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

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

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

Structure of Vitamin D

Endocrine, paracrine and intracrine functions of Vitamin D

Vitamin D Across the Lifespan Factors influencing accumulation of bone minerals: Heredity Gender Diet Physical activity Endocrine status Maternal vitamin D status

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 -</= 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

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 -mother’s exposure to UV rays and use of vit d predicted vit d and childhood bone mass

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

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

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

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

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 immunology…April 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

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.

Adults

Vitamin D Deficiency in Hospitalized Patients

Vitamin D Deficiency in Renal Transplant Patients

Vitamin D Inadequacy in Post-Menopausal Women

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

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

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

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)

1998 Serum levels of 1,25(OH)2D are tightly controlled by the kidneys & don’t 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. Implications profound: they imply that sunlight exposure which produces greater serum levels of 25(OH)D could result in a decreased risk of cancer in the sites where 1,25(OH)2D is synthesized locally.

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

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.

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)

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

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

Insert survival graph from Zhou article here Lung cancer Insert survival graph from Zhou article here

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)

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

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

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 > 10 glasses / week Milder protection seen for people age 20 – 29 No protection for people over age 45

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 <get this article: Breast Cancer Research and Treatment, May>Knight , 2007

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

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

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

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

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 > 600 IU of vitamin D / day vs. those who consumed < 150 IU / day Skinner, et al., 2006

Cancer Survival Summer / Fall (vs. Winter / Spring) diagnosis associated with improved survival in: Colorectal cancer Hodgkin’s lymphoma NSCLC Breast cancer

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

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 β cell function and insulin resistance High calcium intake is inversely associated with body weight

Type 2 Diabetes Nurses’ Health Study – 83,779 women (98% Caucasian) Daily intake of >1,200 mg calcium & >800IU vitamin D was associated with a 33% lower risk of type 2 diabetes compared with an intake of <600 mg calcium & <400 IU vitamin D Pittas, et al., 2006

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

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

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

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

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-α No difference in survival but blood levels not optimized Schleithoff, et al., 2006

Hypertension Prospectively followed two cohorts: Nurses’ Health Study – 1198 women Health Professionals Follow-up Study – 613 men Relative risk of hypertension: < 15 ng/mL vs > 30 ng/mL 25(OH)D Men: RR = 6.13 Women: RR = 2.67

Stroke

Chronic Kidney Disease

Multiple Sclerosis

Osteo- & Rheumatoid Arthritis

Where do we go from here? Routine screening Rectify deficiency / insufficiency Maintain levels through a patient-specific combination of diet, supplementation, and sun exposure

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

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

Goals in Maintaining Vitamin D Levels Prevent disease of deficiency – rickets, osteomalacia Prevent complications of insufficiency – impaired calcium absorption and increased bone resorption Minimize risks of future disease – cancer, cardiopulmonary diseases, diabetes, other immune-related diseases

25(OH)D concentration To prevent deficiency disease – > 25 nmol / L To prevent complications of insufficiency – > 50 nmol/L For maximum bone health and prevention of chronic disease – 75 – 100 nmol/L

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

Supplementation

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

Supplementation (peds) To correct deficiency

IOM Recommendations (AI) Age Children Men Women Pregnancy lactation Birth-13 yrs 5mcgs =200IU 14-18yrs 5 200IU 200 IU 19-50 Yrs 200 IU 51-70 10 400 IU 71+ 15 600 IU

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

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

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

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

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

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

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

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

How much sun? Significant skin exposure Adequate sun strength Time 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

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