Vitamin D: does diet matter? Professor Helen Macdonald, University of Aberdeen

Vitamin D: does diet matter? Professor Helen Macdonald, University of Aberdeen

Overview Introduction Where we get it and world status Current guidelines Sunlight and diet What are the relative contributions

Vitamin D Vitamin D needed for calcium uptake. Vitamin D deficiency - rickets in children. Today rickets emerging in some ethnic groups. Low vitamin D elderly, older children & young adults. Glasgow City Archives. Licensor www.scran.ac.uk Child Welfare Clinic, Cochrane Street, Glasgow 1922: Sunlamp treatment to produce vitamin D to help prevent rickets.

Vitamin D and Chronic Disease Vitamin D receptor (VDR) found in numerous cell types Enzyme that converts circulating form to active form has been found in cell types other than the kidney Epidemiology Low vitamin D status Cancer Coronary Heart Disease Infections Immune type 1 diabetes, Multiple Sclerosis etc TOTAL MORTALITY 18 RCT Autier, P 2007 CONFOUNDING!!: physical activity/ ill health Sunlight effects independent of vitamin D?

Vitamin D and ill health problems of confounding The Lancet Diabetes & Endocrinology 279 prospective cohort studies; 172 randomised trials High 25(OH)D concentrations were NOT associated with a lower risk of cancer, except colorectal cancer. Discrepancy between observational and intervention studies: is low 25(OH)D a marker of ill health? Inflammation reduces 25(OH)D - reason low levels associated with wide range of disorders? Vitamin D supplementation in the elderly (mainly women) at 20 μg/day - slight reduction in all-cause mortality Restoration of vitamin D status (low levels induced by ill health) could explain why low-dose supplementation leads to slight gains in survival

Vitamin D sources

Vitamin D : importance of sunshine Sunlight Diet Sunlight and warmth converts cutaneous (skin)7-dehydrocholesterol to vitamin D3 Only in April to October in the UK Stored and used over the winter Factors affecting production External: pollution, cloud cover Internal: skin colour, behaviour Fortified foods: Margarine Some breakfast cereals Vitamin D3, vitamin D2

Vitamin D 90% sunlight 10% diet LIVER Sunlight source or dietary source of vitamin D (D3 or D2) Converted to 25-hydroxyvitamin D KIDNEY Converted to 1,25-dihydroxyvitamin D (vitamin D-activating cytochrome P450 1alpha-hydroxylase (CYP27b))

Units and definitions Vitamin D international units (IU) and micrograms (µg) 400 IU is 10 µg 25-hydroxyvitamin D (25OHD) marker of vitamin D status Measured in nmol/l also ng/ml 25 nmol/l is 10 ng/ml Standard erythemal dose (SED) 1 SED is 100 J m -2 2-3 SED is 1 MED (minimal erythemal dose for Caucasian)

Hypovitaminosis D in the UK (< 40 nmol/l 25(OH)D) Hypponen E AJCN 2007

Global 25(OH)D (nmol/l) MIDDLE EAST EUROPE AFRICA ASIA van Schoor, N 2011

Global 25(OH)D (nmol/l) NORTH AMERICA SOUTH AMERICA AUSTRALIA van Schoor. best practice & res clin endocrin & metab 2011

KEY POINT NUMBER 1 Lack of UVB at higher latitudes can result in less vitamin D synthesis BUT vitamin D deficiency can still occur in sunnier climates

Dietary and Supplement Guidelines for Vitamin D

Lower threshold for optimal 25OHD levels (nmol/l): shifting opinions IOM, 2011 Willet Proc Nutr Soc 2005

Populations and individuals If healthy population has a mean 25(OH)D 40 nmol/l: 25(OH)D 40 nmol/l To be sure that an individual has adequate recommend 50 nmol/l as that covers 97.5% of population needs 30 nmol/l 50 nmol/l

US Institute of Medicine 2011 (released november 2010) 50 nmol/l or above will be adequate for 97.5% of the population Below 30 nmol/l most of the population could be at risk of deficiency No justification for higher circulating concentrations of 25OHD Most Americans have sufficient vitamin D Recommended vitamin D intakes 600 IU (15 μg) vitamin D daily >70 years 800 IU (20 μg) daily Estimated average requirement 400 IU (10 μg) daily Tolerable upper intake level Adults and children 9 years and older: 4000 IU (100 μg) daily Young Children: from 1000 IU birth-6 mo to 3000 IU at 4y-8 y

