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Folic Acid and Safety Patrick J. Stover, PhD Cornell University. Biological effects of elevated folate intake (< 1 mg/day) There are no demonstrated toxicities or harmful effects resulting from folate intakes currently achieved by the US population, although

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Folic Acid and Safety

Patrick J. Stover, PhD

Cornell University


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  • Biological effects of elevated folate intake

  • (< 1 mg/day)

  • There are no demonstrated toxicities or harmful effects resulting from

  • folate intakes currently achieved by the US population, although

  • some may be achieving intakes > 1mg/day without supplement use.

  • - There are “essentially no data on safety”(Shane, B Am. J. Clin. Nutr. 2003.)

  • Unintended consequences to vulnerable populations is

  • the primary concern.

  • The mechanisms whereby impaired folate metabolism increases risk for NTDs

  • are not known, nor are the mechanisms whereby folate protects against NTDs.


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Folate and Pathology

Folate-Associated Pathologies

Metabolic Disruption

Biochemical Markers

Hypomethylated DNA

Elevated homocysteine

S-adenosylmethionine(vitamin deficiency; SNPs)

Thymidylate

(vitamin deficiency; SNPs)

Purines

- Cancer- CVD- Demyelination- NTDs

- Anemia

- Cognitive decline

Increased uracil in DNA

Decreased DNA synthesis

Decreased DNA synthesis & reduced cell division

Anemia


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  • Biological effects of increased folate intake.

  • The following concerns, new and old, have been raised in the literature:

  • Masking Vitamin B12 deficiency (pernicious anemia).

  • Impairment of Zn absorption (Hansen et al, 2001)

  • Decreasing the effectiveness of drug therapy (Quinlivan and Gregory, 2002).

  • -cancer

  • - anticonvulsants


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Masking Vitamin B12 deficiency

Megaloblastic Anemias – hypersegmented neutrophils

  • Results from vitamin B-12 deficiency

  • Impaired DNS synthesis

  • Diagnostic indicator of B-12 deficiency


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  • Causes of Vitamin B-12 deficiency (20% of elderly)

    • Abnormal gastric events (acid/enzymes)

    • Deficient intrinsic factor (parietal cell destruction)

    • Malabsorption syndromes

    • Diet

  • B-12 associated Neurological symptoms

  • - Posterolateral spinal cord degeneration

    • Paresthesias

    • Gait ataxia

    • Memory loss

  • Folic acid at elevated intakes (> 1mg/day) masks B-12 deficiency-

  • induced hematological abnormalities w/o rescuing irreversible

  • neurological symptoms.

  • Masking Vitamin B12 deficiency


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    • Biological effects of increased folate intake.

    • The following concerns, new and old, have been raised in the literature:

    • Masking Vitamin B12 deficiency(pernicious anemia).

    • Impairment of Zn absorption(Hansen et al, 2001)

    • Decreasing the effectiveness of drug therapy (Quinlivan and Gregory, 2002).

    • -cancer

    • -anticonvulsants


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    Impairment of Zn absorption

    • No long term study (human and animal) has indicated adverse effects of folic acid supplements on Zn balance(Butterworth and Tamura, Am. J. Clin. Nutr.50:353-8 1989)

    • Folic acid (.350-1 mg/day) has been shown to affect Zn excretion, absorption in some but not in other studies.

    • Fortification of white bread did not affect 65Zn absorption in young women (22-33y) at low and high zinc content(Hansen et al. Am J. Clin. Nutr. 74:125-9, 2001)


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    • Biological effects of increased folate intake.

    • The following concerns, new and old, have been raised in the literature:

    • Masking Vitamin B12 deficiency (pernicious anemia).

    • Impairment of Zn absorption(Hansen et al, 2001)

    • Decreasing the effectiveness of drug therapy(Quinlivan and Gregory, 2002).

    • -cancer

    • -anticonvulsants


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    Decreasing the effectiveness of antifolate therapy

    There is no direct evidence, nor is it known, if folic acid supplements negate the effects of antifolate or antiepileptic drugs (Butterworth & Tamura,1989).

    • Cancer – suggested without evidence.

    • Antiepileptic drugs (AEDs) (valproate, carbamazepine, phenytoin)

      • 1/250 newborns exposed to AEDs

      • increase risk for spina bifida; risk for major malformation is 7-10% (Yerby, Epilepsia, 44:33-40, 2003)

      • phenytoin (other AEDs?) decreases folate levels in 50% of epileptic patients

      • Fertile women treated with phenytoin require folic acid to maintain normal serum folate (Berg et al. J. Am. Diet. Assoc. 95:352-6 1995).


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