AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Pyridoxine 5'-phosphate is an essential cofactor in various transamination, decarboxylation, hydrolysis of glycogen, and synthesis pathways involving carbohydrate, sphingolipid, amino acid, heme, and neurotransmitter metabolism. Pyridoxine deficiency causes blood, skin, and nerve changes. This vitamin is unique in that both deficiency and excess can cause peripheral neuropathy.

Pathophysiology

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 both tryptophan and methionine metabolism. With methionine deficiency, S-adenosylmethionine accumulates, resulting in inhibition of both 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. The neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, glycine, glutamate, and gamma aminobutyric acid (GABA) also require PLP for their production. Homocystine metabolism is dependent on pyridoxine, and high homocystine levels can result from pyridoxine deficiency.

Frequency

United States

Idiopathic pyridoxine deficiency is very rare. Acquired deficiency is associated with inflammatory disorders and with concurrent use of several medications. Inherited pyridoxine-dependent seizure is a rare autosomal recessive condition. Pyridoxine-responsive sideroblastic anemia is also rare.

International

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

Race

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

Age

• Although pyridoxine deficiency can develop in persons of any age, elderly persons are at increased risk.
• Pyridoxine-dependent seizures occur almost exclusively in children younger than 3 months, but they usually present in the newborn period.
• Hereditary sideroblastic anemia usually manifests within the first few years of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Conditions that increase risk for pyridoxine deficiency
• 
  
  • Advanced age
  
  
  
  • Medical conditions
  • 
    
    • Severe malnutrition
    
    
    
    • Sickle cell disease
    
    
    
    • Inflammatory conditions
    
    
    
    • Rheumatoid arthritis
    
    
    
    • Hospitalization
    
    
    
    • Celiac disease
    
    
    
    • Hepatitis and extrahepatic biliary obstruction
    
    
    
    • Hepatocellular carcinoma
    
    
    
    • Chronic renal failure
    
    
    
    • Kidney transplant
    
    
    
    • Hyperoxaluria types I and II
    
    
    
    • High serum alkaline phosphatase level, such as in cirrhosis and tissue injury
    
    
    
    • Catabolic state
       
  • Medical procedures
  • 
    
    • Hemodialysis
    
    
    
    • Peritoneal dialysis
    
    
    
    • Phototherapy for hyperbilirubinemia
       
  • Medications
  • 
    
    • Cycloserine
    
    
    
    • Hydralazine
    
    
    
    • Isoniazid
    
    
    
    • D-penicillamine
    
    
    
    • Pyrazinamide
       
  • Social-behavioral conditions
  • 
    
    • Excessive alcohol ingestion (except for pyridoxine-supplemented beer)
    
    
    
    • Tobacco smoking
    
    
    
    • Severe malnutrition
       
  • Other risk factors
  • 
    
    • Poisoning, such as Gyromitra mushroom poisoning
    
    
    
    • Perinatal factors, such as a pyridoxine-deficient mother
    
    
    
    • Inherited conditions, such as pyridoxine-dependent neonatal seizures
       
• Other patient history
• • 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
• • General
  • • Weakness
    
    
    
    • Dizziness
    
    
    
    • Inflammation
       
  • Cardiovascular
  • • Atherosclerosis
    
    
    
    • Early myocardial infarction
    
    
    
    • Early stroke
    
    
    
    • Recurrent venous thromboembolism
       
  • Hematologic, such as anemia causing fatigue
  
  
  
  • Peripheral nervous system
  • • Bilateral distal limb numbness appears early.
    
    
    
    • Bilateral distal limb burning paresthesia replaces the numbness later in the course.
    
    
    
    • Distal limb weakness is rare.
       