Endocrine Society Guidelines Deficiency < 50 nmol/l Adults 600 IU for bone health but may need 1500-2000 IU for 25(OH)D > 75 nmol/l Obese people, those on anticonvulsant therapy, steroids, AIDS treatment, malabsorption syndrome need 2-3x as much (ie 3000 6000 IU a day)

Blurring of treatment of patients versus public health National osteoporosis guidelines Results of testing < 30 nmol/l treat 30-50 nmol/l treat if... > 50 nmol/l reassure and advice

Treatment of PATIENTS with bone disease LOADING DOSE 50,000 IU one a week for 6 weeks (300,000 IU) 10,000 IU two a week for 7 weeks (280,000 IU) 800 IU, five a day for 10 weeks (280,000 IU) MAINTENANCE OF DOSE (1 month after loading) 800 IU 2000 IU (occasionally up to 4000 IU) daily DO NOT RECOMMEND Annual depot (intramuscular or orally) Activated preparations (calcitriol)

KEY POINT NUMBER 2 There are many opinions and guidelines as to what concentration of 25(OH)D constitutes appropriate vitamin D status Consider whether it is population means, individual recommendations, public health guidelines or treating patients with symptoms

KEY POINT NUMBER 3 Although 25OHD currently remains the best marker of vitamin D status, there still problems in standardising 25OHD values from different studies Depending on laboratory used

Sunlight and diet contributions

Dietary intakes Most populations have limited dietary vitamin D intakes Survey data 3µg/d (120 IU) The mean daily vitamin D intake of older women was 3.5µg (140 IU) and addition of supplements increased this by 46% to 5.1µg (200 IU) Study data - low intakes 2.5 µg (100 IU) Increased with supplements (cod liver oil 5 µg, 200 IU)

Food Foods containing vitamin D Oily fish: mackerel Vitamin D μg/100g 8.2 Tuna 3.6 Salmon Eggs 1.8 Egg yolks 4.9 Milk 5.9 Atlantic 12.5 Pacific Tr-0.1 Butter 0.9 Fortified Food Hard Margarine 7.9 Vitamin D μg/100g Soft margarine 5.0-8.4 Breakfast cereals All bran, cornflakes, frosties, museli, fruit & fibre Bran flakes Shreddies Ricicles Special K 10 ug=400iu McCance and Widdowson s v6 0 4.2 (1.3) 2.8 4.2 8.3 H. Macdonald

Vitamin D status in Scottish men and women Excluding metabolites in meat Including metabolites in meat 2.5 11.5 4.4 12.9 0.0 17.9 2.4 48.3 Meat Fish Dairyeggs Fruitveg Cerealspasta biscakeconf misc fats 0.3 4.9 17.5 0.0 14.6 8.8 16.9 37.0 Meat Fish Dairyeggs Fruitveg Cerealspasta biscakeconf misc fats Vitamin D intake 3.77 ug/day Contribution from meat is less. More from fish Vitamin D intake 3.62 ug/day This includes potency factors for vitamin D metabolites in meat Unclear how robust this evidence is. H. Macdonald

Holick sunlight prescription for optimal vitamin D Whole body exposure to sun can produce 10,000 25,000 international units of vitamin D in one day If a quarter of MED (minimal erthymal dose) (about 0.5 SED for a Caucasian) if expose face hands and arms or legs (25% body): produce around 1000 IU vitamin D

Holick sunlight prescription for optimal vitamin D nearer the equator Can make vitamin D all year round when nearer the equator Minutes of sunshine BUT need to be exposed to sunlight to make it

Websites for exposure times to obtain sufficient vitamin D http://nadir.nilu.no/~olaeng/fastrt/vitd_quartmed.html Recommended UV exposure of face, hands and arms at least every other day to obtain sufficient vitamin D, equivalent of 25 micrograms vitamin D, if no dietary vitamin D is available: Processing... (this may take a minute)done Output: minimum recommended exposure time (hours:minutes) 0: 4

Singapore - estimate of required sunlight exposure Skin type type 1-4 min type 3-5 min type 6-19 min Weather Overcast 40 min

KEY POINT NUMBER 4 Only minutes of sunlight exposure are required, more exposure will not mean more vitamin D, as it will be broken down if there is sufficient sunlight exposure, diet plays a minor role in vitamin D status but it may play a crucial role when sunlight is limited

Diet and sunlight contributions when sunlight is lacking (Aberdeen Studies)

Aberdeen Sunlight, Nutrition and VItamin D longitudinal study Diet Aberdeen Nutrition Sunlight and Vitamin D study (ANSAViD) First UK longitudinal study 15 month study starting Spring 2006 plus extra visit in Spring 2008 360 women visit unit every 3 months Food Standards Agency funded Surrey followed the Aberdeen design for 12 mo so could compare North and South Alex Mavroeidi Sunlight dosimeter badges Skin colour Assessment Sunlight exposure diary

