holick vitamin d - for andrew weil...
TRANSCRIPT
THE D-LIGHTFULVITAMIN
FOR HEALTHMichael F. Holick
Boston University Medical Center
Teaching Goals1. How to Dx Vitamin D Deficiency
A. Which Vitamin D metaboliteshould be ordered?
2. How to Tx Vitamin D DeficiencyA. Vitamin D2 vs Vitamin D3
3. What are the non-calcemic Benefits of Vitamin D?
Institute of MedicineIOM
Agency for Healthcare Research
AndQuality
Depended onRandomized Controlled Trials
RCTs
AHRQ
Ignored Association Studies
AI for Vitamin D
1997 0-50 yrs
50-70 yrs
70+ yrs
200 IU
400 IU
600 IU Need at L
east 1000 -2
000IU/d IOM RDA UL0-0.5 YEARS0.5-1 YEARS
400 IU/D 10001500
1-8 YEARS9-12 YEARS
600 IU/D 25003000
13-70YEARS 600IU/D 400070+YEARS 800IU/D 4000
Consultant and SpeakerBayerQuest DiagnosticsMerckP&G,Aventis, WarnerNational Dairy CouncilAmgenNovartis
8
And SupportFrom The
Sun
How much calcium do we need ?Who is at
Risk for
Vitamin D Deficiency
???
RICKETS
OSTEOMALACIADM,MS,RA,
HBP,CHDINFECTIONS
CANCER
VITAMIN D DEFICIENCY
OUR SKIN WAS DESIGNED
TO MAKEVITAMIN D
Do you know why I became
hypopigmented ????????
Rachitic PelvisNormal Female
Pelvis
HOW DO YOU MAKEVITAMIN D ????
7-DHC
HO
Vitamin D3HO
ΔH
CH2
PreD3
HO
Solar UV Radiation Can I make Too muchVitamin D
?????
ΔH
7-DHC
HO
PreD3
HO
Vitamin D3
HO
UV
Lumisterol3
HO H
Tachysterol3
OH
H3C
UV
UV
Suprasterol I
OH
Transvitamin D3
OH
Suprasterol II
HO
UVUV
UV
CH2
YOU CANNOT BECOMEVITAMIN D TOXIC FROM
SUN EXPOSURE
OCTOBER 1, 1918 NOVEMBER 12, 1918
UVR 1 Hr2/WK FOR6 WEEKS
1931 US GOVERNMENTPROVIDED RECOMMENDATIONSFOR SUN EXPOSURE
DermatologySocieties
FOR 40 YEARS ARE YOUSURE?????
WHAT WILL HAPPEN IF MYCHILDREN GO OUT WITHOUTSUNSCREEN ?
STEENBOCK 1920s
VITAMIN Dis
ESSENTIALFOR
BONE HEALTH
Case #1 • 7 month Old Female
• Muscle Weakness
• Tetanic seizures
• Serum calcium 4.2mg%•
BOSTON MEDICAL CENTER
MY DOCTOR SAIDBREAST MILK PROVIDESALL THE NUTRITIONMY INFANT NEEDS.
42
THERE IS LITTLE VITAMIN D
BREAST MILK
~ 25 IU/L
IS VITAMIN D DEFICIENCYA COMMON PROBLEM
FOR PREGNANT WOMEN??????
44
BOSTON MEDICAL CENTER
40 MOTHERS AND THEIR INFANTSAT BIRTH
MEASURED VITAMIN D STATUS25-HYDROXYVITAMIN D
45
70% MTVDRANK
2.3 GLASSESMILK/D
Daily Intake Vitamin D~600 IU
76% Mothers
Vitamin D Deficient
81% Newborns25(OH)D < 20NG/ML
IOM600 IU/d
47
Strong, inverse relation between maternal 25(OH)D at <22 weeks and risk of preeclampsia
Adjusted OR (95% CI) associated with a 50-nmol/l decline in 25(OH)D:
2.4 (1.1, 5.4))
20 ng/ml
Bodnar et al 07
RISK PREECLAMPSIA
49
Poster title: Maternal Vitamin D Status and Cesarean Birth: Is There a Connection?Session time: 4276.0: Tuesday, November 06, 2007: 4:30 PM-5:30 PM 0 20 40 60 80
Mother’s 25(OH)D ng/ml
Probability C-Section
Risk C-section
400 %
I NEED 1000 IU VITAMIN D/DAYTO PROVIDE ENOUGH VITAMIN D
FOR ME & MY INFANT
52
HOW MUCH VITAMIN D DOES MY MOM NEED TO PROVIDEME WITH ADQUATE VITAMIN D
??????
