B6 deficiency. [Neurology in Clinical Practice, 2022, "Deficiency Diseases of the Nervous System"]

In pregnant women, vitamin B6 deficiency has been linked with an increased risk of preterm birth and early pregnancy loss. Because many pregnancies are unplanned, all women of childbearing age should consume adequate amounts of vitamin B6 in their diets or with supplements.[19]

Ongoing trials study the possible role of vitamin B6 deficiency in cardiovascular disease, cancer, and cognitive decline. Vitamin B6 deficiency can lead to higher homocysteine levels, a known risk factor for the development of atherosclerotic cardiovascular disease. However, no clear evidence supports supplements for these conditions beyond the recommended dietary intake. Some studies demonstrate a reduction in premenstrual syndrome symptoms with supplementation of vitamin B6, including less moodiness, irritability, and forgetfulness. The American College of Obstetrics and Gynecology also recommends vitamin B6 treatment for hyperemesis gravidarum.[20][21] The mechanism of the therapeutic effect is unclear and not thought to be related to an underlying deficiency. 

Toxicokinetics

Vitamin B6 is one of three water-soluble vitamins that can be toxic at excessive doses, the others being niacin (vitamin B3) and ascorbic acid (vitamin C).

It is unusual to develop vitamin B6 toxicity through natural food sources alone. High-dose supplements taken for months or years can result in sensory neuropathies and movement disorders. Affected individuals may experience decreased touch, temperature, and vibratory sensation as well as poor coordination and can suffer serious injuries. Neuropathy may not be reversible despite discontinuing the vitamin B6. Supplements of 100 mg or less of vitamin B6 daily are considered safe. Most case reports of neuropathy occur at intakes over 250 mg daily and often as high as 1000 mg, about 800 times the typical daily dietary intake.[22]

The severity of symptoms is usually dose-dependent. In addition to neuropathy, clinical findings of toxicity include photosensitivity, GI symptoms such as nausea and heartburn, and painful skin eruptions. These non-neurologic symptoms typically resolve after discontinuation of the vitamin. High-dose supplements may also interact with the action of medications, including levodopa, phenobarbital, and phenytoin.[23][24][23]

History and Physical

The medical history should be targeted and age-focused. When a neonate presents with seizures, the mother's nutritional status and the possibility of an inborn error in pyridoxine metabolism should be considered. Pyridoxine-dependent seizures, unlike other seizures, are not responsive to typical anticonvulsants. But they do usually respond rapidly to pyridoxal phosphate administration. Although extremely rare, this genetic condition is treatable and should always be considered when a neonate or young infant presents with seizures. [25][26]

After infancy, history should include presenting symptoms, a thorough review of systems, medications, supplements, dietary intake, prior medical diagnoses, and surgeries. Patients with borderline or mildly low vitamin B6 levels are often asymptomatic. Typical signs and symptoms of moderate deficiency, such as glossitis, stomatitis, cheilosis, mental status changes, and peripheral neuropathy, may occur in other medical conditions and are not unique to vitamin B6 deficiency. Severe deficiency can result in seborrheic dermatitis and anemia. The past medical history will reveal malabsorptive conditions possibly leading to vitamin B6 deficiency, such as inflammatory bowel disease, celiac disease, or intestinal surgery, including bariatric surgery. On review of systems, weakness, mental status changes, paresthesias, or dermatological symptoms may suggest the diagnosis.

A complete physical examination may reveal skin conditions, oral mucosal lesions, weakness, movement disorders, and evidence of peripheral neuropathy.

Evaluation

Early or subclinical vitamin B6 deficiency may have minimal or vague symptoms or none at all. New-onset sensory neuropathy, altered mental status, anemia, dermatitis in adults, or seizures in infancy should raise suspicion of a clinically significant deficiency. Direct biomarkers measure B6 vitamers in serum, plasma, erythrocyte, and urine. The plasma PLP concentration is most commonly used to assess vitamin B6 status.[27] It reflects liver concentration and is minimally influenced by dietary fluctuation. However, the assay is not always widely available, and results may be delayed. Greater than 30 nmol/l is considered sufficient, 20-30 nmol/l marginal, and less than 20 nm/l insufficient. 

An alternative is an indirect measurement technique of vitamin B6, which includes measuring the urinary excretion of xanthurenic acid (an amino acid catabolite of tryptophan) following a measured bolus of tryptophan. Increased levels may indicate inadequate active vitamin B6 needed to formulate the amino acid tryptophan.[28] Urinary excretion of xanthurenic acid is usually less than 65 mmol/day following a 2-gram tryptophan load. Excretion of xanthurenic acid above this threshold suggests abnormal tryptophan metabolism due to vitamin B6 insufficiency.

Erythrocyte transaminase activity is a functional test of pyridoxine status and can be a more accurate reflection of vitamin B6 status in critically ill patients.[29] Urinary 4-pyridoxic acid excretion, reported as "urinary pyridoxic acid," greater than 3.0 mmol/day can indicate adequate short-term vitamin B6 status. 

