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.

Contributing factors

Several factors contribute to an increased risk for pyridoxine deficiency,[15] as follows:

• Advanced age

• Medical conditions that may increase the risk for pyridoxine deficiency include the following:

  • Severe malnutrition

  • Sickle cell disease

  • Inflammatory conditions[10, 11]

  • Rheumatoid arthritis[10]

  • Hospitalization

  • Celiac disease

  • Hepatitis and extrahepatic biliary obstruction

  • Hepatocellular carcinoma

  • Chronic renal failure

  • Kidney transplant[18]

  • Hyperoxaluria types I and II

  • High serum alkaline phosphatase level, such as in cirrhosis and tissue injury

  • Catabolic state

• Medical procedures that may increase the risk for pyridoxine deficiency include the following:

  • Hemodialysis

  • Peritoneal dialysis

  • Phototherapy for hyperbilirubinemia

• Medications that may increase the risk for pyridoxine deficiency include the following:

  • Cycloserine

  • Hydralazine

  • Isoniazid

  • D-penicillamine

  • Pyrazinamide

• Social-behavioral conditions that may increase the risk for pyridoxine deficiency include the following:

  • Excessive alcohol ingestion (except for pyridoxine-supplemented beer)

  • Tobacco smoking

  • Severe malnutrition

• Other risk factors that may increase the risk for pyridoxine deficiency include the following:

  • Poisoning, such as Gyromitra mushroom poisoning

  • Perinatal factors, such as a pyridoxine-deficient mother

  • Inherited conditions, such as pyridoxine-dependent neonatal seizures[12, 13, 14]

Other patient history

A patient's medical history may include the following:

• Sideroblastic anemia

• Pregnancy - Pregnancy can cause a pyridoxine-deficient state; however, a change in the ratio of plasma PLP to pyridoxal does occur, thereby falsely suggesting a deficiency state if only serum PLP is measured.

• Physical exercise - This may transiently increase plasma PLP levels.

Symptoms and conditions associated with low pyridoxine levels

Symptoms and conditions associated with low pyridoxine levels include the following:

• General

  • Weakness

  • Dizziness

  • Inflammation[10, 11]

• Cardiovascular

  • Atherosclerosis

  • Early myocardial infarction

  • Early stroke[11]

  • Recurrent venous thromboembolism

• Hematologic - Fatigue resulting from anemia is an example.

• Peripheral nervous system

  • Bilateral, distal limb numbness (appears early)

  • Bilateral, distal limb burning paresthesia (replaces numbness later in the course)

  • Distal limb weakness (rare)

• Central nervous system (CNS)

  • Depression

  • Irritability

  • Confusion

  • Generalized seizures

  • White matter lesions

• Gastrointestinal

  • Anorexia

  • Vomiting

Symptoms and conditions associated with secondary niacin deficiency (ie, pellagra)

Symptoms and conditions associated with secondary niacin deficiency (ie, pellagra) include the following:

• Skin

  • Erythematous itching and burning

  • Blisters and vesicles

  • Hyperpigmentation and thickening

• CNS

  • Depression

  • Anxiety

  • Irritability

  • Disorientation

  • Stupor

  • Coma

• Gastrointestinal

  • Anorexia

  • Nausea

  • Abdominal discomfort and pain

  • Glossitis

  • Diarrhea

Physical examination findings may include the following:

• Oral

  • Glossitis

  • Cheilosis

• Dermatologic - Seborrheic dermatitis is an example.

• Adult, neurologic

  • Distal limb numbness and weakness

  • Impaired vibration and proprioception

  • Preserved pain and temperature

  • Sensory ataxia

  • Generalized seizures

• Neonatal and young infant, neurologic

  • Hypotonia

  • Irritability

  • Restlessness

  • Focal, bilateral motor, or myoclonic seizures

  • Infantile spasms

• Secondary niacin deficiency

  • Skin - Dermatitis over sun-exposed areas; blisters and vesicles; beefy red, raw tongue

  • CNS - Confusion, dementia, disorientation, rigid tone, primitive reflexes

Serum pyridoxal 5'-phosphate (PLP) is the primary active pyridoxal form and is used as the primary index of whole-body pyridoxal levels.

Albumin level should be measured with serum PLP, as PLP levels are dependent on albumin levels so PLP levels can be falsely interpreted as low if the albumin level is not taken into account.[19]

Levels of 4-pyridoxic acid can be measured in the urine.[16] This compound is the major inactive metabolite of pyridoxine metabolism and its levels normally are 128-680 nmol per nmol of creatinine. Excretion of this compound reflects the pyridoxine body pool in the absence of an exogenous pyridoxine load. Urine levels of 4-pyridoxic acid are lower in females than in males and will be reduced in persons with riboflavin deficiency. Neither age nor alcohol intake affects the measured level.

