Continuing Education Activity

Water-soluble vitamin B6 is widely present in many foods, including meat, fish, nuts, beans, grains, fruits and vegetables. As a coenzyme, vitamin B6 is involved as a cofactor in over 100 enzymatic reactions including amino acid metabolism, carbohydrate metabolism, and lipid metabolism. It contributes to cognitive development via neurotransmitter synthesis, immune function via interleukin-2 production, and hemoglobin formation. Vitamin B6 deficiency may present with seizures, mental status changes, normocytic anemia, a nonspecific pruritic rash, cheilitis, glossitis, and depression. This activity reviews the evaluation, and treatment of vitamin B6 deficiency and explains the role of the interprofessional team in managing the patients affected by the vitamin B6 deficiency.

Objectives:

• Explain the the risk factors for developing a vitamin B6 deficiency.
• Describe the pathophysiology of vitamin B6 deficiency.
• Outline the typical presentation of a patient with vitamin B6 deficiency.
• Explain the importance of coordination among interprofessional team members to improve outcomes for patients affected by vitamin B6 deficiency.

Introduction

Vitamin B6 is one of the central molecules in the cells of living organisms. Water-soluble vitamin B6 is widely present in many foods, including meat, fish, nuts, beans, grains, fruits, and vegetables. Additionally, B6 is present in many multivitamin preparations for adults and children and is added to foods as a supplement to foods, power bars, and powders.

There are several active compounds or vitamers which fall under the generic B6. These include pyridoxine alcohol, pyridoxal an aldehyde, pyridoxamine, which differs from the first two with an amine group, and a 2,5' phosphate esters. The major esters are the active coenzyme form and are pyridoxal 5'phosphate (PLP) and pyridoxamine 5'phosphate (PMP). The primary form of B6 in meats are the esters, and the dominant plant source is pyridoxine, which is less bioavailable. Pyridoxine is the most common form found in multivitamins. 

As a coenzyme, B6 is involved as a co-factor in over 100 enzymatic reactions, including carbohydrate metabolism, amino acid metabolism, particularly homocysteine, gluconeogenesis, glycogenolysis, and lipid metabolism. Vitamin B6 is also involved in the critical functioning of cells. It plays a significant role in transamination, decarboxylation, initial steps of porphyrin synthesis.[1] Pyridoxine has a role in cognitive development through neurotransmitter synthesis, immune function with interleukin-2 (IL-2) production, and hemoglobin formation.

Fetal brain development requires adequate B6, and this continues throughout infancy. Vitamin B6 recommendations are made in accordance with age and life stage with pregnancy and breastfeeding, involving the highest recommended daily allowance.[2][3][4][5]

Etiology

In the United States and other western cultures, the deficiency is rare with adequate diets, including B6 sources from fish, organ meats, poultry, potatoes, grains, legumes, and non-citrus fruits.

Isolated B6 deficiency is rare and usually found in association with other B vitamin deficiencies such as folic acid and B12. 

Low plasma levels of active B6 are found in chronic alcohol dependence, with obese states, protein-energy malnutrition. Pregnancy, preeclampsia and eclampsia, and malabsorptive states such as celiac, inflammatory bowel disease, and bariatric surgery.

Additional at-risk groups with inadequate intake or increased metabolic requirements may become functionally deficient in B6. Included in this group are those with renal impairment, autoimmune disorders, and chronic alcohol use. Patients with chronic renal failure, especially those receiving hemodialysis or peritoneal dialysis, have low plasma levels of B6. Autoimmune diseases, such as rheumatoid arthritis, have increased catabolism of B6, resulting in higher demand for dietary supplementation of B6.