  • Central nervous system

    • Depression
    
    
    
    • Irritability
    
    
    
    • Confusion
    
    
    
    • Generalized seizures
    
    
    
    • White matter lesions
       

  • Gastrointestinal

    • Anorexia
    
    
    
    • Vomiting
       
• Symptoms and conditions associated with secondary niacin deficiency (ie, pellagra)
• • Skin
  • • Erythematous itching and burning
    
    
    
    • Blisters and vesicles
    
    
    
    • Hyperpigmentation and thickening
       
  • Central nervous system
  • • Depression
    
    
    
    • Anxiety
    
    
    
    • Irritability
    
    
    
    • Disorientation
    
    
    
    • Stupor
    
    
    
    • Coma
       
  • Gastrointestinal
  • • Anorexia
    
    
    
    • Nausea
    
    
    
    • Abdominal discomfort and pain
    
    
    
    • Glossitis
    
    
    
    • Diarrhea

Physical

• Oral
• • Glossitis

  • Cheilosis

• Dermatologic, such as seborrheic dermatitis
• 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

  • Central nervous system
    • Confusion

    • Dementia

    • Disorientation

    • Rigid tone

    • Primitive reflexes

Causes

• Intake is reduced in cases of severe malnutrition.
• Absorption is reduced in elderly persons and patients with intestinal disease or surgery.
• Pyridoxine clearance is enhanced by liver disorders, such as hepatitis, and several medications.
• Pyridoxine breakdown is enhanced in conditions associated with increased alkaline phosphatase levels.
• Hematological pathway enzymes with 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.
• Hydrazones from isoniazid and certain mushrooms bind PLP to form isoniazid-hydrazone complexes, which results in decreased pyridoxal availability for use in other reactions.
• CNS glutamic acid decarboxylase with a low affinity for pyridoxine results in pyridoxine-dependent seizures by causing low GABA and high glutamate levels.
• Low maternal pyridoxine levels can cause pyridoxine-responsive seizures.
• 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. Kynureninase is pyridoxine-dependent, making it the same enzyme inhibited in the pyridoxine-deficient state. Altered tryptophan metabolism as a consequence of high estrogen levels may be attributed to a pyridoxine deficiency if the former is not considered.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Homocystinuria
Homocystinemia
Isoniazid toxicity
Pellagra
Neonatal seizures

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serum PLP is the primary active pyridoxal form and is used as the primary index of whole-body pyridoxal levels.
• Levels of 4-pyridoxic acid can be measured in the urine. This compound is the major inactive metabolite of pyridoxine metabolism and is normally 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 effects the measured level.
• Erythrocyte aspartate aminotransferase (EAST) and 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, and these indexes decrease with age. Hemolytic anemia reduces the lifespan of erythrocytes.
• Conversion of tryptophan to niacin relies on pyridoxine-dependent enzymes. A tryptophan load of 50-100 mg/kg is administered. Urine excretion of tryptophan metabolites is measured. High excretion of kynurenine, kynurenic acid, and xanthurenic acid indicate 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.
• 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.

Other Tests

• 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Supplementation of pyridoxine hydrochloride in various medical conditions is 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

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 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.

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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Supplemental vitamins

Essential for normal DNA synthesis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Prophylactic administration of pyridoxine should be provided when 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.

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

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Monitor patients for signs of toxicity when administering pyridoxine supplements.

Special Concerns

• Other rare medical conditions, such as cystathionase deficiency, can be treated with large doses of pyridoxine but are not due to a deficiency in pyridoxine.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Balasa VV, Kalinyak KA, Bean JA, Stroop D, Gruppo RA. Hyperhomocysteinemia is associated with low plasma pyridoxine levels in children with sickle cell disease. J Pediatr Hematol Oncol. Jun-Jul 2002;24(5):374-9. [Medline].
• Bender DA. Vitamin B6 requirements and recommendations. Eur J Clin Nutr. May 1989;43(5):289-309. [Medline].
• Beutler E, Lichtman MA, Coller BS, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001.
• Chiang EP, Smith DE, Selhub J, Dallal G, Wang YC, Roubenoff R. Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Res Ther. 2005;7(6):R1254-62. [Medline].
• Goetz CG. Vitamin Deficiencies. In: Goetz CG, Pappert EJ, eds. Textbook of Clinical Neurology. 1st ed. Philadelphia, Pa: WB Saunders; 1999.
• Kelly PJ, Kistler JP, Shih VE, et al. Inflammation, homocysteine, and vitamin B6 status after ischemic stroke. Stroke. Jan 2004;35(1):12-5. [Medline].
• Scriver CR, Gibson KM. Disorders of Beta- and Gamma-Amino Acids in Free and Peptide-Linked Forms. In: Scriver CR, Beaudet A, Sly W, Valle W, eds. The Metabolic Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:. 1349-68.
• Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. 40th ed. New York, NY: McGraw-Hill; 2001.

Article Last Updated: Jul 11, 2006