1. A Modern Day Epidemic: Vitamin D Deficiency Amy B. Locke, M.D., ABHIM March 2009

2. The Industrial Diseases  17 th Century: First cases of Rickets described –Rickets became endemic until early 20 th Century when treatments of sun exposure and cod liver oil discovered  Early 20 th Century: Tuberculosis common –Patients improved with sun exposure  21 st Century: Link with many diseases better described including CVD, DM, osteoporosis, fracture and fall risk, cancer, susceptibility to infection, depression, etc. Misra et al Pediatrics 2008 and Tavera-Mendoza and White Sci Am 2007

3. Case 1  57 year old woman presents with increased fatigue over the last few years. She works long hours. She feels achy, her mood is generally lower than in the past. She sleeps 8 hours nightly. Her diet is generally healthy but quantity may be an issue. Her blood pressure is 140/86. BMI is 31. Her thyroid labs are slightly off. Vitamin D level is 13 in March.

4. Case 2  25 year old woman of Indian descent presents with depression, much worse since moving to Michigan from California 18 months ago. Last winter was the worst she’s been. She has tried light therapy (helps some), omega-3 fatty acids and a B- complex vitamin. She exercises regularly. Vitamin D level is 16 in January.

5. Overview  Physiology: the basics  Definition and prevalence of deficiency  Causes of deficiency  Clinical implications and screening  Treatment options  Safety and toxicity concerns

6. A modern day pandemic  Estimated 1 billion people worldwide  64% of women in multinational study in 18 countries: S. America, Europe, The Middle East, Asia, Australia 1  U.S. study showed 84% of Boston AA men and women > 65 yrs had 25D of 65 yrs had 25D of < 20 2  Pregnant women 50% and infants 65% in one Boston study 3 J Steroid Biochem Mol Biol 2007 2 Curr Opin Endocrinol Diabet 2002 3 Clin Pediatr 2007 1 J Steroid Biochem Mol Biol 2007 2 Curr Opin Endocrinol Diabet 2002 3 Clin Pediatr 2007

7. Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004  NHANES III data compared from 1988-1994 with NHANES 2001-2004  Increased rates of deficiency (25D)  Those with adequate levels (>30) fell from 45% to 23%  Those with most severe deficiency (<10) increased from 2% to 6% (in blacks 9% to 29%) Ginde et al Arch Intern Med 2009

8. Disorders possibly related to deficiency of vitamin D  Rickets  Osteoporosis  Cardiovascular Disease  Cancer, multiple types  Diabetes, Types I and II  Multiple Sclerosis  Influenza susceptibility  Tuberculosis susceptibility  Osteoarthritis  Psoriasis  Depression  Asthma  Schizophrenia (in utero deficiency)  Autism (in utero deficiency)  Gout  Migraine  Seizure disorders  Pancreatitis  Pre-eclampsia  Chronic kidney disease  PCOS

9. Definitions  Cholecalciferol (D3)  Ergocalciferol (D2)  25-hydroxyvitamin D (25D) –Measured in serum  1, 25-dihydroxyvitamin D (1,25D) –Active metabolite

10. Definition of Vitamin D deficiency Serum 25HD (ng/ml) Vitamin D status <10 Severe deficiency 10-20Deficiency 21-29Insufficiency >30Sufficiency >150Toxicity J Am Coll Cardiol 2008; 52:1949-56

11. UVB light + 7- hydrocholesterol 25, hydroxy-Vitamin D (Calcidiol) Vitamin D3 (Cholecalciferol) Kidneys (skin/immune cells) To Vitamin D Receptors Keratinocytes D3 or D2 Liver (or skin) 1,25 dihydroxy-Vitamin D (Calcitriol) 25D Target cells

12. Vitamin D Receptors (VDR)  1, 25D acts as switch to turn genes on and off in almost all cells in body by binding to VDR  VDR combines with another protein, binds to region of DNA called vitamin D response element and aids in transcription of genes  At least 1000 genes known to be regulated by 1,25D Tavera-Mendosa and White, Scientific American

13. Causes of Deficiency  Reduced skin synthesis –Sun screen blocks 99% absorption –Skin pigment –Geographic and seasonal effects –Clothing and lifestyle  Decreased bioavailability  Medications  Liver and kidney diseases  Heritable/acquired disorders  Genetic polymorphisms