4000 IU/D
American Academy PediatricsBeginning at Birth
AllINFANTS need400 IU Vitamin D/d
Infants400-800 IU/d
Pregnant & LactatingWomen
2000 IU/d
55
What is a CommonSymptom of Vitamin D Deficiency ??????
Night Sweating !!!
And VAGINITIS
IOM RDA UL
1-70YEARS 600IU/D 4000
No Need To Increase Intake Pregnancy
orLactation
Case #2 • 1 Year Old Female
• Muscle Weakness
• Boney Deformities
• Failure to Thrive Osteomalacia
RX Rickets
?
We need Calcium &
Vitamin D for Strong Bones
& Teeth
IOMYou can get your
Vitamin D from Diet
Vitamin D is Rare in Foods
Dairy Fortified with Vitamin D
100 IU/Serving
100 IUof
VITAMIN D8 OZ GLASS
Did you KnowMushrooms
Make Vitamin D?????
UV-B Exposed Portabellas have 387 IU vitamin D per raw 84 gram serving.
Shrooms’ plant sterol - ergosterol -converts to vitamin D when exposed to light.
Growers can expose mushrooms to UV light to increase vitamin D levels.
UM,UM GOODUM,UM GOOD
73
BUT I EAT FISH
OILY FISHSALMON
HOW MUCH?????
5-7 Times/Week
500-1000 IU/3.5 oz
100-250 IU/3.5 oz
10-25% VIT D in FARMEDVS
WILD CAUGHT SALMON
SUMMER
UVB
PRODUCE VITAMIN D
WINTERUVB
NO VITAMIN D
???????
Jul A ug Sep Oct A pr M ay JunN ov D ec Jan F eb M ar
0
2
4
6
M onth
Seasonal Effect on Cutaneous Vitamin D Synthesis in Boston
Vitamin D Synthesis %
Webb et al
Nov-Feb0%
Can You Make Any??????
CannotMake
Vitamin DIn
WinterAbove32 N
Jul Aug Sep O ct Apr M ay JunNov Dec Jan Feb M ar
0
2
4
6
M onth
Seasonal Effect on Cutaneous Vitamin D Synthesis in EDMONTON
Vitamin D Synthesis %
Webb et al
OCT-APRIL0%
85
Great for RomanceNot for Vitamin D
10am-3pm
-1 0 1 2 3 4 5 6 7 8 9 1 01 11 21 31 41 50
5
1 0
1 5
2 0
2 5
3 0
3 5
Days
Se
rum
Co
nc
en
tra
tio
n
of
Vit
am
in D
(n
g/m
l)
Holick, 1987
Without Sunscreen
With Sunscreen
SPF30 99%
UVBUVB
Vitamin D3
Vitamin D3
~1%
SPF-30 -99%
90-95% of our Vitam in D com es from Exposure to Sunlight
HOW MUCH
SUNEXPOSURE????????????
Exposure to
1 Minimum Erythemal
Dose
~20,000 IU Vitamin D3
Does Sunlight ReallyProvide us with
Vitamin D
???????
Brot et al, Brit J Nutr (2001), 86, Suppl. 1, S97-S103
SUMMER
WINTER
Did You KnowObesity Causes
Vitamin D Deficiency?
Wow !!!