The patients with impaired renal function, patients on dialysis, and the patient who have undergone renal transplants are more at risk of Vitamin B6 deficiency. The pathophysiology behind this is low serum PLP concentrations in such patients. They exhibit similar signs and symptoms of B6 deficiency as compared to other individuals and usually respond well to oral or parenteral B6 therapy.[6][7]

Of great clinical importance in toxicology is that drug antagonists to vitamin B6 occurs with the tuberculosis medicine isoniazid. Also, penicillamine and levodopa, as well as some anticonvulsant medications, may interfere with B6 metabolism.[8][9][10][11]

Epidemiology

Risk factors for altered B6 may include excessive or inadequate ingestion. Specifics causes of B6 deficiency have been attributed to insufficient gastrointestinal (GI) absorption, hepatic dysfunction, protein-energy malnutrition, and drug interaction or antagonism.[5]

The human body cannot store B6, and thus a daily source is required. There appears to be a bioavailability preference for meat over plant source B6. This may be important to those who favor a plant-based diet exclusively. These individuals may need added supplementation. The major supplement in multivitamins is pyridoxine hydrochloride. Dietary intake and the bioavailability of ingested B6 may vary, as well as the urinary excretion.

RDA or recommended dietary allowance for  B6 in adults is 1 mg to 1.7 mg per day. Children ages 1 to 3 are recommended to have 0.5 mg per day, and those 3 to 13 are recommended to have 1 mg per day. During pregnancy and lactation, the recommendations are 1.9 mg and 2 mg per day.

The average diet for adults is estimated to include 6 mg to 10 mg of Pyridoxine vitamers. Excessive amounts exceed 250 mg per day and, on a chronic basis, may result in toxicity leading to untoward effects on the skin, GI, and the neurologic system.

Pathophysiology

Vitamin B6 is predominantly absorbed in the small intestine jejunum and is metabolized at the cellular level in the mitochondria and cytosol to active forms in the liver. The phosphorylated form of the vitamin is converted in dephosphorylated form and the pool of free vitamin B6 in jejunum by passive diffusion.[12] Excretion of excess B6 occurs in the kidney and is albumin-bound in plasma. The half-life elimination exceeds 15 to 20 days.

Vitamin B6 deficiency may present with seizures in the young. Severely deficient adults commonly present with rashes and mental status changes. Additional clinical findings of deficiency may include normocytic anemia, a nonspecific pruritic rash, cheilitis with scaly lip skin and cracks in the corner of the mouth, and glossitis (swelling of the tongue). Depression is associated with a severe B6 deficiency as well.

Current studies are evaluating the role of B6 deficiency in heart disease, cancer, and cognitive decline as medical conditions that may respond to supplementation. To date, there is no clear evidence to support supplement use beyond the normal dietary intake. However, some studies indicate a reduction of symptoms in the premenstrual syndrome with supplementation of B6, particularly a decrease in moodiness, irritability, and forgetfulness. The American College of Obstetrics and Gynecology recommend vitamin B6 supplementation (1.9 mg per day) for hyperemesis gravidarum.[13]

Toxicokinetics

Vitamin B6 is water-soluble. B6 is one of three water-soluble vitamins that can have toxicity at excessive doses, the others being Niacin (Vitamin B2) and Ascorbic acid (Vitamin C).

It is rare to develop B6 toxicity for an individual on ordinary food diets without supplementation. Excessive supplementation for chronic periods (months to greater than a year) has resulted in sensory neuropathies and movement disorders. Consumption of Vitamin B6 more than 100 mg/dl in adults is required to cause toxicity in an individual. The severity of symptoms is dose-dependent. Additional clinical findings of toxicity may include photosensitivity, GI symptoms such as nausea and heartburn, as well as painful dermatological eruptions. These symptoms resolve for the most part over time with the elimination of the B6 supplement. The B6 toxicity-induced sensory polyneuropathy causes decreased touch, temperature, and vibration sensation and resulted in poor coordination. Increased intakes from supplements may interact with the action of drugs, including levodopa, phenobarbital, and phenytoin.[14][15][14]

In toxicology, Vitamin B6 is clinically important in the treatment of Isoniazid (INH), ethylene glycol, and Gyromitrin (toxic mushroom) poisoning.  Additionally, it is used preventatively during isoniazid (INH) therapy of tuberculosis to prevent INH-induced polyneuropathy.

