VITAMIN D3

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Vitamin D Current Research and Recommendations
Across the Life Span

• Seema Desai, MS, RD, LDN, CNSD Kerry Harwood,
  MSN, RN

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Vitamin D Overview

• It is a fat soluble vitamin.
• Not just a vitamin it is a prehormone
• Found in some food and made in the body after
  exposure to UV rays
• Major biological function is to maintain normal
  blood levels of Ca and Po4
• Other tissues like macrophages, prostrate tissue
  also have vit D receptor

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History of Vitamin D

• Existed over 500 million years
• Industrial revolution rickets
• Cod liver oil common folklore medicine
• Discovery of Vit D as the antirachitic factor in
  cod liver oil(1920)
• Discovery of conversion of 7-dehydrocholesterol
  in the skin to vit D (1937)
• Antirachitic property in food
• Fortification of food with vitamin D was patented
• Complete eradication of rickets in US
• US public service issuing warnings about
  sun-induced health risk
• Over next 30 yrs skin cancer hazard of excessive
  sun exposure became well established

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Structure of Vitamin D
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Endocrine, paracrine and intracrine functions of
Vitamin D
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Vitamin D Across the Lifespan

• Factors influencing accumulation of bone
  minerals
• Heredity
• Gender
• Diet
• Physical activity
• Endocrine status
• Maternal vitamin D status

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Maternal Vitamin D Status

• Association of low intake of milk and vit D
  during pregnancy with decreased birth weight.
• C.A. Mannion, Katherine Gray-Donald, kristine G.
  Koski. CMAJ April 25, 2006
• -Women between ages 19-45yrs
• -In Calgary
• -lt/ 250 ml of milk low birth weight
• -milk or vit D independent predictor of BW
• -1 cup milk 41 gm increase in BW
• -1 Mcg increase in dietary vit D 11 gm
  increase in BW

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Maternal vitamin D.

• Maternal vitamin D status during pregnancy and
  childhood bone mass at age 9yrs.
• M.K. Javaid, SR Crozeir at al. Lancet Jan 7 2006
• -198 children born in 1991-92 in South Hampton UK
• -children were followed up at age 9yrs
• -31 mother had insufficient and 18 had
  deficient serum vit D during late pregnancy
• -decrease vit D in mothers decrease bone
  mineral content in children at age 9 yrs
• -mothers exposure to UV rays and use of vit d
  predicted vit d and childhood bone mass

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Breastfed infants

• Vitamin D deficiency in breastfed infants in
  Iowa.
• Ekhard E. Ziegler, Bruce w. Hollis, Steven E
  Nelson and Janice M. Jeter. Pediatrics 2006
• -84 breastfed infants
• -blood samples and dietary records were taken
• -35 infants were unsupplemented
• -49 infants were either supplemented with
  formula or vit D
• -10 were vit D deficient
• -Marked seasonal affect more so in the
  unsupplemented group
• -mainly but not exclusively during winter and
  occurred in light and dark skinned infants

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Healthy adolescents

• Prevalence of vitamin D deficiency among healthy
  adolescents.
• Catherine M Gordon, Kerrin C. DePeter, Henry A.
  Feldman, Estherann Grace, Jean Emans. Arch
  pediatr Adolesc med June 2004
• -307 healthy adolescents 11-18 yrs,
• -annual physical between july 2001-june 2003
• -Data collected on age, sex, ethnicity, Ht, wt,
  exercise, medical hx diet
• -Blood samples were drawn at the end of the
  visit
• -24.1 of the participants were vit D deficient
• -highest prevalence in African American
• -Most prevalent during winter
• -no difference in prevalence between girls and
  boys
• - correlation between soft drink consumption
  and vit D deficiency
• -inverse correlation between vit D deficiency
  and milk and cold cereal consumption

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Young girls in southern US

• Serum 25-hydroxy vitamin D concentration in girls
  aged 4-8 y living in the southeastern United
  States. Stein et al.. Am J clinical nutrition
  2006
• -168 prepubertal girls 4-8 yrs old
• -120 non-Hispanic white
• -48 non-Hispanic black
• -Oct 1997-Oct 2000 at U of GA
• -with in 1 wk of blood draw bone scan,
  anthropometric measure dietary intake, and
  physical activity were assessed

https//docme.mc.duke.edu/ada/index.asp
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• Mean vitaminD, Calcium and multivitamin use was
  higher in white girls than in black
• Both races had mean dietary vitamin D intake
  above adequate levels
• Race and season strongest predictor of vit D
  status
• Black girls had lower mean vit D value
• Vitamin D value were significantly higher in
  summer than in winter
• Living at low latitude does not entirely prevent
  poor vitamin D status

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Milk Allergies and vitamin D deficiency

• Milk allergy and vitamin D deficiency rickets a
  common disorder associated with an uncommon
  disease. Case Report
• Joyce w. Yu at el
• Annals of allergy, asthma and immunologyApril
  2006
• -Case report of Vit D deficiency rickets in 2 yr
  old boy with
• milk allergy
• -BF for 6-7 months
• -failed trail of cows milk formula
• -drank 500-700ml of fruit juice with no vit D
  and Ca supplementation
• -18 months of age started to regress
• -Lab values Vit D of 8 mmol/l, Ca 1.98 mmol/l,
  alk phos
• -2,822u/l

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• Discharged taking 4000IU of vit D, 200mg
  calcitriol, and 300mg elemental Ca
• 2 weeks later was able to stand, and his lab
  values were improved.