Erythrocyte aspartate aminotransferase (EAST) and the EAST activation coefficient (EAST-AC) are long-term indicators of functional pyridoxine status due to the 120-day life span of erythrocytes. EAST-AC reduction lags behind the onset of the pyridoxine deficiency. Thus, a low EAST-AC value confirms a subacute to chronic deficiency state. Chronic alcoholism causes these indexes to be falsely low; in addition, these indexes decrease with age. Hemolytic anemia reduces the life span of erythrocytes.

Conversion of tryptophan to niacin relies on pyridoxine-dependent enzymes. A tryptophan load of 50-100 mg/kg is administered, and the urinary excretion of tryptophan metabolites is measured. High excretion of kynurenine, kynurenic acid, and xanthurenic acid indicates a functional deficiency in pyridoxine-dependent enzymes. This test is influenced by protein intake, exercise, lean body mass, and pregnancy. Hormonal factors and infections enhance tryptophan-to-niacin conversion. Thus, this test is most useful for monitoring an individual's response to pyridoxine supplementation rather than for diagnosing a deficiency.

If arteriosclerosis is present, the homocysteine level should be measured.[18]

Hematologic indexes may indicate the presence of a hypochromic-microcytic anemia with normal iron levels. Patients with inherited sideroblastic anemias have marked red blood cell dimorphism, anisocytosis, and poikilocytosis.

Elevation in urinary α-aminoadipic semialdehyde and serum or CSF pipecolic acid are nonspecific biomarkers for pyridoxine dependent seizures. Additionally, the ALDH7A1 gene can be sequenced.[7]

Electroencephalogram findings in neonates and infants with pyridoxine-dependent seizures are characterized by repetitive runs of high-voltage, generalized, bilateral, synchronous 1- to 4-Hz spikes and sharp wave bursts.

Normalizing electroencephalogram findings or causing clinical cessation of seizures by injecting 100 mg of intravenous pyridoxine identifies pyridoxine-dependent and pyridoxine-responsive seizures.

Levels of pyridoxine hydrochloride supplementation in various medical conditions are as follows:

• Cirrhosis - 50 mg/d

• Hemodialysis - 5-50 mg/d

• Peritoneal dialysis - 2.5-5 mg/d

• Chronic renal failure - 2.5-5 mg/d

• Sideroblastic anemia - 50-600 mg/d

• Pyridoxine-dependent seizures - 100 mg/d

• Homocystinuria - 100-500 mg/d

• Homocystinemia - 100-500 mg/d

• Gyromitra poisoning - 25 mg/kg IV

At one time, pyridoxine supplementation was given to people with sickle cell anemia; however, no changes were noted in these patients' hematologic indexes or disease activity.

Diet

Pyridoxine is widespread in foods. Rather robust quantities can be found in meats, particularly liver, fish, and chicken; vegetables, particularly beans, peas, and tomato; fruits, such as oranges, bananas, and avocados; and grains, such as enriched breads, cereals, and grains.

Some vegetables contain up to 70% biologically unavailable pyridoxine as pyridoxine-5-glucoside.

Some heat-treated foods may contain pyridoxine-lysine, which has antivitamin activity.

The minimum daily requirement of pyridoxine is approximately 1.5 mg; however, the recommended daily intake by the US National Research Council is 2 mg for adults and 0.3 mg for infants.

A lysine-restricted diet appears to be well tolerated and results in improved development and metabolic biomarkers in children with a mutation in the ALDH7A1 (antiquitin) gene and pyridoxine-dependent seizures.[20]

Activity

Vigorous exercise results in a transient increase in plasma PLP, probably from the release of muscular glycogen phosphate. Carbohydrate loading prior to exercise reduces this response. Within 30 minutes of discontinuing exercise, PLP levels return to normal.

Prophylactic administration of pyridoxine should be provided when a patient is using certain medications, such as isoniazid (30-450 mg/d, which may be based gram for gram) and penicillamine (100 mg/d).

Estrogen-induced reduction in tryptophan metabolism may require supplementation of 20-25 mg/d.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Class Summary

Essential for normal deoxyribonucleic acid (DNA) synthesis.

Pyridoxine, vitamin B-6 (Nestrex)

Necessary for normal metabolism of proteins, carbohydrates, and fats. Pyridoxine is also involved in the synthesis of GABA within the CNS.