History and Physical

History should be targeted, and age focused. In the neonate with seizures, mothers with poor nutritional status may be suggestive of a vitamin B6 deficiency.  Also, consideration should be given to the inborn error of metabolism that is Vitamin B6-dependent.

Pyridoxine dependent seizures are a rare cause of seizures in neonates, and these seizures, unlike other seizures, are not responsive to the typical anti-epileptic drugs. But they respond significantly after pyridoxal phosphate administration. More than 100 cases of pyridoxine dependent seizures are documented worldwide, especially in neonates. The majority of these cases are due to genetic mutation in the pyridoxamine phosphate oxidase gene. Genetic causes should be kept in mind while treating seizures, which are refractory to conventional anti-epileptics.[16][17]

The older patient should be questioned on nutritional intake, supplement use, and medication history. Also critically important is eliciting a history of potential malabsorption syndromes, which have been strongly associated with Vitamin B6 deficiency, such as inflammatory bowel disease, celiac disease, or surgery of the small intestines including bariatric surgery. On a review of systems, the finding of weakness, mental status change, paresthesias, or other sensory or dermatological symptoms may suggest the diagnosis.

Physical exam findings may include confusion and skin lesions, particularly facial lesions such as stomatitis, glossitis, seborrheic dermatitis, and angular cheilitis. Objective physical findings may include peripheral neuropathies, skin photosensitivity, and movement disorders.

Evaluation

Early or subclinical vitamin B6 deficiency may have vague or fleeting symptoms; however, new-onset sensory polyneuropathy, altered mental status, dermatitis in adults, or seizures in infancy should raise clinical suspicion of a clinically significant B6 deficiency. Testing for vitamin B6 can be difficult in real-time in many clinical scenarios. Direct biomarkers B6 vitamers in serum, plasma, erythrocyte, and urine are used. Serum measurement of the active vitamin Pyridoxal 5′-phosphate (PLP) form is available in some clinical settings. However, the assay is not widely available or timely. A clinical alternative is an indirect measurement technique of vitamin B6, which includes measuring urinary excretion of xanthurenic acid (an amino acid catabolite of tryptophan) following a measured bolus of tryptophan. Increased levels of xanthurenic acid may indicate inadequate active B6 for the formation of the amino acid tryptophan.[18] Urinary excretion of xanthurenic acid is usually less than 65 mmol/day following a 2 g tryptophan load. Excretion of xanthurenic acid above this threshold suggests abnormal tryptophan metabolism due to vitamin B6 insufficiency.

Erythrocyte transaminase activity, with and without PLP added, has been used as a functional test of pyridoxine status and maybe a more accurate reflection of vitamin B6 status in critically ill patients.[19] Urinary 4-pyridoxic acid excretion greater than 3.0 mmol/day can be used as an indicator of adequate short-term vitamin B6 status (this is often reported as "urinary pyridoxic acid").

Treatment / Management

In vitamin B6-deficient states and illnesses, treatment dosage is variable and depends on the severity of symptoms. The vitamin is available therapeutically in both oral and parenteral formulations. Neonates with B6 deficiency seizures may require 10 to 100 mg intravenous (IV) for effective treatment of active seizures. Less serious or less acute presentations can be supplemented with doses ranging from 25 mg to 600 mg per day orally depending on symptom complex.

Importantly, Vitamin B6 therapy can be life-saving in refractory INH overdose-induced seizures. The dose is equal to the known amount of INH ingested or a maximum of 5 gms and is dosed 1 to 4 grams IV as the first dose, then 1 g IM or IV every 30 minutes.[4] In ethylene glycol overdose, vitamin B6 is recommended at 50 to 100 mg IV every 6 hours to facilitate shunting the metabolism of ethylene glycol to nontoxic pathways leading to glycine (nontoxic) instead of toxic pathways leading to toxic metabolites such as formate.