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Adults
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Vitamin D Deficiency in Hospitalized Patients
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Vitamin D Deficiency in Renal Transplant Patients
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Vitamin D Inadequacy in Post-Menopausal Women
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Vitamin D and Cancer

• May influence both incidence and mortality
• Linked with GI cancer, prostate and breast
  cancers, lymphomas, endometrial and lung cancers

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Something New Under the Sun?

• Apperly FL. The relation of solar radiation to
  cancer mortality in North America.
• Cancer Research.1941(1)191-195

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1979 - 1981

• Vitamin D receptors found in malignant melanoma
  cells and myeloid leukemia cells
• 1,25(OH)2D inhibited melanoma cell proliferation
  and induced myeloid cell differentiation

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Northern vs. Southern U.S.
1 2 extra skin cancer deaths (per 100,000)
30 40 extra deaths for other major cancers (per
100,000)
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1998

• Serum levels of 1,25(OH)2D are tightly controlled
  by the kidneys dont vary by sun exposure so
  how could vitamin D contribute to the north-south
  gradients and African-American excess in cancer
  rates?
• Non-renal cells discovered to hydroxylate 25(OH)D
  and synthesize 1,25(OH)2D locally.

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Vitamin D Cancer

• Environmental sunlight diet
• Calcitriol (hormonal form of vitamin D) controls
  the differentiation of many cells that possess
  vitamin D receptors (VDR)
• Induce cell differentiation and apoptosis of
  cancer cells while inhibiting cell proliferation,
  angiogenesis, and metastasis
• Genetic VDR polymorphisms

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June, 2007 American Journal of Clinical Nutrition

• Women who regularly took vitamin D3 and calcium
  had a 60 reduction in all-cancer incidence
  compared with a group taking placebo and a 77
  reduction when the analysis was confined to
  cancers diagnosed after the first 12 months.

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Lung cancer

• 1,25(OH)2D
• inhibits proliferation and induces
  differentiation of lung cancer cell lines
  (Higashimoto, et al., 1996, Guzey, et al., 1998)
• inhibits metastatic growth and locoregional
  recurrence of lung cancer cells in mice (Wiers,
  et al., 2000)

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Lung cancer

• 456 patients with early stage NSCLC
• Median age 69
• 96 Caucasian
• Data collection
• Season of surgery
• Food frequency questionnaire
• Recurrence free survival (RFS)
• Overall survival (OS)
• Zhou, et al., 2005

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Lung cancer

• Patients who had surgery during summer with the
  highest vitamin D intake had better RFS that
  patients who had surgery during winter with the
  lowest vitamin D intake.
• Similar associations were seen for overall
  survival.
• Zhou, et al., 2005

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Lung cancer

• Insert survival graph from Zhou article here

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Breast cancer

• 1,25(OH)2D
• inhibits cell proliferation, induces
  differentiation apoptosis, and inhibits
  angiogenesis in normal and breast cancer cells
  (Colston, et al, 1989, Saez, et al, 1993,
  Mantell, et al., 2000)
• suppresses high-fat diet-induced mammary
  tumorigenesis in rats (Jacobson, et al., 1989,
  Xue, 1999)

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Breast cancer

• Inverse association between vitamin D calcium
  intake and breast density
• Inconclusive results in studies looking at VDR
  genetic polymorphisms and breast cancer
• Inverse association between high sunlight
  exposure and breast cancer risk
• Association may be stronger for premenopausal
  than postmenopausal women due to interactions
  between vitamin D, the VDR, estrogen and
  insulin-like growth factor-I (IGF-I)
• Cui Rohan, 2006

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Breast cancer

• Case-control study 972 women with
  newly-diagnosed breast cancer 1,135 healthy
  controls
• Interviews regarding vitamin D-related exposures,
  e.g. outdoor activities, use of sunscreen,
  dietary contributions
• Knight, 2007

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Breast cancer

• More frequent sun exposure during adolescence was
  associated with a 35 reduction in breast cancer
  risk later in life
• Lower risk also linked to cod liver oil and milk
  intake gt 10 glasses / week
• Milder protection seen for people age 20 29
• No protection for people over age 45

