Pyridoxine Deficiency

After absorption, pyridoxine, pyridoxamine, and pyridoxal are transported into hepatic cells by facilitated diffusion. Pyridoxal kinase phosphorylates pyridoxine and pyridoxamine, after which they are converted to pyridoxal 5'-phosphate (PLP) by a flavin-dependent enzyme. PLP either remains in the hepatocyte, where it is bound to an apoenzyme, or it is released into the serum, where it is tightly bound to albumin. Free pyridoxal is degraded by alkaline phosphatase, hepatic and renal aldehyde oxidases, and pyridoxal dehydrogenase.

Pyridoxine 5'-phosphate is an essential cofactor in various transamination, decarboxylation, and synthesis pathways involving carbohydrates, sphingolipids, sulfur-containing amino acids, heme, and neurotransmitters. PLP is a coenzyme of tryptophan, methionine, and gamma aminobutyric acid (GABA) metabolism. With methionine deficiency, S -adenosylmethionine accumulates, resulting in the inhibition of sphingolipid and myelin synthesis. Tryptophan is a precursor to several neurotransmitters and is required for niacin production. Thus, pyridoxine deficiency can cause a syndrome indistinguishable from pellagra. PLP is a cofactor for glutamic acid decarboxylase, the enzyme that produces GABA, such that PLP deficiency results in insufficient GABA. Since GABA is the major inhibitor cortical neurotransmitter, PLP deficiency can lead to seizures. Interestingly, pyridoxine-dependent seizures are not caused by a pyridoxine deficiency per se but rather due to an increased depletion of PLP.

The neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, glycine, glutamate, and GABA also require PLP for their production. Homocystine metabolism is dependent on pyridoxine, and high homocystine levels can result from pyridoxine deficiency.

Causes of pyridoxine deficiency may include the following:

• Pyridoxine intake is reduced in cases of severe malnutrition.

• Pyridoxine absorption is reduced in elderly persons and in patients with intestinal disease or who have undergone surgery.

• Pyridoxine clearance is enhanced by liver disorders, such as hepatitis, and by several medications.

• Pyridoxine breakdown is enhanced in conditions associated with increased alkaline phosphatase levels.

• Hematologic pathway enzymes with a low affinity for pyridoxine cause a microcytic-hypochromic pyridoxine-responsive anemia (ie, sideroblastic anemia). An X-linked inherited condition is observed in carrier females and affected males. An autosomal form of this disorder has been reported in a single family. Long-term alcohol ingestion and iatrogenically induced deficiencies can also result in this type of anemia. ^[6]

• Hydrazones from isoniazid and certain mushrooms bind PLP to form isoniazid-hydrazone complexes, resulting in decreased pyridoxal availability for use in other reactions.

• Pyridoxine-dependent seizures are caused by pyridoxine complexing with an excessive amount of Δ¹ –piperideine 6-carboxylate, resulting in a pyridoxine deficiency. Excessive Δ¹ –piperideine 6-carboxylate results from a deficiency in the enzyme α-aminoadipic semialdehyde dehydrogenase due to a mutation in the ALDH7A1 (antiquitin) gene. ^[7]  Consensus guidelines have been issued for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency. ^[8]

• Low maternal pyridoxine levels can cause pyridoxine-responsive seizures. ^[9]

• Excessive maternal pyridoxine supplementation can induce pyridoxine turnover, resulting in a higher requirement. Pyridoxine-responsive seizures may result.

• Endogenous or exogenous estrogens can alter tryptophan metabolism by directly inhibiting kynureninase, a proximal, potentially rate-limiting enzyme in tryptophan metabolism. A pyridoxine-dependent compound, kynureninase is the same enzyme that is inhibited in the pyridoxine-deficient state. Altered tryptophan metabolism resulting from high estrogen levels may be attributed to a pyridoxine deficiency if the former is not considered.

United States statistics

Idiopathic pyridoxine deficiency is very rare. Acquired deficiency is associated with inflammatory disorders and with concurrent use of several medications. ^{[10, 11]} Inherited pyridoxine-dependent seizure is a rare autosomal-recessive condition. ^{[12, 13, 14, 9]} Pyridoxine-responsive sideroblastic anemia is also rare. ^[15]

International statistics

Malnutrition or a diet limited to unenriched grains increases the risk for developing pyridoxine deficiency.

Race- and age-related demographics

Chinese women of childbearing age have an increased risk of developing pyridoxine deficiency.

Although pyridoxine deficiency can develop in persons of any age, elderly persons are at increased risk. ^{[15, 16]}

Pyridoxine-dependent seizures occur almost exclusively in children younger than 3 months, usually presenting in the newborn period. ^{[12, 13, 14]}

Hereditary sideroblastic anemia usually manifests within the first few years of life.

Complications

Care should be taken when supplementing pyridoxine, because high pyridoxine states can cause a neuropathy characterized by ataxia and burning pain in the feet, beginning approximately 1 month to 3 years following supplementation. Although this usually occurs at very high supplementation doses, complications have been reported with doses as low as 50 mg/d. 

Care should also be taken when prescribing pyridoxine supplementation to postpartum women who are breastfeeding, because high doses of pyridoxine can cause hypolacticemia.

A cohort study of postmenopausal women found that a high intake of pyridoxine, coupled with a high intake of vitamin B12, is linked to an increased risk of hip fracture. Compared with women who consumed less than 2 mg/d of total pyridoxine, those whose intake was 35 mg/d or higher had an elevated fracture risk. ^[17]

Injecting pyridoxine into an infant or neonate can cause a precipitous decrease in blood pressure.

Pyridoxine has the highest adverse outcome per toxic exposure for any vitamin, although no deaths have been reported.