ANSAViD Macdonald OI 2011

Aberdeen: holidays abroad and cod liver oil associated with improved vit D status 25(OH)D holiday vs no holiday goers CLO users vs non-clo users 80.00 80.00 70.00 70.00 25(OH)D nmol/l 60.00 50.00 40.00 30.00 20.00 ALL 25(OH)D no hols 25(0H)D hols 25(OH)D 25(OH)D nmol/l 60.00 50.00 40.00 30.00 20.00 ALL 25(OH)D Non CLO CLO 10.00 10.00 0.00 Spring 06 Summer 06 Autumn 06 Winter 06/07 Spring 07 Spring 08 0.00 Spring 06 Summer 06 Autumn 06 Winter 06/07 Spring 07 Spring 08 visits visits Mavroeidi, Macdonald PLOSone 2013 i. Small amounts make a difference (CLO provides 200 IU) ii. Consistency between measurements at the nadir

VICtORy intervention study Vitamin D and CardiOvascular Risk Study design 1 year intervention 2 doses of vitamin D and placebo (400 IU and 1000IU), 100 subjects in each group Healthy women, non-smokers, age 65 years (60-70y) HIGHLIGHT FEATURE Start everyone at Jan- Feb and see every 2 months Dr Adrian Wood, Karen Secombes

25(OH)D according to treatment group 90.0 80.0 70.0 60.0 50.0 40.0 30.0 Group 1 Group 2 Group 3 20.0 10.0.0 Jan-Feb Mar-Apr May-Jun Jul-Aug Sep-Oct Nov-Dec Jan-Feb A.Wood, JCEM, 2012; Macdonald JBMR 2013

Seasonal variation in systolic BP Systolic BP, mean ± 95% CI 135 High vit D Placebo 133 Low vit D 131 129 mmhg 127 125 123 121 119 Visit 117 115 0 1 2 3 4 5 6 There was a significant seasonal variation in mean sys BP (p<0.001, repeated measures ANOVA) No difference between groups A.Wood, JCEM, 2012

New findings: vitamin D and immune system regulation Autoimmune diseases occur when immune system becomes over active and attack own cells Regulatory T-cells are key in keeping immune system in balance At 25(OH) D nadir (low point), association between 25(OH)D and regulatory T cells (T-regs) Light (UVB) treatment in dermatology patients rapidly increased T-regs Regression models: 25(OH)D and oral vitamin D predictors of early rise in Tregs UVB dose associated with IL10

Arguments for and against diet Arguments for advising increasing dietary vitamin D Sunlight is dangerous Skin cancer Cataracts Diet can provide a safe alternative Arguments against advising against increasing dietary vitamin D Reliance on diet miss out on benefits of small amounts of sunlight Immune function sunlight has an effect independent of vitamin D Toxicity is rare but may not be measuring all adverse outcomes Interaction between diet and sunlight, and data from oral dosing studies suggest resistance to increasing 25(OH)D Vitamin D stores provide vitamin D in winter Season is the major determinant of vitamin D status Individual exposure less important due to degradation pathways with longer exposure If require high 25(OH)D cut-offs the amount required from oral route will be very high and foreign to the gut (except unusual diets)

Conclusions Diet is important If no sunlight exposure reliant on diet, but the diet does not provide enough For those at risk of deficiency there are recommendations for taking supplements For normal healthy people Some populations may currently be at risk of deficiency Do we need to completely avoid the sun and increase amounts orally?? Calcium deficiency? Dietary calcium is vitamin D sparing Still arguments whether current guidelines are sufficient If need more then how we achieve this may change Sunlight Food fortification

Acknowledgments ANSAViD Alex Mavroeidi Fiona O Neill Sharon Gordon John Leiper Kim Giles Lana Gibson Lorna Aucott Bill Fraser (Liverpool) Brian Diffey (Newcastle) VICtORY Adrian Wood Karen Secombes Lismy Cherapetti Roger Francis Bill Fraser Lorna Aucott Bill Simpson Kim Giles Bill Fraser (UEA) Funders: Food Standards Agency: Any views expressed are the authors own NbUVB Collaboration with Tony Ormerod, Mark Vickers, Rob Barker BMedSci: Sarah Milliken APOSS Thanks to David Reid: Set up APOSS Alison Black consultant rheumatologist Radiographers Elaine Rennie Lana Gibson, Jenny Scott. Thank you to all the participants who took part in our trials National Osteoporosis Society