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Breast cancer

• Epidemiologic study of different regions of
  Norway, each with a different annual UV exposure
• Prognosis 15 25 better for women diagnosed /
  treated in the summer vs. winter
• ltget this article Breast Cancer Research and
  Treatment, MaygtKnight , 2007

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Endometrial cancer

• Is ultraviolet B irradiance inversely associated
  with incidence rates of endometrial cancer an
  ecological study of 107 countries.
• Mohr, et al, 2007

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Endometrial cancer

• Objective perform an ecological analysis of the
  relationship between low levels of ultraviolet B
  irradiance and age-standardized incidence rates
  of endometrial cancer by country, controlling for
  known confounders

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Endometrial cancer

• 107 countries
• UVB irradiance
• cloud cover
• intake of energy from animal sources
• proportion overweight
• skin pigmentation
• cigarette consumption
• health expenditure
• total fertility rates
• vs. age-standardized incidence of endometrial
  cancer

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Endometrial cancer

• Association found between endometrial cancer
  incidence rates and
• Low UVB irradiance
• High intake of energy from animal sources (?
  IGF-I?)
• Per capital health expenditure
• Proportion of population overweight

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Pancreatic cancer

• Prospectively collected diet and lifestyle data
• Nurses Health Study 75,427 women
• Health Professionals Follow-up Study 46,771 men
• Pancreatic cancer risk 41 lower among those who
  consumed gt 600 IU of vitamin D / day vs. those
  who consumed lt 150 IU / day
• Skinner, et al., 2006

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Cancer Survival

• Summer / Fall (vs. Winter / Spring) diagnosis
  associated with improved survival in
• Colorectal cancer
• Hodgkins lymphoma
• NSCLC
• Breast cancer

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Cancer Survival

• Intermittent sun exposure associated with
  increased survival following a diagnosis of
  melanoma
• Berwick, et al., 2005

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Type 2 Diabetes

• Altered vitamin D and calcium homeostasis may
  play a role in development of type 2 diabetes
• Low serum levels of 25(OH)D are associated with
  impaired pancreatic ß cell function and insulin
  resistance
• High calcium intake is inversely associated with
  body weight

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Type 2 Diabetes

• Nurses Health Study 83,779 women (98
  Caucasian)
• Daily intake of gt1,200 mg calcium gt800IU
  vitamin D was associated with a 33 lower risk of
  type 2 diabetes compared with an intake of lt600
  mg calcium lt400 IU vitamin D
• Pittas, et al., 2006

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Type 1 Diabetes

• Birth-cohort study in Finland all women due to
  give birth in 1966 enrolled
• 10,366 children born alive and followed to one
  year 81 diagnosed with Type 1 diabetes
• Children who regularly took recommended dose of
  vitamin D (2000 IU) had a RR of 0.22 compared
  with those who did not.
• Children suspected of having rickets had a RR of
  3.0 compared with those not suspected.
• Hopponen, et al., 2001

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Metabolic Syndrome

• Third National Health Nutrition Examination
  Survey (NHANES III)
• 8,421 men and non-pregnant women gt 20 years of
  age and had fasted gt 8 hrs
• Unadjusted prevalence of metabolic syndrome -
  21.9

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Metabolic Syndrome

• After adjustments for known risk factors, odd of
  metabolic syndrome decreased progressively across
  increasing concentrations of 25(OH)D
• Relative risk compared with bottom quintile of
  vitamin D level
• 2nd quintile 0.85
• 3rd quintile 0.75
• 4th quintile 0.62
• 5th quintile 0.46
• Ford, et al., 2005

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Pulmonary / COPD

• Third National Health Nutrition Examination
  Survey (NHANES III)
• 14,000 subjects
• Dose-response correlation between percent
  predicted FEV1 and FVC values and circulating
  25(OH)D
• Plausibility vitamin D shown to prevent
  experimental inflammatory diseases in mice
  including allergic asthma
• Black, et al., Chest, 2005

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Congestive Heart Failure

• RCT of vitamin D calcium vs. placebo calcium
  x 9 months in subjects with CHF
• 93 subjects completed study
• Anti-inflammatory cytokine interleukin 10
  significantly higher
• Suppressed release of TNF-a
• No difference in survival but blood levels not
  optimized
• Schleithoff, et al., 2006

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Hypertension

• Prospectively followed two cohorts
• Nurses Health Study 1198 women
• Health Professionals Follow-up Study 613 men
• Relative risk of hypertension
• lt 15 ng/mL vs gt 30 ng/mL 25(OH)D
• Men RR 6.13
• Women RR 2.67

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Stroke
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Chronic Kidney Disease
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Multiple Sclerosis
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Osteo- Rheumatoid Arthritis
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Where do we go from here?