50
40
30
20
10
0Seru
m V
itam
in D
3 (n
mol
/L)
NormalWeight
*
Obese BM I>30
**
Serum Vitamin D Levels After ExposureOf Non-obese And Obese Adults To TSame Amount Of Ultraviolet Radiation
55%
4-320ng/gVitamin D Both
D2&D3
Rx Obese pts need
2-3 X vitamin D 50,000 IU vitamin D/wk
Recommendation in Boston
5 to 15 Minutes Sunlight 2-3X/wk LEGS
ARMS
5-15 MINUTES THEN
SUNPROTECTION
Time (days)
Vit
amin
D (n
g/m
l)
Effect of UVB on Serum Vitamin D Levels in Caucasian and Black Subjects
0 5 1 0 1 5 2 00
1 02 03 04 05 06 07 0
Vit
amin
D (n
g/m
l)
54 mJ/cm2
Time (days)
0 5 1 0 1 5 2 00
1 02 03 04 05 06 07 0
320 mJ/cm2
Black
Black
Caucasian
5-10 X
CAUCASIAN
0 5 1 0 1 5 2 00
1 02 03 04 05 06 07 0
54 mJ/cm2 BLACK
60 ng/ml
30 ng/ml
0 ng/ml
30-50% African Americans
Vitamin D Deficient
How Do You KnowWhat Your Vitamin D
Status Is ?????????
1,25(OH)2D
Serum 25(OH)Dis
the barometerfor
vitamin Dstatus
Excess
NormalDeficient
55 ng/ml
10 ng/ml
25(OH)DH
N
L
Normal
Deficient10 ng/ml
25(OH)D
L
CU ORC
111
SERUM 25(OH)D (nmol/L)0 25 50 75 100 125 150 175 200
SERU
M iP
TH (p
g/m
L)
0
20
40
60
80
100
120
140
25(OH)D & SERUM iPTH*
10 20 30 40 50
25(OH)D ng/ml
PTH
pg/
ml 30-40 ng/ml
Chapuy et alCU ORC
112
VITAMIN D STATUS & THE Ca ECONOMY
· 31 women· age: 63.2 + 9.3
· studied 2x – 1 yr apart in Spring
· given 10 μg 25(OH)D/day (D+)
or· no treatment (D–)
25(OH)D
D+ D–
nm
ol/
L0
20
40
60
80
100
+65%
25(O
H)D
ng/
ml
20
30
10
40
+D -DHeaney et al 2004
32 ng/ml
ExcessNormative
20-100 ng/ml
Deficient
>100 ng/ml
<20 ng/ml
25(OH)D
Preferred30-60 ng/ml
Did you know25(OH)D
Assay Most ordered AssayIn US
What does 25(OH)D2 & 25(OH)D3mean ?????
Should I just use thetotal ??
Use Total25(OH)D
Is Vitamin DDeficiency
a Health Problemfor
adults 50+ yrs?????
0
40
20
60
80
% o
f vo
lunt
eers
< 2
0 ng
/ml 25
(OH)D
Percent ADULTS>50 YRS who were vitamin D Deficient <20 ng/ml in August
White
30%
Black
84%
Hispanic
42%
Sunlight Deprivation > 65 years
25(OH)D < 10 ng/ml
In
54% community dwellers
38% nursing home
Gloth et al JAMA, 1995
Vitamin D DeficiencyIs an
unrecognizedepidemic
inadults 50+ yrs
CDC 42%
AFRICAN AMERICAN WOMENIN US AGES 15-49Y <15NG/ML
VITAMIN D DEFICIENT
37%
BMC MEDICAL STUDENTSAND RESIDENTS 18-29 y?????????????????????????VITAMIN D INSUFFICIENT
????% VITAMIN D
INSUFFICIENT
0
10
20
30
18-29(n=69) (n=69
Inci
denc
e of
Vita
min
D
Insu
ffici
ency
(%)
% VITAMIN D INSUFFICIENT <20ng/mlBMC RESIDENTS & STUDENTS
32% END WINTER
Tangpricha et al Am J Med 2002
4% END SUMMER0
20
40
60
80
100
120
Sep-00 Mar-01 Sep-01 Mar-02 Sep-02 Mar-03
Date
25(O
H)D
(nm
ol/L
)
0
1
0
20
3
0
40
48% D-DEFICIENT<20 ng/mlEND OF WINTER
MAINE GIRLS AGES 9-11
SULLIVAN,ROSEN,HOLICK
25
(OH
)D N
G/M
L
0
20
40
60
80
100
120
Sep-00 Mar-01 Sep-01 Mar-02 Sep-02 Mar-03
Date
25(O
H)D
(nm
ol/L
)
0
1
0
20
3
0
40
SULLIVAN,ROSEN,HOLICK 2002
25(O
H)D
NG
/
17% D-DEFICIENT<20 ng/ml
END OF SUMMER
MAINE GIRLS AGES 9-11
52% D-deficient
<20 ng/ml
1-5 yrs 50 %< 30 ng/ml
6-11 yrs 70 %< 30 ng/ml
Vitamin D Deficiency
• Osteomalacia
• Osteoporosis• 2º HPTH
Subclinical
Vitamin D Deficiency
PRECIPITATES &
EXACERBATES OSTEOPOROSIS
Symptoms• Generalized bone pain
• Muscle aches
• Isolated bone pain
40-60% OSTEOMALACIA
25(OH)D<5ng/ml
25(OH)D = 35ng/ml
23%
Non-immigrant and Immigrant SubjectsSerum 25-Hydroxyvitamin D Levels (ng/ml) in
35
30
25
20
15
10
5
0Non-immigrant Subjects Immigrant Subjects
150 aged 10-65 yrsBone & Muscle Pains
93% Vitamin D Deficient
Subjects With Undetectable 25-Hydroxyvitamin D
Rx NSAID, intermittent narcotic agents,SSRI, TCA, Cardiovascular
Dysthymia/MDD,DJD refractory to surgery, angina refractory to PTCASomatoform D/O?
