Vitamin and mineral supplements: benefits

1
Vitamin and mineral supplements benefits
risksL. John Hoffer MD PhDLady Davis Institute
for Med. ResearchJewish General Hospital May
29, 2008
2
Teaching objectives

• Summarize a scientifically and conceptually valid
  framework for evaluating the evidence pertaining
  to vitamins in clinical practice
• Give examples of clinically important
  scientifically supported indications for
  supplements
• Point out the clinically important risks
• WARNING this presentation cannot be
  comprehensive!

3
Questions you want answers to

• Should I routinely prescribe a vitamin/mineral
  supplement in my practice, and if so which one?
• What about vitamin D? Is it necessary, or toxic?
• Where do we stand on folic acid and homocysteine?
• Which micronutrient supplements should I warn my
  patients against?

4
Should a supplement be routinely prescribed?

• 2006 State-of-the-Science NIH Conference
  regarding use of supplements by the general
  population to prevent chronic disease Evidence
  is insufficient to recommend either for or
  against.
• The data evaluated were almost entirely based on
  RCTs
• Ignored were mechanistic, epidemiologic
  (including genetic) and metabolic data

5
Problems using RCTs alone to set nutritional
requirements and recommendations

• RCTs have been nutritionally naïve in failing to
  select patients at risk
• Such RCTs are very difficult to carry out
  properly few have been done and few will ever be
  done
• Built-in EBM conceptual biases
• fallacy of concreteness
• inverted burden of evidence

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Institute of Medicines Food and Nutrition
Board
EBM gurus
The basic, biological, epidemiologic, genetic,
animal, metabolic and clinical data show that
vitamin deficiencies are bad and should be
prevented.
But theres no EVIDENCE!
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Vitamin D

• It is becoming apparent that vitamin D
  deficiency is epidemic both in children and
  adults worldwide. Vitamin D has been taken for
  granted and is not appreciated for its importance
  for overall health and well-being.
• Holick MF, AJKD 45 1119, 2005

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Vitamin D
bone, intestine parathyroids
Classic view of vitamin D physiologic role and
action
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Vitamin D deficiency

• Transiently lowered 1,25(OH)2 D Ca levels
• Triggering of secondary hyperparathyroidism which
  restores 1,25(OH)2D calcium levels
• ? Hypophosphatemia, ? bone alk phosphatase,
  ? PTH
• ? Bone calcium loss and demineralized bone
  matrix
• mild deficiency ? osteoporosis (due to mild 2dry
  hyperPTH)
• severe deficiency ? rickets/osteomalacia (matrix
  demineralizn)

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Vitamin D status is determined by 25(OH)D
concentration

• In D deficiency
• 1,25(OH)2D level normal or increased
• In D toxicity
• 1,25(OH)2D level typically normal
• DO NOT MEASURE 1,25(OH)2D !

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25(OH)D reference range

• Most modern labs 50 375 nmol/L
• Current best data (2007) 75 375 nmol/L
• (My hospital 25 95 nmol/L)

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Why recommend 25(OH)D gt 75 nmol/L?

• PTH profiles
• Calcium transport kinetics
• Muscle strength
• Epidemiologic studies
• Osteoporosis, cancer, etc.
• Clinical trials in osteoporosis
• Cancer prevention trial (2007)

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Vitamin D deficiency is highly prevalent
gt 50 of general population gt 75 of hospitalized
patients 1/3 of academic physicians and medical
residents in Boston
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Clinical diagnosis of overt osteomalacia

• Press thumb firmly against patients sternum or
  anterior tibia if this is painful, the patient
  almost certainly has the disease

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Nonskeletal functions of Vit D

• Immune cells
• TB, MS
• Cell proliferation
• Cancer
• Muscle
• Performance speed and muscle strength
• Falls

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bone, intestine parathyroids
Vitamin D has a multitude of target tissues
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bone, intestine parathyroids
Vitamin D has a multitude of target tissues
This process requires 25(OH)D gt 75 nmol/L
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Lappe et al. Am.J.Clin.Nutr. 2007

• Four year study of 1200 healthy post-menopausal
  Nebraska women
• Supplement of 1100 IU/day of D3 versus placebo
• This dose is necessary to achieve 25(OH)D levels
  in the sufficient range

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Lappe et al. Am.J.Clin.Nutr. 2007

• 60 RR reduction of all cancers
• colon, breast, lung, etc.
• If cancers diagnosed in first year are
  eliminated, the RR increases to 77
• The findings are consistent with existing
  epidemiologic data

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Vitamin D Bottom Line

• Vitamin D is like hypertension and cholesterol in
  1960s and 1970s
• But the evidence is stronger and more consistent
  for vitamin D in 2008 than for BP and cholesterol
  in 1985
• Population health implications may be greater
• Everyone (including children) needs a supplement
  of at least 1000 IU vitamin D3 daily until proven
  otherwise
• It is usually unnecessary to measure 25(OH) D
• Sunlight exposure

21
Folate, Cobalamin and Homocysteine

• Homocysteine is a vascular toxin
• Homocystinuria epidemiologic studies gene
  randomization studies in vivo studies in
  animals genetic polymorphism studies recent
  changes in stroke and cancer incidence following
  folic acid fortification of the US and Canadian
  food supply in 1998

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Folate, Cobalamin and Homocysteine

• The homocysteine hypothesis
• homocysteine is toxic but in what concentration?
• homocysteine is toxic in concentrations that
  occur either in the general population (512
  µmol/L) or when higher (1550 µmol/L)
• lowering toxic concentrations sufficiently will
  prevent or slow disease progression

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Most RCT of folate, B6 and B12 have not improved
hard CVD endpoints. Why not?

