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Pyridoxine Deficiency

Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University

Updated: Dec 8, 2008

Introduction

Background

Pyridoxine 5'-phosphate is an essential cofactor in various transamination, decarboxylation, glycogen hydrolysis, 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 either deficiency or excess can cause peripheral neuropathy.1,2,3,4,5

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 tryptophan and methionine 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. 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.6,7 Inherited pyridoxine-dependent seizure is a rare autosomal-recessive condition.8,9,10 Pyridoxine-responsive sideroblastic anemia is also rare.11

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.11,12
  • Pyridoxine-dependent seizures occur almost exclusively in children younger than 3 months, usually presenting in the newborn period.8,9,10
  • Hereditary sideroblastic anemia usually manifests within the first few years of life.

Clinical

History

  • Factors that increase the risk for pyridoxine deficiency11
    • Advanced age
    • Medical conditions
      • Severe malnutrition
      • Sickle cell disease
      • Inflammatory conditions6,7
      • Rheumatoid arthritis6
      • 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 seizures8,9,10
  • 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
      • Inflammation6,7
    • Cardiovascular
      • Atherosclerosis
      • Early myocardial infarction
      • Early stroke7
      • 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)
    • 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

  • 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

Causes

  • 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.
  • Hydrazones from isoniazid and certain mushrooms bind PLP to form isoniazid-hydrazone complexes, resulting 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.11
  • 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.

Differential Diagnoses

Anemia
Malabsorption
Beriberi (Thiamine Deficiency)
Neonatal Seizures
Depression
Pellagra
Diabetic Ketoacidosis
Porphyria, Acute Intermittent
Dissociative Disorders
Porphyria, Hereditary Coproporphyria
Folic Acid Deficiency
Toxicity, Isoniazid
Homocystinuria

Other Problems to Be Considered

Homocystinemia

Workup

Laboratory 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.13 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 effects 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.14
  • 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

Medical Care

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.

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

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

Supplemental vitamins

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.

Dosing

Adult

Variable depending on indication
Gyromitra poisoning: 25 mg/kg IV over 15-30 min, repeat prn (total dose 15-20 g/d)
Cirrhosis: 50 mg/d PO
Hemodialysis: 5-50 mg/d PO
Peritoneal dialysis or chronic renal failure: 2.5-5 mg/d PO
Sideroblastic anemia: 50-600 mg/d PO
Homocystinuria or homocystinemia: 100-500 mg/d PO
Pyridoxine-dependent seizures: 100 mg/d PO

Pediatric

Variable depending on indication
Pyridoxine-dependent seizures:
Neonates with seizures: 50-100 mg IV/IM as a single dose
Infants with pyridoxine-responsive seizures: 50-100 mg PO qd (with no other identifiable cause)
Children without neuritis: 5-25 mg PO qd for 3 wk, then 1.5-2.5 mg PO qd
Children with neuritis: 10-50 mg PO qd for 3 wk, then 1-2 mg PO qd
Not established for cirrhosis, hemodialysis, peritoneal dialysis, chronic renal failure, sideroblastic anemia, homocystinuria, homocystinemia, or Gyromitra poisoning

Interactions

May decrease levodopa, phenytoin, and phenobarbital serum levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

>200 mg/d may precipitate withdrawal effects when medication is discontinued

Follow-up

Deterrence/Prevention

  • 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.

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

Medicolegal 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, even though they are not due to a pyridoxine deficiency.

References

  1. Bender DA. Vitamin B6 requirements and recommendations. Eur J Clin Nutr. May 1989;43(5):289-309. [Medline].

  2. Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. 40th ed. New York, NY: McGraw-Hill; 2001.

  3. Goetz CG. Vitamin deficiencies. In: Goetz CG, Pappert EJ, eds. Textbook of Clinical Neurology. Philadelphia, Pa: WB Saunders; 1999.

  4. Scriver CR, Gibson KM. Disorders of beta- and gamma-amino acids in free and peptide-linked forms. In: Scriver CR, Beaudet A, Sly W, et al, eds. The Metabolic Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:1349-68.

  5. Beutler E, Lichtman MA, Coller BS, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001.

  6. Chiang EP, Smith DE, Selhub J, et al. Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Res Ther. 2005;7(6):R1254-62. [Medline]. [Full Text].

  7. 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]. [Full Text].

  8. Kaczorowska M, Kmiec T, Jakobs C, et al. Pyridoxine-dependent seizures caused by alpha amino adipic semialdehyde dehydrogenase deficiency: the first Polish case with confirmed biochemical and molecular pathology. J Child Neurol. Oct 14 2008;[Medline].

  9. Striano P, Battaglia S, Giordano L, et al. Two novel ALDH7A1 (antiquitin) splicing mutations associated with pyridoxine-dependent seizures. Epilepsia. Aug 19 2008;[Medline].

  10. Khayat M, Korman SH, Frankel P, et al. PNPO deficiency: an under diagnosed inborn error of pyridoxine metabolism. Mol Genet Metab. Aug 2008;94(4):431-4. [Medline].

  11. Morris MS, Picciano MF, Jacques PF, et al. Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004. Am J Clin Nutr. May 2008;87(5):1446-54. [Medline].

  12. Woolf K, Manore MM. Elevated plasma homocysteine and low vitamin B-6 status in nonsupplementing older women with rheumatoid arthritis. J Am Diet Assoc. Mar 2008;108(3):443-53; discussion 454. [Medline].

  13. Baggot PJ, Eliseo AJ, DeNicola NG, et al. Pyridoxine-related metabolite concentrations in normal and Down syndrome amniotic fluid. Fetal Diagn Ther. 2008;23(4):254-7. [Medline].

  14. Balasa VV, Kalinyak KA, Bean JA, et al. 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].

Keywords

pyridoxine deficiency, vitamin deficiency, vitamin B, vitamin B6, pyridoxine, vitamin B deficiency, pyridoxine 5'-phosphate, pyridoxal 5'-phosphate, PLP, vitamin B-6 deficiency, malnutrition, peripheral neuropathy, poor diet, pyridoxine-dependent seizures, hereditary sideroblastic anemia, cirrhosis, hemodialysis, peritoneal dialysis, chronic renal failure, homocystinuria, homocystinemia, Gyromitra poisoning, mushroom poisoning, fungus toxicity, mushroom toxicity

Contributor Information and Disclosures

Author

Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and International Neuropsychological Society
Disclosure: Nothing to disclose.

Coauthor(s)

Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University
Serge A Jabbour, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Thyroid Association, Endocrine Society, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Further Reading

Related eMedicine topic:
 Vitamin B-6 Dependency Syndromes

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