Severe non-radicularlow back pain, intermittent chest pain,depressed mood, insomnia, weakness
AA58Male
OTC NSAID, SSRI,Neuroleptic agent
MDD/PTSDDiffuse MSK pain,fatigue, insomnia, headache, weakness
EastAfrican
35Female
OTC NSAID,Pre-natal vitaminsInsulin
Pregnancy 3rd T.Gestational DM
Severe non-radicularLBP, fatigue, depressed mood, insomnia, weakness
AA27Female
OTC and Rx NSAIDs, TCA
Dysthymia, stress reaction
Diffuse MSK pain,Fatigue, insomnia
Asian26Female
OTC and Rx NSAIDs
Dysthymia, non-DJD low back pain
Non-radicular LBP, weakness, fatigue
Cauc23 Female
MedicationsDiagnosesSymptomsRaceAge/Sex
VITAMIN D DEFICIENT
WHY DO YOU HAVE PAIN WITH
OSTEOMALACIA
???????
IT IS THE JELLO
PHENOMENON
!!!!!!!!!!!!!!!!!!!!!
142
Priemel et al.100% > 30 ng/ml
Holick There is TOOMuch scatterFor the PTH
Plateau!!!
Serum 25(OH)D (ng/mL)
20 25 30 35 40 45 50 55
OV/
BV (%
)
0
1
2
3
4
5
6IOM>20
Priemel>30 ng/ml
IOM25(OH)D > 20 ng/ml97.5 % no evidence
OSTEOMALACIA
25(OH)D> 30 ng/ml= no Osteomalacia!
151
78 Y/O MMUSCLE WEAKNESS
ATROPHY, DENERVATION
+EMG
+NCS 152
ALSSymptoms resolved
Rx VITAMIN Dprogressive painless muscle weakness with muscle atrophy,which manifests like lower motor neuron diseaseand improves after vitamin D supplementation
153 154
Time to Stand vs 25(OH)D Levels
Bischoff-Ferreri et al
~20-40 ng/ml
155 156
DID YOU KNOWVDR IS IN
SKELETAL MUSCLE!!!
157
VITAMIN D IS GOOD FOR
MUSCLE STRENGTH
158
72% Less Falls800 IU/d 5 months
159
28-32 ng/ml
JCEM 2007 160
WHITE
Mex Am
BLACK
~20-40 ng/ml
162
163
0 6 12 18 24 30 360
2
4
6
8
10
12
14
Month
Cum
ulat
ive
Inci
denc
e (%
)
After Dawson-Hughes, NEJM 1997
Incidence of Non-Vertebral Fractures in Men & Women >65yrs
Placebo
500 mg Ca 700 IU D
~58%
164
25(OH)D > 30 ng/ml
↑Muscle strength, ↑balance,
↑lower extremity function↑ BMD
↓Fall risk ↓ Fxs
TREAT VITAMIN D DEFICIENCY
50,000 IU VITAMIN D2
ONCE/WEEK
8 WEEKS
6000 IU/d
Cut in halfAdd Milk etc
MAINTAIN VITAMIN D SUFFICIENCY
50,000 IU VITAMIN D
ONCE/ 2WEEKS3000 IU/d
DEFICIENT
INSUFFICIENT
SUFFICIENT
0
20
30
40
50
60
70
0 72Time (Months)
Me
an
25(O
H)D
(n
g/d
L)
20 ng/ml
40 ng/ml6 yrs
MEAN 25(OH)D LEVELS IN PATIENTS RECEIVING 50,000 IU VITAMIN D2 EVERY 2 WEEKS FOR 6 YRS
3000 IU/d
Pietras Arch Int Med 2009 R2D2
IS D3REALLY MORE
EFFECTIVETHAN D2
????