14. Vitamin D oral intake  Foods – –Salmon 3.5 oz   Wild ~ 600–1000 IU   Farmed ~ 100–250 IU   Canned ~ 300–600 IU – –Sardines ~300 IU – –Tuna, canned ~230 IU – –Shitake mushrooms   3.5 oz fresh 100 IU   3.5 oz dried 1600 IU – –Fortified foods   8oz ~ 100 IU   Milk/Yogurt   Infant formula   Orange Juice  Supplements –D3 vs. D2 –Prescription D2  50,000 IU/weekly –Over the counter  MVI – generally 200-400 IU –D2 or D3  D3 – 400 IU &1000 IU tabs  D3 – liquid 1000 IU/drop

15. Vitamin D from the Sun  Depends on skin pigment, sun screen use, shade, season, latitude, clothing choice, etc.  Mid-summer, fair skin –Full exposure: 10,000 IU in 15-20 minutes  further time in sun does not create more vitamin D –Arms/legs: 3000 IU in 10 minutes  Winter in the North –The further North, the less vitamin D –None Nov to Feb at 35-42 degrees latitude –Related to angle of sun and distance waves travel through atmosphere

16. Tavera-Mendoza and White, Scientific American November 2007 Availability of adequate UVB to synthesize Vitamin D

17. Skeletal processes  Rickets  Osteomalacia, osteopenia, osteoporosis  Musculoskeletal pain/weakness, loss of balance  Falls – Meta-analysis of supplementation –NNT = 15. JAMA 2004 –NNT = 15. JAMA 2004;291(16):1999-2006  Osteoarthritis progressed more rapidly if 25D levels: < 36 (knee) or 30 (hip) Ann Intern Med 1996 Sep 1;125(5):353-9

18. Cardiovascular Disease  Chronic Vitamin D deficiency associated with: –Coronary artery disease –Congestive heart failure –Left ventricular hypertrophy –Chronic vascular inflammation Circulation 2008; 118:1476-1485  Major adverse Cardiovascular events 53-80% higher in people with Vitamin D deficiency –1,739 Framingham Offspring participants –Risk magnified in those with HTN –Adjustment for CRP, physical activity, vitamin use did not alter findings Circulation 2008;117:503-511

19. Hypertension  Lower 25D levels independently associated with a higher risk of developing hypertension Hypertension 2008; 52: 828-832  Correction of Vitamin D deficiency –BP reduction up to 13/7 mmHg J Clin Endocrinol Metab 2001;86(4):1633-7

20. Diabetes  Vitamin D deficiency –Increases risk of Type 1 and 2 DM 1 –Decrease insulin sensitivity and production 1  Supplementation to normal levels –Improves insulin secretion 2 –Improves glucose control 2 –Improved endothelial function 3 Am J Clin Nutr, 2004; 79: 820-5 2 Palomer Diabetes Obes Metab 2008 3 Sugden et al Diabet Med 2008 1 Am J Clin Nutr, 2004; 79: 820-5 2 Palomer Diabetes Obes Metab 2008 3 Sugden et al Diabet Med 2008

21. Autoimmune disorders  Multiple Sclerosis:  Living below 35’ latitude for the first 10 years of life reduces risk of developing MS by as much as 50% Ann Neurol. 2000; 48:271-272  High circulating levels of vitamin D are associated with a lower risk of multiple sclerosis. JAMA 2006; 296:2832-8  Type 1 Diabetes Mellitus:  2000 IU Vitamin D/day regularly in first year of life ~78% reduced risk of developing Type 1 Diabetes Lancet 2001; 358: 1500-1503

22. Immunity  1,25D stimulates transcription of genes that encode antimicrobial peptides that are active against viruses, bacteria and fungi 1  Rates of viral illness go down with supplement 2 1 Tavera-Mendoza and White Sc Amer 2007 2 Epidemiol Infect 2007; 135: 1095–96

23. Cancer  25D <20  30-50% increased risk of developing and dying from colorectal, prostate, breast, ovarian, or pancreatic cancers Am J Public Health, 2006; 96: 252-261  Estimated 50,000 to 70,000 die prematurely in US yearly due to cancer related to D deficiency Photochem Photobiol 2005; 81 (6):1276-86  Cancer incidence 77% lower if supplemented with 1000 IU Vit D and calcium (vs. calcium only or placebo) AJCN 2007; 85:1586-91

24. All Cause Mortality  Meta analysis: –18 independent RCT’s –57,311 participants –Average of 528 IU/d supplemental Vitamin D –5.7 years  7% reduction in all-cause mortality Arch Intern Med 2007; 167:1730-7

25. Pregnancy  Many diseases linked to antepartum and infant exposure to adequate levels –Diabetes –Schizophrenia –Small for gestational age –Rickets –Likely others  Good time to check level