• Insufficient power for the small Hcy reduction
  and consequently small effect?
• Studies too short in duration?
• Bizarre nutrient cocktails
• Did concurrent CVD medications block or mitigate
  beneficial effect?
• Baseline Hcy levels were normal

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Folate, Cobalamin and Homocysteine

• The homocysteine hypothesis remains unproven, but
  has not been disproven
• Lack of proof of efficacy is not proof of lack
  of efficacy
• We still treat homocystinuria
• What should you do about a Hcy concentration gt 12
  µmol/L?
• What should be the burden of evidence?

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My suggested EBM bottom line

• Measure Hcy in patients in whom serious
  hyperhomocystinemia could plausibly occur
• Patients with issues related to folate, B12,
  renal insufficiency
• Or, presumptively treat them
• Measure Hcy in patients with undiagnosed
  thrombophilia, cerebrovascular disease or
  premature CVD to screen
• Aggressively treat when Hcy conc gt 12 in
  appropriate setting
• What else?...

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Folic acid new pre-conceptual guidelines Dec 2007

• http//www.sogc.org/media/pdf/advisories/JOGC-dec-
  07-FOLIC.pdf

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Case presentation

• Mr. M 59 man with right central retinal artery
  occlusion
• Plasma total Hcy 16.2,18.9 µmol/L
• EBM review Hcy gt 15 µmol/L is an independent
  risk factor for central retinal artery occlusion
• multivariate odds ratio 4.0 (1.7 9.5)

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How to treat?

• Thrombophilia clinic Rx with high-dose B vitamin
  complex, but Hcy level stayed high 17.7 µmol/L
• My Rx N-acetylcysteine 1 g tid Hcy fell to14.0
  µmol/L
• My next Rx add hydroxycobalamin 1 mg s/c
• 4 days later, Hcy 7.8 µmol/L
• 14 days later, Hcy 10.0 µmol/L
• His current regimen hydroxcobalamin 1 mg s/c q
  14 d and NAC 1 g tid plus B-vitamins

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Vitamin C
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Gingival swelling and bleeding
New Zealand Medical Journal 2007 120
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Follicular hyperkeratosis
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Perifollicular hemorrhage
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Highly positive tourniquet test!
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Plasma ascorbic acid mg/dL
Jacob RA, et al Am.J.Clin.Nutr. 46818-26, 1987
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52.7 22.5 µmol/L
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23.0 µmol/L (IR 15.0 -37.0)
52.7 22.5 µmol/L
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28.4 µmol/L
11.4 µmol/L
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In my EBM-based adult practice

• I prescribe a one-a-day supplement (hopefully
  providing 1 mg folic acid, 5 to 50 µg B12, 400
  IU D3, 90 mg vitamin C) plus 500 mg vitamin C,
  plus 1000 IU D3, plus 400 - 500 mg calcium
• For enthusiasts I may also prescribe organic
  selenium 200 µg, zinc 50 mg (NB, the supplement
  will contain 2 mg copper),

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In my EBM-based adult practice

• I refrain from such prescription only if my
  assessment indicates no need i.e., set the
  appropriate burden of proof.
• Be willing to discuss the evidence with patients
  and listen to them they are often better
  informed than you are. Let them to teach you!
• Which micronutrient supplements should I warn my
  patients against?

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Micronutrient risks

• Therapeutic iron
• In the folic acid supplemented era, early vitamin
  B12 deficiency now presents with a normal MCV
  check B12 levels in older patients
• Retinol gt 3500 IU/day (osteoporosis)
• Beta-carotene safe in non-alcoholic non-smokers

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Micronutrient risks, ctd.

• Chronic high-dose zinc inhibits copper absorption
• High-dose vitamin C has not been shown to induce
  oxalate crystallization in the urinary space but
  patients with a history of stone and
  hyperoxaluria may be at higher risk of recurrence
• Meta-analysis conclusion that vitamin E and other
  antioxidants are dangerous is likely specious

42
Your patient has had a kidney stone? What should
you advise about dietary calcium?
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Should someone with a kidney stone restrict
calcium intake?

• 10 of adults will have a kidney stone, 90
  calcium oxalate
• Risk of stone is increased by low calcium intake
  (lt 850 mg/day)
• How to prevent recurrent Ca-oxalate stone?
• restrict sodium, increase hydration, increase
  calcium intake to gt 800 mg/day
• avoid high-dose vitamin C, if hyperoxaluric
• if hypercalciuric on normal calcium intake, HCTZ

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Sources

• Multivitamin/mineral supplements and chronic
  disease prevention. Am J Clin Nutr 200785
  (suppl) 254S-327S.
• Ames BN et al. Evidence-based decision making on
  micronutrients and chronic disease long-term
  randomized controlled trials are not enough. Am J
  Clin Nutr 2007 86522-3.
• Holick MF. Vitamin D deficiency. N Engl J Med
  2007357266-81.
• Lappe JM, Travers-Gustafson D, Davies KM, Recker
  RR, Heaney RP. Vitamin D and calcium
  supplementation reduces cancer risk results of a
  randomized trial. Am J Clin Nutr 2007851586-91.
• Wald DS, Wald NJ, Morris JK, Law M. Folic acid,
  homocysteine, and cardiovascular disease judging
  causality in the face of inconclusive trial
  evidence. BMJ 20063331114-7.
• Hoffer LJ. Testing the homocysteine hypothesis in
  end-stage renal disease Problems and a possible
  solution. Kidney International 2006691507-10.
• Hoffer LJ. Nutrition supplements in adults. IN
  Grey J, ed, Therapeutic Choices, 5th edition,
  Ottawa, Canadian Pharmacists Association, pp
  371-378, 2007.