C3PO
10
15
20
25
30
35Mean Serum Total 25(OH)D Levels
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12
25
(OH
)D L
eve
l (n
g/m
l)
P=0.45
P=0.63
P=0.45
P=0.75P=0.65
P=0.27
P=0.59P=0.17 P=0.71
P=0.45 P=0.30
P=0.54
Time (weeks)
PLACEBO
1000 IU D2
1000 IU D3
Time (weeks)
Me
an 2
5(O
H)D
Levels
(ng/m
l)
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
1 2 3 4 5 6 7 8 9 10 11 12
Mean Serum 25(OH)D2 and 25(OH)D3 in Subjects receiving Vitamin D2
1000 IU D2
25(OH)D2
25(OH)D3
173
1000 IU Vitamin D3/d
or500 IU Vitamin D3
+500 IU Vitamin D2/d
Ch
ang
e in
Se
rum
25
(OH
)D L
eve
ls (
ng
/ml)
Time (weeks)
1 2 3 4 5 6 7 8 9 10 11 12
32
30
28
26
24
22
20
18
1000 IU D2
500 IU D2+500 IU D3
Ch
ang
e in
Se
rum
25
(OH
)D L
eve
ls (
ng
/ml)
Time (weeks)
1 2 3 4 5 6 7 8 9 10 11 12
32
30
28
26
24
22
20
18
1000 IU Vitamin D
Sufficient
No one was sufficient
WILL YOU BECOME VITAMIN D
INTOXICATED????
,ELEVATEDCa,Pi,25(OH)D
CALCIFY BLOOD
VESSELS &KIDNEYS
CU ORC
177
SAFETY AT HIGH DOSES· 33 males· aged 38.7 yr
(± 11.2 )· dosed with
vit D3 from October thru February
· 5,000 & 10,000 IU/d
Pre Post
SERU
M C
ALCI
UM (m
g/dL
)
8.0
8.5
9.0
9.5
10.0
10.5
11.0
Vieth et al 1998
10,000 IU/dIs Safe
1 MILLION IUVITAMIN D/DAY
1000 IU/TSP
KOUTIA et al NEJM 20002
Ca= 15.2 mg/dl
25(OH)D= 520 ng/ml
IT IS DIFFICULT
TO BECOMEVITAMIN D
INTOXICATED
WHO IS AT RISK FOR VITAMIN DDEFICIENCY????????
H o w m u c h c a l c i u m d o w e n e e d ?
EVERYONE
!!!!!!!!!!!!!!!
WHY SHOULDI CARE ??????
