Wake Forest School of Medicine

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Wake Forest School of Medicine

• Robert H. Fletcher, MD
• Multivitamin Presentation
• March 16, 2005

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Vitamin Deficiency Syndromes

• Vitamin C Scurvy
• Niacin Pellagra
• Thiamine Beriberi
• Folic Acid Macrocytic anemia
• Vitamin D Rickets, osteomalacia
• Vitamin B12 Anemia, neurologic disease

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Sub-optimal Vitamin Intake

• Most people ingest enough vitamins to prevent
  vitamin deficiency syndromes
• Many take less that what seems needed for normal
  metabolism
• Sub-optimal vitamin intake is a risk factors for
  chronic diseases

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The Vitamins Micronutrients Essential for Normal
Health

• Water Soluble
• B1 (thiamine)
• B2 (riboflavin)
• B3 (niacin)
• B6 (pyradoxine)
• Folic acid
• B12
• C
• Biotin
• Pantothenic Acid

• Fat Soluble
• A ( beta-carotene)
• D
• E (alpha-tocopherol)
• K

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Folic Acid Supplementation May Prevent Chronic
Diseases
Proposed mechanism reduction in homocysteine
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The MRC Vitamin Study
Folic acid (4 mg)
33 Centers
Neural Tube Defects Folic acid groups 6 Other
groups 21 Relative risk 0.26 (0.12, 0.71)
Other vitamins
1817 High risk women
Both
Neither
7 Countries
MRC Vitamin Study Research Group. Lancet
1991338131
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Reduction in NTD with Folic Acid Supplementation
in China
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Folic Acid is Added to Cereals

• An opportunity to reach all childbearing women at
  time of conception
• Cereals supplemented since 1998
• Raises average folic acid intake from 250 to 350
  mcg/d (Daily value 400 mcg/d)

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Reduction in Risk of Neural Tube Defects
According to Increase in Intake of Folic Acid.
From Baseline Serum Folate Of 7.5 ng/ml (Wald NJ.
Lancet 20013582069)
Daily Value
0 20 40 60 80 100
Reduction in Risk
0 0.5 1.0 2.0 3.0
4.0 5.0 Increase in
Folic Acid Intake (mg/d)
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Neural Tube Defects in Relation to Folic Acid
Recommendations. (Botto LD. BMJ 2005)
Began Program
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Origins of The Homocysteine Hypothesis

• Children with homocysteinuria have
• - Very high blood levels of homocysteine
• - Severe vascular disease in adolescence
• Might lesser levels cause smaller risk?

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Methionine synthetase
Homocysteine
Methionine
Folate, B12, B6
Atherosclerosis
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Folic Acid Intake in Framingham, Massachusetts
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of Population
10
5
0 200 400
600 800 Folic Acid
(micrograms/ml)
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Observational Studies of homocysteine and
Ischemic Heart Disease
Homocysteine Studies Collab. JAMA 2002 2882015
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Effects of Vitamins of Plasma Homocysteine Levels

• Folic acid alone 25 reduction
• Add B12 additional 7 reduction
• Add B6 to the other 2 no additional reduction

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An RCT of Folic Acid B12 and Hip Fractures in
Elderly Japanese Patients with Stroke
Sato Y. JAMA 20052931082
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Is Folic Acid Safe?

• Yes, for most of us extraordinarily safe
• But
• - Masking vitamin B12 deficiency in the elderly
• - Accelerating tumor growth in people with
  cancer

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Vitamin D Deficiency

• Several sources
• - Added to dairy and cereal products
• - Synthesize in skin (requires UV light)
• - Eat eggs and oily fish
• - Take supplements
• Prevalence of deficiency high (e.g., 50)
• in the elderly
• Biologic confirmation of deficiency elevated PTH
• Effects depend on adequate calcium intake

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Effect of Four Monthly 100,000 IU Oral Vitamin
D3 on Fractures. An RCT.
Trivedi DP. BMJ 2003326469.
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Vitamin D and Falls Meta-analysis of RCTs
Bischoff-Ferrari. JAMA 20042911999
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The Antioxidant Hypothesis

• Free radicals cause oxidative damage to tissues
• Antioxidants block oxidation, preventing
• - Cardiovascular disease (via LDL)
• - Cancer
• - Other chronic diseases such as
• macular degeneration
• impaired immunity
• dementia

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Antioxidants Effects of Class, Individual
Vitamins, or Specific Forms?
Antioxidant Vitamins
Vitamin C Vitamin A Vitamin E
(Ascorbic Acid)
Retinol Beta-carotene Others Cis, trans
Alpha Beta Gamma Delta (Total of 8)
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Vitamin E and Cardiovascular Disease in
Observational and Experimental Studies
Jha P. Ann Intern Med 1995123860
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Risk of Cardiovascular Disease for People Treated
with Vitamin E or Control Therapy
Vivekananthan DP. Lancet 20033612017
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Observational and Experimental Studies Usually
Agree With Each Other (Benson K. NEJM
20003421878)
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Observational and Experimental Studies Which is
the Gold Standard?
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Beta-Carotene and Lung Cancer
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A Meta-Analysis of Antioxidants and
Gastrointestinal Cancers
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Current Bottom Line for Antioxidants for
Prevention of Cancer

• Theory attractive
• Dont know if really works
• Evidence so far discouraging
• Maybe for some antioxidants, doses, people...
  (work in progress)

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Are Antioxidants Safe?

• Wide therapeutic ratio for acute toxicity
• Unsafe situations
• - Beta-carotene and cardiovascular disease
• - High dose vitamin E and total mortality?
• - Vitamin A and bone density/fractures
• - Vitamin A in pregnancy

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A Meta-Analysis of Cardiovascular Deaths in Beta
Carotene and Control Patients
ATBC CARET HPS NSCP PHS WHS Pooled
Vivekananthan DP. Lancet 20033612017
0 0.5 1.0 1.5
2.0
Beta carotene better
Beta carotene worse
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All Cause Mortality According to Dose of Vitamin
E.
Miller ER III. AnnIntern Med 2004142
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Dose-response Relationahip Between Vitamin E
Supplementation and All-cause Mortality
Miller ER III. Ann Intern Med 2005142
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Two Cohort Studies of Vitamin A is a Risk Factor
for Osteopenia and Fractures
Mehhus H. AIM 1998129770
Melhus H. AIM 1998129770 Feskanich D. JAMA
200228747.
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Daily Intake of Retinol and Estimated Relative
Risk of Hip Fracture
Retinol Intake Mg/Day
Melhus H. Ann Intern Med 1998129770
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Chronic Effects of Suboptimal Vitamin B12

• Vitamin B12 deficiency common in elderly
• Marked by elevated methylmelonic acid levels
• Clinically important?
• - Anemia
• - Cardiovascular effects via homocysteine,
• - Neurologic defects dementia, balance
• - Immunologic impairment

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My Case for Multivitamin Use

• Effective for some conditions (e.g., vitamin D
  and falls and fractures, folic acid and birth
  defects)
• May be effective for others (e.g., folic acid and
  CVD, cancer, bone density B12 and neurologic
  impairment)
• Safe within broad limits (but some concerns)
• Cheap

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Not Yet Consensus on Multivitamin Supplements
The U.S. Preventive Services Task Force
Concludes that the evidence is insufficient to
recommend for or against the use of supplements
of vitamins A, C, or E multivitamins with folic
acid or antioxidant combinations for the
prevention of cancer or cardiovascular disease
Ann Intern Med 200313951-55.