26. Nursing  Average breast milk has very little Vitamin D due to widespread deficiency (~20IU/L)  Lactating women taking 4000 IU daily of D3 rose their own 25OHD > 30; Breast milk was adequate 1 1. Am J Clin Nutr 2004; 80: suppl 6:1752S-1758S

27. Safety and Toxicity  Toxicity (>150 ng/ml) results in hypercalcemia and hyperphosphatemia  Daily 50,000 IU can raise 25D >150 ng/ml  Absence of toxicity in healthy adults taking 10,000 IU D3 daily for several months 1  Consider following calcium levels in high risk individuals (i.e. renal failure) 1 Hathcock et al Am J Clin Nutr 2007

28. Supplementation - Adult Recommendations  “Adequate Intake”  Children/adults <50: 200 IU  Adults 51-70 : 400 IU  Adults >70: 600 IU  National Osteoporosis Foundation:  400-800 IU adults <50  800-1000 IU adults >50  Holick, in NEJM 2007  Treatment of deficiency then maintenance  800-1000 IU daily with sensible sun exposure or use of tanning bed/UVB radiation device or 50,000 IU D2 monthly to biweekly  Higher for specific conditions  Our recommendation depending on serum levels  2000-3000 IU common generic recommendation

29. Supplementation - Pediatrics  Current recommendations –American Academy of Pediatrics  400 IU daily –Review article in Pediatrics 2008 1  400 IU daily unless deficient/insufficient then –1000 IU daily for infants in first month of life –1000 -5000 IU daily for infants 1-12 months –>5000 IU daily for children over 1 year –They recommend using these values until replete then going back to 400 IU –In our experience with adults, as soon as the higher dose is stopped the serum level goes back down  Recommend 1000 IU daily in Winter and 400 IU Summer 1 Misra et al Pediatrics 2008

30. Treatment of Deficiency/Insufficiency  D3 at higher doses (2000 to 10,000 IU) daily vs.  50,000 IU weekly D2 for 8 weeks (Rx) –Good idea if severely deficient  Generally, check level in 8 weeks to monitor progress  Choose maintenance dose

31. Monitoring  25D eight weeks after initiate treatment  Consider season, sun exposure and supplementation (add up what getting in all supplements – MVI, calcium, etc.)  Consider checking calcium in those at very high doses and if renal failure  After that, may want to check intermittently to make sure adequate

32. Costs  Supplementation –Recently paid $8 for 180 1000 IU tablets ~ $1.33 for 30 day supply of 1000 IU daily ~ $4 for 30 day supply of 3000 IU daily  Serum 25D ~ $50 –Covered by insurance for dx of “screening”  Costs of not addressing problem –Estimated at $40-53 billion/yr in U.S. 1 1. Grant et al. Photochem Photobiol. 2005;81(6)

33. Cases revisited: Case 1  57 year old woman presents with increased fatigue over the last few years. She works long hours. She feels achy, her mood is generally lower than in the past. She sleeps 8 hours nightly. Her diet is generally healthy but quantity may be an issue. Her blood pressure is 140/86. BMI is 31. Her thyroid labs are slightly off. Vitamin D level is 13 in March.  Supplementation with 4000 IU of vitamin D leads to significant improvement in her fatigue and aches. Her blood pressure comes down to 130/80. Her thyroid numbers normalize.

34. Case 2  25 year old woman of Indian descent presents with depression, much worse since moving to Michigan from California 18 months ago. Last winter was the worst she’s been. She has tried light therapy (helps some), omega-3 fatty acids and B-complex vitamins. She exercises regularly. Vitamin D level is 16 in January.  Supplementation with 50,000 IU weekly of D2 combined with multiple trips back to California during the winter help significantly with her depressive symptoms.

35. Take home message  Vitamin D Deficiency –High prevalence –Easy to screen –Wide range of diseases may be modified –Opportunities for primary and secondary prevention –Supplementation is inexpensive and carries low risk

36. General Guidelines  Consider screening widely  Correct to at least 30 ng/ml  Sun exposure without sunburn  Vitamin D3 common daily dosing: –Adult: 2000-3000 IU Winter &1000 IU Summer –Kids: 1000 IU Winter & 400 IU Summer –Take with food – fat soluble  Consider following levels

37. Resources  “Cell Defenses and the Sunshine Vitamin”, Tavera-Mendoza and White, Scientific American, Nov 2007  “Vitamin D Deficiency”, Holick,  “Vitamin D Deficiency”, Holick, N Engl J Med July 2007   “Vitamin D Deficiency in Children and Its Management: Review of Current Knowledge and Recommendations”, Misra et al. Pediatrics Aug 2008  The Vitamin D Council –www.vitaminDcouncil.org www.vitaminDcouncil.org