Skin
1,25(OH)2D3
25(OH)D3
Liver
25-OHase
Kidney
1α-OHase
VDR
VDR
VDR
VDR
VDR VDR
VDR
VDR
VDRVDR
VDRVDR
VDRVDR
VDR
VDREVERY TISSUE AND CELL HAS A VDR
Suda et al 1979 RX -1,25(OH)2D3
1915 8X more likely to
DieWorked Indoors
Colon Cancer M ortality Rates
1970-80 in W hite Fem alesHighest 10% for Colon Cancer Mortality
Garland & Garland. Intern J Epid. 1980
Colon Cancer M ortality Rates1970-1994
Inverse Relationshipbetween 25(OH)D Levels & Risk of Colon Cancer
Garland et al 1989
195
50% PROJECTED REDUCTION25(OH)D = 40 ng/ml
50% PROJECTED REDUCTION25(OH)D = 27 ng/ml
50% PROJECTED REDUCTION25(OH)D = 38 ng/ml
50% PROJECTED REDUCTIONWITH 480 IU/D
50% PROJECTED REDUCTIONCOLON CANCER WITH 1000 IU/D
Garland et al 2005
I HATE TAKING CALCIUM & VITAMIN DEVERY DAY
60 %Did not follow
Protocol
<12 ng/ml
253%
INVASIVE COLORECTALCANCER
8 years
Breast Cancer Mortality Inversely Correlates with Mean Solar Radiation
Breast Cancer Mortality Inversely Correlates with Mean Solar Radiation
After Garland et al., Preventive Med, 1990
Solar radiation(calories per square centimeter)
250 300 350 400 450 500 550
Bre
ast c
ance
r mor
talit
yra
te p
er 1
00,0
00
20
22
24
26
28
30
32
34
PhoenixHonolulu
TampaFort Worth
El PasoAlbequerque
San AntonioLexington
Oklahoma City
Salt Lake CityMiamiNashville
Lincoln
San Diego
OmahaAtlanta
Los AngelesBrookhaven
Omaha
New Orleans
IndianapolisLong Island
Columbus
CambridgeWashington D.C.
Cleveland
Boston
Seattle
Pittsburgh
Lynn, MAChicago
New York MORTALITY
25(OH)D = 48 ng/ml
50% LOWER RISK
By looking at the latitudinal variation ofbreast cancer mortality rates in Europe,and controlling for diet, Grant foundthat lack of UV-B from sunlight accountsfor perhaps 25% of the breast cancermortality ratesin northern Europe. 47,800 MEN
INCREASEDDECREASEDRISK
43% LOWER RISK> 400 IU/d
Premature Mortality due to Cancer with Insufficient UV-B, White Males, U.S., 1970-1994, vs. July 1992 DNA-Weighted UV-B Radiation
UV-B (kJ/m2)
3 4 5 6 7 8 9 10 11
Mor
talit
y R
ate
(cas
es/1
00,0
00/y
ear)
-10
0
10
20
30
W. Grant 2002
MORTALITY
INCREASE SUN EXPOSURE
WHITE MALES & FEMALES
y = 0.2238x + 25.905R2 = 0.1888
30
32
34
36
38
40
42
40 45 50 55 60 65
Rate (Cases per 100,000)
Latit
ude
(Deg
rees
N)
r = 0.44
latitude versus the number of all individuals diagnosed with colon cancer independent of race in the state of California.
COLON CANCER IN CALIFORNIA
INCREASE LATITUDE
MORTALITY
San Diego
San Francisco
223 224
Kaplan-Meier plot showing association of UVR exposure and age at diagnosis with prostate cancer
Age at diagnosis (years)
Pro
porti
on tu
mor
free
Lowest quartile
cumulative exposure
1.00
0.75
0.50
0.25
09080706050
C. J. Luscombe et al, The Lancet Vol 358 Num 9282, 2001
Upper three quartiles of exposure
3-5 YEARS
Lappe et al AJCN 2007
60%LESS
CANCERS1179 PM WOMEN1200MG Ca +- D3ALL CANCERS
YEARS 0-4
1100 IU D3
Girls 10-19 yrs most sun 69%
Women 20-29 yrs most sun 51%
Women 45-54 yrs most sun 0.0%Cancer Epi Biomarkers & Prev 07
25(OH)D
1,25(OH)2D
This is a REAL
CONUNDRUM!!!!!!!!!
1-OHase
25(OH)D 1,25(OH)2D
Autocrine Regulation of Cell Growth
Control of cell growth
CALCITROIC ACID
INACTIVE
Colon Cell
Gene Transcription
Apoptosis
Bcl-2Bcl-XLMcl-1
BAG1LXIAPcIAP1cIAP2
DifferentiationMATURATION
Nucleus
Cell-cycle Arrest
CDK2, p21, p27, p53Ki67, E-Cadherin
25(OH)D>30 ng/ml
RXRVDR
1-OHaseMitochondria
1,25(OH)2D3
1,25(OH)D3
~ 2000 Genes Affected
By 1,25(OH)2D236
ACTIVATED MACROPHAGES
Metabolize 25(OH)D3 to 1,25(OH)2D3
25(OH)D3 1,25(OH)2D3
Adams et al JCEM 1987
1849
Brompton Hospital Records, 38 1849
Codliver oil - Rx Tuberculosis
25(OH)D
1,25(OH)2D
Death
19K
Da
Cathelicidin mRNA
TB
1-OHase mRNA
1-OHase
Cathelicidin
TLR2/1MACROPHAGE
Liu et al Science 2006
Why is fluSeason alwaysIn the WINTER
???????
