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Title: VITAMIN D3


1
Vitamin D Current Research and Recommendations
Across the Life Span
  • Seema Desai, MS, RD, LDN, CNSD Kerry Harwood,
    MSN, RN

2
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

3
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

4
Structure of Vitamin D
5
(No Transcript)
6
Endocrine, paracrine and intracrine functions of
Vitamin D
7
Vitamin D Across the Lifespan
  • Factors influencing accumulation of bone
    minerals
  • Heredity
  • Gender
  • Diet
  • Physical activity
  • Endocrine status
  • Maternal vitamin D status

8
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

9
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

10
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

11
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

12
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
13
  • 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

14
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

15
  • 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.

16
Adults
17
Vitamin D Deficiency in Hospitalized Patients
18
Vitamin D Deficiency in Renal Transplant Patients
19
Vitamin D Inadequacy in Post-Menopausal Women
20
Vitamin D and Cancer
  • May influence both incidence and mortality
  • Linked with GI cancer, prostate and breast
    cancers, lymphomas, endometrial and lung cancers

21
Something New Under the Sun?
  • Apperly FL. The relation of solar radiation to
    cancer mortality in North America.
  • Cancer Research.1941(1)191-195

22
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

23
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)
24
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.

25
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

26
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.

27
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)

28
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

29
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

30
Lung cancer
  • Insert survival graph from Zhou article here

31
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)

32
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

33
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

34
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

35
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

36
Endometrial cancer
  • Is ultraviolet B irradiance inversely associated
    with incidence rates of endometrial cancer an
    ecological study of 107 countries.
  • Mohr, et al, 2007

37
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

38
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

39
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

40
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

41
Cancer Survival
  • Summer / Fall (vs. Winter / Spring) diagnosis
    associated with improved survival in
  • Colorectal cancer
  • Hodgkins lymphoma
  • NSCLC
  • Breast cancer

42
Cancer Survival
  • Intermittent sun exposure associated with
    increased survival following a diagnosis of
    melanoma
  • Berwick, et al., 2005

43
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

44
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

45
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

46
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

47
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

48
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

49
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

50
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

51
Stroke
52
Chronic Kidney Disease
53
Multiple Sclerosis
54
Osteo- Rheumatoid Arthritis
55
Where do we go from here?
  • Routine screening
  • Rectify deficiency / insufficiency
  • Maintain levels through a patient-specific
    combination of diet, supplementation, and sun
    exposure

56
Recommendations
  • Annual testing of 25(OH)D
  • Consider time of year in testing
  • Lowest levels generally towards end of winter,
    early spring

57
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

58
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

59
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

60
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

61
Supplementation
62
Supplementation (adults)
  • To correct deficiency 50,000 IU vitamin D
    weekly x 8 weeks, reassess and repeat if
    necessary

63
Supplementation (peds)
  • To correct deficiency

64
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
65
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

66
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

67
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

68
National Academy of Science Tolerable Upper
Intake Levels
  • Pediatrics 0 12 months
  • 1000 IU / Day
  • All others
  • 2000 IU / Day

69
USDHHS Dietary Guidelines for America - 2005
  • Special groups elderly and individuals with
    dark skin
  • 1,000 IU / day

70
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

71
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

72
How much sun?
  • Depends on
  • Age
  • Amount of vitamin D obtained from diet
  • Skin darkness
  • Sunshine intensity

73
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

74
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
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