Treatment / Management

In vitamin B6-deficient states and illnesses, treatment dose varies with the patient's age and severity of symptoms. The vitamin is available in both oral and parenteral formulations. Neonates with suspected pyridoxine-dependent seizures should be given pyridoxine, 100 mg IV.[30] Infants diagnosed with pyridoxine-dependent seizures require lifelong treatment. A wide range of dosing has been recommended, from 5 to 20 mg/kg/day to 500 mg/day.[31]  

The recommended dietary allowance (RDA) of vitamin B6 is 0.5 to 1 mg/day in children and increases with age, up to 1.7 mg/day for men older than 50 and 1.5 mg/day for women older than 50. The RDA for pregnant women is 1.9 mg/day and 2 mg/day during lactation. [NIH Dietary Supplement Fact Sheet 2022 vitamin B6]. In patients with a deficiency, oral vitamin B6 from supplements and a varied, nutritious diet are adequate treatments. Healthy individuals eating whole grains, starchy vegetables, meats, fish, nuts, and egg yolks will likely obtain sufficient vitamin B6 from food sources. The average intake for adults consuming a healthy diet is estimated at 6 to 10 mg of vitamin B6 vitamers. Bioavailability is about 75% from most combined dietary sources. Cooking and food processing can reduce bioavailability by 10-50 percent.[18]

For hyperemesis gravidarum, pyridoxine, 25 mg administered three times daily, can relieve symptoms.[32] For premenstrual dysphoric disorder, a dose of pyridoxine between 50 and 100 mg often alleviates symptoms. Some studies have shown an increased effect when it is combined with calcium.[33][34]

Isoniazid (INH) can interfere with vitamin B6 metabolism and result in a deficiency. Patients receiving INH for the treatment of tuberculosis should be supplemented with vitamin B6. Dose recommendations range from 6 to 50 mg daily as prophylaxis to 100 to 200 mg if neurotoxicity and documented vitamin B6 deficiency develop, especially in patients with drug-resistant tuberculosis treated with higher doses of INH.[10]

Vitamin B6 therapy can be life-saving in refractory INH overdose-induced seizures. The dose equals the known amount of INH ingested, up to a maximum of 5 grams, and is administered 1 to 4 grams IV as the first dose, then 1 gram IM or IV every 30 minutes.[5]

Vitamin B6 is also indicated in less common emergencies. In ethylene glycol poisoning, 50 mg is an adjunct treatment that aids in converting glyoxylic acid into nontoxic glycine. [35] In cases of Gyromitra mushroom poisoning, pyridoxine is administered 25 mg/kg IV to prevent or control seizures. [36]

Differential Diagnosis

The differential diagnosis list is long due to the diverse symptoms and clinical findings associated with vitamin B6 deficiency. The typical oral lesions of cheilosis, stomatitis, and glossitis resemble those of disease states caused by low levels of other vitamins, such as thiamine and folic acid. In anemia, more common causes must also be considered, and multiple contributing conditions can be present. Psychiatric symptoms such as depression and cognitive change can have other organic or functional etiologies. A thorough medical history and physical examination will usually lead to the appropriate differential diagnosis for each patient.

Prognosis

Vitamin B6 deficiency can be effectively treated with adequate oral or parenteral pyridoxine and prevented by a varied diet or oral supplementation. Prognosis is excellent when vitamin B6 deficiency is suspected, diagnosed, and treated, especially in individuals with medical conditions requiring greater than the typical RDA.

Complications

There are no known adverse outcomes related to a high intake of vitamin B6 from natural foods. However, high-dose supplementation can cause irreversible peripheral and sensory neuropathy.

Deterrence and Patient Education

Individuals with impaired renal function, alcohol use disorder, malabsorption, and older age are at increased risk of developing vitamin B6 deficiency. They should be encouraged to take vitamins appropriate for their age and condition. Patients undergoing bariatric and metabolic surgery may become deficient due to malabsorption and should be monitored closely for increased vitamin B6 needs.

In the United States and other developed countries, the risk of overt vitamin B6 is unlikely in the absence of a poor diet or chronic medical conditions. Especially in resource-limited communities in all countries, patients should be evaluated for vitamin B6 deficiency if they present with signs or symptoms such as oral lesions, chronic rashes, or neuropathy. 

Patients on Isoniazid (INH) therapy should be educated about the need for prophylactic vitamin B6 supplementation. They should be screened for deficiency if they present with symptoms, especially after six months of therapy.

Pearls and Other Issues

A nutritious, varied diet can prevent vitamin B6 deficiency. However, suboptimal levels may be present without symptoms. Low vitamin B6 status has been associated with several chronic conditions, including cardiovascular disease and colorectal, breast, and ovarian cancers. However, there are no current recommendations for routinely ingesting more than the RDA to prevent such disease states. 

When patients present with nonspecific or vague symptoms, a high index of suspicion for vitamin B6 deficiency is warranted to avoid missing a treatable diagnosis. 

Neonatal pyridoxine-dependent seizures are extremely rare. Prompt pyridoxine administration can be life-saving, and treatment with supplements must be lifelong. 

Enhancing Healthcare Team Outcomes

Healthcare workers should encourage adequate nutrition in all their patients. However, some groups are at risk for vitamin B6 deficiency, including those with renal impairment, autoimmune disorders, and chronic alcohol use. Patients with chronic renal failure, especially those on hemodialysis or peritoneal dialysis, may have low plasma levels of vitamin B6. Autoimmune disorders, such as rheumatoid arthritis, lead to increased catabolism of vitamin B6, often resulting in a need for dietary supplementation.

Emergency department physicians and nurses should know that pyridoxine is an emergency antidote for isoniazid (INH) overdose and gyromitrin mushroom poisoning. 

INH, penicillamine, levodopa, and some anticonvulsants may interfere with B6 metabolism. Communication with pharmacists is essential to enhance patient care when prescribing these medications. 

The outcome for patients with B6 deficiency is excellent if supplementation or replacement is provided before severe deficits develop. All interprofessional team members should consider the importance of vitamin B6 deficiency and consider nutritional factors when assessing their patients.