1981 Edgar Hope-SimpsonSuggested a “SEASONAL STIMULUS”
Jan-Mar
Jan-Mar25(OH)D
winter
32 ng/ml
12 ng/ml
Aloia et al 2007
2000 IU/D
90% URIs
25(OH)D=38 ng/ml 2X
Influenza A + School Children
Placebo 18.6%
+1200 IU Vitamin D 10.8%
Type 1 Diabetes/100,000Boys<14 yrs
10X
15X
Garland et al 2008
Hypponen et al. Lancet 2001
Annual age-adjusted incidence rates of type 1 diabetes, children < 14 years old, per 100,000 population, Finland, 1965-2005
15
25
35
45
55
65
1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010
Year
Inci
denc
e ra
te 1964RecommendedVitamin D intakeReduced from4500 to 2000 IU/d
Beta-ISLET CELL1,25(OH)D3
VDR +VDR +
Insulin+
Metabolic Syndrome & Type 2 Diabetes
Ca<500 mg
> 1200 mg
< 400 IU
> 800 IU
D D+
Ca
0.67
RR
Typ
e 2
DM R
R 33%
Ca > 1200 MG+
VIT D > 800 IU
Pittas et al JCEM 07
Scragg et al Diabetes Care 27:2813;04
DIABETES INVERSELY RELATED
SERUM 25(OH)D
WHITES-NH 75%
MEXICAN-AM 83%
BLACKSNO EFFECT
North-South Gradient in Mortality from MS
100%MS 35
Vitamin D Intake (>400IU/D) Inversely Related To MS
In Women
41%
Vitamin D Intake (>400IU/D) Inversely Related To RA
In Women
44%
OSTEOARTHRITIS
Rostand 1979Reported
Inverse ReationshipBetween
BP & Latitude
Association between Latitude
andBlood
Pressure
Hypertension 1997; 30:150-156262
263
PVD & 25(OH)D
80%
>29 ng/ml
PVD vs 25(OH)D Quality Heath Care Worldwide
ABBOTTRENAL GLOBALDevelopment
264
Vitamin D deficiency in humansis associated with heart failure.
RXRDNA binding
RNA Pol IICoReg
VDR
VDR
B
VDRERNA Pol II
Suppression of Renin Transcription by VDR
Activation
VDRRXR
↓ Renin
Blood Pressure
LVH
ReninRenin TGACCT TGACCT
Atherosclerosis,Inflammation,
oxidative stress
> 200 Genes inHeart & Vessels
RXR
First MI >50% Increase Associated
With Vitamin D Deficiency
Arch Int Med 2008
28 ng/ml
8-13 ng/ml
All108%
CV122%
What are the consequences of
Vitamin D Deficiency on
Our health ???
2.4 X HBP2.5 X Elevated BS4 X Metablolic Syndrome
50 Million TeensDeficient/Insufficient 49 NT Blacks 16 yrs
400 vs 2000 IU/d 4 Mos
25(OH)D 11 to 24 ng/ml 400 IU/d
25(OH)D 11 to 34 ng/ml 2000 IU/d
Significant Decrease inArterial Wall Stiffness
Dong et al JCEM 95;2010
All Cause MortalityDecreased 7%On 528 IU Vitamin D
IOMIncrease mortality 25(OH)D> 30 ng/ml
ADEQUATE VITAMIN D
IS NECESSARY FROM BIRTH-
DEATH
IS A DISEASE OF NEGLECT
VITAMIN D THERE IS NOWA MOUNTAIN OFEVIDENCE LINKINGVITAMIN D DEFICIENCY
WITH CANCER RISK & MORTALITY
AUTOIMMUNE DISEASESTYPE 1 DIABETESHYPERTENSIONTYPE 2 DIABETES
!!!!!
100 IU VITAMIN D3RAISES 25(OH)D
BY ONLY
1NG/ML.