Additional, less common uses are in hydralazine overdose, where the recommended dose of vitamin B6 is 25 mg/kg, the first third administered intramuscularly, and the remainder as a 3-hour IV infusion. Gyromitra (mushroom) toxicity treatment is at 25 mg/kg infused IV over 30 min.

Hyperemesis gravidarum may respond to vitamin B6 at a dosage of 25 mg orally every 8 hours.

Differential Diagnosis

The differential is wide due to the multitude of symptoms and clinical findings associated with B6 deficiency. Some specific disease states with similar symptoms include porphyria, beriberi (thiamine deficiency), normocytic anemias, depression, and the various disorders associated with cognitive decline, folic acid deficiency, INH toxicity, and neonatal seizures.

Prognosis

If diagnosed appropriately, the deficiency is effectively treated with adequate oral or parenteral supplementation.

Deterrence and Patient Education

Patients with impaired renal function, alcohol use disorder, malabsorption, and geriatric patients are more at risk of developing Vitamin B6 deficiency. They should be encouraged to take vitamins appropriate for their age and condition. Young patients undergoing bariatric surgery are at risk of developing B6 deficiency and should be educated about their conditions and risk of future complications.

In the United States and other developed countries, the risk of developing Vitamin B6 is unlikely unless they have chronic conditions. Meanwhile, in less developed countries, patients should be screened for Vitamin B6 deficiency if they present with dermatologic signs or polyneuropathy. 

Especially patients on Isoniazid (INH) therapy should be educated about the medications' side effects and the importance of B6 supplementation. Such patients should be screened for deficiency if they present with symptoms, mainly after six months of therapy.

Pearls and Other Issues

Pyridoxine is the emergency antidote for isoniazid (INH) overdose, ethylene glycol, hydralazine, and gyromitrin mushroom poisoning.  The two most common uses of vitamin B6 are in the treatment of toxicological emergencies: INH and ethylene glycol overdoses. In INH overdose-related seizure, the dose is 5 grams in adults and 1 gram in children unless the amount of INH is specifically known. Pyridoxine can be given at a rate of 0.5 to 1 gram/minute until seizures stop or maximum dose given. Patients who are asymptomatic and have not had seizures after potentially toxic ingestion of isoniazid within 2 hours should receive the recommended dose of pyridoxine. In ethylene glycol overdose, vitamin B6 is recommended at 50 to 100 mg IV every 6 hours to facilitate shunting the metabolism of ethylene glycol to nontoxic pathways leading to glycine (nontoxic) instead of toxic pathways leading to toxic metabolites such as formate.

Enhancing Healthcare Team Outcomes

Healthcare workers should encourage healthy nutrition in all their patients. However, some groups may be at risk for B6 deficiency. These include patients with renal impairment, autoimmune disorders, and chronic alcohol use. Patients with chronic renal failure, especially those receiving hemodialysis or peritoneal dialysis, have low plasma levels of B6. Autoimmune disorders, such as rheumatoid arthritis, have increased catabolism of B6, resulting in higher demand for dietary supplementation of B6. 

Besides, emergency department physicians should be aware that pyridoxine is the emergency antidote for isoniazid (INH) overdose, ethylene glycol, hydralazine, and gyromitrin mushroom poisoning.  The two most common uses of vitamin B6 are in the treatment of toxicological emergencies: INH and ethylene glycol overdoses.

Of great clinical importance in toxicology is that drug antagonists to vitamin B6 occurs with the tuberculosis medicine isoniazid. Also, penicillamine and levodopa, as well as some anticonvulsant medications, may interfere with B6 metabolism.

The outcomes for patients with B6 deficiency are good if supplementation is undertaken before severe deficits have developed. (Level V)