• Routine screening
• Rectify deficiency / insufficiency
• Maintain levels through a patient-specific
  combination of diet, supplementation, and sun
  exposure

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Recommendations

• Annual testing of 25(OH)D
• Consider time of year in testing
• Lowest levels generally towards end of winter,
  early spring

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Vitamin D Assessment

• Lab assays are available to measure both 25(OH)D
  and 1,25-D.
• 25(OH)D closely reflects total amount of vit D
  produced in the skin and from diet
• D2 and D3 have similar biological activity
• Both D2 and D3 should be measured
• DO NOT USE - 1,25-D. This can often be normal
  with vit D deficiency

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Goals in Maintaining Vitamin D Levels

1. Prevent disease of deficiency rickets,
   osteomalacia
2. Prevent complications of insufficiency impaired
   calcium absorption and increased bone resorption
3. Minimize risks of future disease cancer,
   cardiopulmonary diseases, diabetes, other
   immune-related diseases

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25(OH)D concentration

• To prevent deficiency disease
• gt 25 nmol / L
• To prevent complications of insufficiency
• gt 50 nmol/L
• For maximum bone health and prevention of chronic
  disease
• 75 100 nmol/L

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Who is at greatest risk?

• Low dietary intake BF infants, children who do
  not drink fortified milk
• Malabsorption syndrome
• Severe liver disease
• Kidney disease
• Drugs
• Higher latitudes
• People who spend little time outside
• Older adults
• Decreased sun exposure due to cultural reasons
• Races with high skin melanin levels

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Supplementation
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Supplementation (adults)

• To correct deficiency 50,000 IU vitamin D
  weekly x 8 weeks, reassess and repeat if
  necessary

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Supplementation (peds)

• To correct deficiency

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IOM Recommendations (AI)
Age Children Men Women Pregnancy lactation
Birth-13 yrs 5mcgs 200IU
14-18yrs 5 200IU 5 200 IU 5 200IU 5 200IU
19-50 Yrs 5 200 IU 5 200 IU 5 200 IU 5 200 IU
51-70 Yrs 10 400 IU 10 400 IU
71 15 600 IU 15 600 IU
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Do recommendations reflect the state of the
science?

• Our studies in children (3 16 years of age)
  in Edmonton, Alberta, show that 200 IU daily is
  not even adequate for maintaining levels now
  considered mildly to moderately deficient (40
  nmol/L), let alone optimum (80 nmol/L).
• A.B. Jones, Canadian Family Physician, 2006

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Do recommendations reflect the state of the
science?

• Oral doses currently consumed in the US (an
  estimated mean of 320 IU / day) are far too low,
  and the designation of the 2000 IU/day dosage as
  safe by NAS provides latitude to the community to
  increase intakes to levels required to reduce
  risk of cancer, with essentially no likelihood of
  adverse effects.
• Grant and Gorham, International J of
  Epidemiology, 2006

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Do recommendations reflect the state of the
science?

• the present recommended allowance for vitamin
  D 400 IU for individuals aged 50 70 years
  is inadequate even to maintain skeletal health
  and is probably too low for meaningful anticancer
  effects.
• Schwartz Blot, J National Cancer Institute, 2006

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National Academy of Science Tolerable Upper
Intake Levels

• Pediatrics 0 12 months
• 1000 IU / Day
• All others
• 2000 IU / Day

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USDHHS Dietary Guidelines for America - 2005

• Special groups elderly and individuals with
  dark skin
• 1,000 IU / day

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Maintenance (adults)

• To maintain recommended levels 800 - 1000 IU /
  day if not getting enough sun exposure to
  maintain vitamin D levels or 50,000 IU 1-2 times
  monthly

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North American Conference on Vitamin D

• to minimize the health risks associated with
  UVB radiation exposure while maximizing the
  potential benefits of optimum vitamin D status,
  dietary supplementation and small amounts of
  sun exposure are the preferred methods of
  obtaining vitamin D.
• Consensus statement, 2006

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How much sun?

• Depends on
• Age
• Amount of vitamin D obtained from diet
• Skin darkness
• Sunshine intensity

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How much sun?

• Significant skin exposure
• Face, neck, arms, hands
• Arms, legs
• Adequate sun strength
• Time
• 25 of the time it would take to cause pinkness
  of the skin (Caucasians)
• People with dark skin require significantly more
  sun exposure
• Holick, 2004

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Food Sources of Vitamin D

• Cod liver oil 1 TBS
• Salmon 3.5 oz.
• Mackerel 3.5 oz.
• Tuna, canned, in oil, 3 oz.
• Sardines 3.5 oz.
• Milk (fortified) 8 oz.
• Ready to eat cereal (fortified) ¾ - 1 cup
• Egg 1 whole
• Liver, 3.5 oz.
• Cheese, swiss 1 oz.

• 1,360 IU
• 360
• 345
• 200
• 250
• 98
• 40
• 20
• 15
• 12