CHILDREN & ADULTS HAVE
25(OH)D ~18 -25 ng/ml
Seru
m 2
5(O
H)D
Leve
ls (
ng
/ml)
Time (weeks)
1 2 3 4 5 6 7 8 9 10 11 12
32
30
28
26
24
22
20
18
1000 IU vitamin D/d
Sufficient
No one was sufficient
HOLICK HOW DO YOU GET
THE MESSAGE OUT ??????
MAY 04
I DO NOT ADVOCATETANNING !!!!!!!!!!!!
ANCESTORS APPRECIATION OF THESUN FOR ITS LIFE GIVING BENEFITS
UNENLIGHTENED DERMATOLOGISTSVIEW OF THE SUN’S EFFECT ON HEALTH
Galileo recanted IMPRISIONED FOR THE REST OF HIS LIFE
InquisitorsNEED
Large RCTs
Agency for Astronomical Research
AndQuality
AARQ
Need more Randomized Controlled
AstronomicalTrialsRCATs
!!!!!!!!!!!!!!!!!!!
AARQ
Need more Randomized Controlled
AstronomicalTrials
!!!!!!!!!!!!!!!!!!!
RCATs
Instituted Hand WashingPrevent Maternal & Infant
Mortality
Commited himselfInsane Asylum
Died Infection
ALWAYS WEARA SUNSCREEN
DERMATOLOGIST ADVISING ABOUT SUN EXPOSURE
NEVER BE EXPOSED
TO THE SUN !!!!!!!!!!!!!!!!!!!
Slip, Slap, Slop
87% < 20 ng/ml
87% Vitamin D Deficient end of Summer
Australian dermatologist
Schizoprehenia
Vitamin D DeficiencyAssociated with:
DepressionDementia
25(OH)D <10 ng/ml
RR=31%
YOU CAN GET IT FROM
DIET !!!
YOU CANNOT GET IT FROM
DIET
00If you and your familyare not taking at least
1000-2000 IU/dYou are
Vitamin D Insufficient
316
WHAT IS YOUR 25(OH)D LEVEL
????????
+ 2000 IU Vitamin D3+ MTV=400 IU+ 3 glasses milk += 300 IUMy Total Vitamin D= 2700 IU/d
My 25(OH)D = 52 ng/mlVitamin D Deficiency
Is TheMost COMMON
Medical Condition
VITAMIN D DEFICIENCYCAUSES CONSEQUSUN SUNSCREEN
MELANINLATITUDEWINTER
MALABSORPTIONCrohn’s Whipple’sCystic FibrosisCeliacLiver disease
Hepatic Failure
Renal FailureNephrotic syndrome
Obesity
MEDICATIONS AntiseizureGlucocorticoidsRifampinHAARTSt John’s Wart
SchizophreniaDepression
FEV1
Wheezingillnesses
Muscle weaknessMuscle aches
OsteoporosisOsteomalaciaRickets
AutoimmuneType 1 DiabetesMSCrohn’sRA
AODMSyndrome X
HBPCHD
CANCERColonBreastProstateetc.
INFECTIONSURITB
Osteoarthritis
X
Holick NEJM July 07
There Is NoDownside
To IncreasingVitamin D Intake !!!!
We NeedSensible
Sun &
Vitamin D Supplementation
Recommendations !!!!!!!!
You Do Not Need To Be A Genius To Know
This is NOT
HYPOTHESIS
Do we need toScreen everyoneFor their 25(OH)D level???????????????
No !!!!!!!
But YesBMI>30
MalabsorptionMeds/AEs., Glc
Sarcoidosis
April 1, 2010
DrHolick.com
IOM RDA UL0-0.5 YEARS0.5-1 YEARS
400 IU/D 10001500
1-8 YEARS9-12 YEARS
600 IU/D 25003000
13-70YEARS 600IU/D 400070+YEARS 800IU/D 4000
Adequate Intake 0-1 YEAR 600-1000 IU/D
1-12 YEAR 1000-2000 IU/D13+ YEARs1500-2000 IU/D
Obesity 2-3 Times more
SAFE UPPER LIMIT
0-1 YEAR 2000 IU/D1-12 YEAR 5000 IU/D13+ YEARs 10,000 IU/D DrHolick.com