Vitamin B6 Deficiency

Brown MJ, Ameer MA, Beier K.

Brown MJ, Ameer MA, Beier K. Vitamin B6 Deficiency. [Updated 2020 Oct 3]. In: StatPearls [Internet]. Treasure
Island (FL): StatPearls Publishing; 2020

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)

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