Part 1: Vitamin D Update 2010


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This a lecture that I delivered to the Missouri State Chiropractic Association in February 2010 in Kansas City, Missouri.

Published in: Health & Medicine

Part 1: Vitamin D Update 2010

  1. 1. Missouri State Chiropractors Association District II Andrew S. Bonci, BA, DC Private Practice of Chiropractic Instructor, National American University
  2. 2. Disclosure ● I work for NO special interest or lobbying groups nor do I receive stipends, consulting fees, gratuities or honoraria from any pharmaceutical or nutritional companies. ● I am anti-Big Pharma and it will show. (sorry folks)
  3. 3. Objectives ● Causes of Vitamin D Deficiency ● Consequences of Vitamin D Deficiency ● Clinical Considerations for Vitamin Deficiency Recommendations
  4. 4. ● Because of the convincing evidence for benefit and the strong evidence of safety, we urge those who have the ability to support public health—the media, vitamin manufacturers, and policy makers—to undertake new initiatives that will have a realistic chance of making a difference in terms of vitamin D nutrition. nutrition ● We call for international agencies such as the Food and Nutrition Board and the European Commission’s Health and Consumer Protection Directorate-General to reassess as a matter of high priority their dietary recommendations for vitamin D, because the formal nationwide advice from health agencies needs to be changed.
  5. 5. Vitamin D and All-Cause Mortality ● The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population. Arch Intern Med. 2008 Aug 11;168(15):1629-37.
  6. 6. What is Vitamin D? ● Vitamin D (calciferol) comprises a group of fat soluble seco-sterols found naturally only in a few foods, such as fish-liver oils, fatty fish, mushrooms, egg yolks, and liver. ● The two major physiologically relevant forms of vitamin D are D2 (ergocalciferol) and D3 (cholecalciferol).
  7. 7. “D” Facts ● Is a hormone not a vitamin. ● Controls 2,000 genes. ● RDA is 400 IU/day ● Is non-toxic under 40,000 IU/day ● Is the most Anti-American “vitamin” ● Is anti-aging, anti-cancer, anti-hypertension, anti-infection … it's anti-everything … almost!
  8. 8. A History of Vitamin D
  9. 9. History of D Dificiency ● Is the History of Rickets ● Mellanby and McCollum 1919/20
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  11. 11. An American Version
  12. 12. Vitamin D Endocrinology: Canonical Mechanism
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  14. 14. Ultraviolet-B penetrates into the Stratum Spinosum and Ultraviolet-B the Stratum Basale of the epidermis. SS SB M
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  16. 16. Where is Vitamin D Synthesized? ● Vitamin D from the skin or diet is only short-lived in circulation (with a half-life of 1–2 days), as it is either stored in fat cells or metabolized in the liver (Mawer 1972). ● In circulation, vitamin D is bound to vitamin D-binding protein and transported to the liver, where it is converted to 25-hydroxyvitamin D [25(OH)D] (DeLuca 1984).
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  18. 18. Vitamin D is a Hormone ● Active vitamin D functions as a hormone, and its main biologic function in people is to maintain serum calcium and phosphorus concentrations within the normal range by enhancing the efficiency of the small intestine to absorb these minerals from the diet (DeLuca 1988; Reichel 1989).
  19. 19. Negative Feedback Regulation ● In the liver, vitamin D-25- hydroxylase is down- regulated by vitamin D and its metabolites, thereby limiting metabolites any increase in the circulating concentration of 25(OH)D following intakes or following production of vitamin D after exposure to sunlight. ● In the kidney, in response to serum calcium and phosphorus concentrations, the production of 1,25(OH)2D is regulated through the action of parathyroid hormone (PTH) (DeLuca 1988; Reichel 1989).
  20. 20. Vitamin D Endocrinology ● When dietary calcium intake is inadequate to satisfy the body’s calcium requirement, 1,25(OH)2D, along with PTH, mobilizes calcium stores from the bone. ● In the kidney, 1,25(OH)2D increases calcium reabsorption by the distal renal tubules. ● Apart from these traditional calcium-related actions, 1,25(OH)2D and its synthetic analogs are increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities (Nagpal 2005).
  21. 21. Vitamin D Activation ● To be biologically activated at physiologic concentrations, 25(OH)D must be converted in the kidneys to 1,25- dihydroxyvitamin D [1,25(OH)2D], which is thought to be responsible for most, if not all, of the biologic functions of vitamin D (DeLuca 1988; Reichel 1989). ● The production of 25(OH)D in the liver and of 1,25(OH)2D in the kidney is tightly regulated.
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  24. 24. Steroid Action Steroid hormone Cell membrane Newly forming protein molecule Ribosome mRNA Nucleus mRNA Intracellular protein receptor DNA Hormone-receptor complex Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
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  26. 26. Vitamin D Endocrinology: Non-Canonical Mechanisms
  27. 27. Paracrine Vitamin D ● The revelation that the colon, breast, prostate, macrophages and skin among other organs have the enzymatic machinery to produce 1,25-dihydroxyvitamin D provides further insight as to how vitamin D plays such an essential role for overall health and well being. Mol Aspects Med. 2008 Dec;29(6):361-8.
  28. 28. “The classical renal regulators of 1-hydroxylase, parathyroid hormone, and ambient calcium do not regulate 1-hydroxylase in osteoblasts. This study showing expression, activity, and functionality of 1-hydoxylase unequivocally demonstrates that vitamin D can act in an auto/paracrine manner in bone.”
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  30. 30. Schematic diagram of auto/paracrine actions of vitamin D in bone. ●The 25-(OH)D3-vitamin D binding protein (DBP) complex binds to its receptors cubilin and megalin on the membrane of osteoblasts and is internalized. ●The complex is dissociated and DBP degraded while 25- (OH)D3 is converted into 1,25- (OH)2D3 in the mitochondria. ●Next, 1,25-(OH)2D3 can bind to its receptor (VDR) and modify cellular activity. ●The eventual result is induction of CYP24 and osteocalcin mRNA expression, an increase in osteocalcin protein, alkaline phosphatase activity, and enhancement of mineralization.
  31. 31. Vitamin D Receptor ● … [vitamin D's ability] to play such an important role in health is based on observation that all tissues and cells in the body have a vitamin D receptor, and, thus, respond to its active form 1,25-dihydroxyvitamin D. Mol Aspects Med. 2008 Dec;29(6):361-8.
  32. 32. ● Ultraviolet-A penetrates to the level of the dermis. ● This can have deleterious effects on dermal Ultraviolet-A collagen fibers SS and serum folic acid levels. SB M
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  35. 35. Melanin, Protection & Folate Nina Jablonski, PhD, Anthropologist, Penn State University (TED.COM)
  36. 36. Vitamin D Improves Folate Status ● Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol. 2009 Nov;76(5):1062-71.
  37. 37. Folate and DNA Methylation Functions of DNA methylation in mammals: ● Transcriptional gene silencing ● Chromatin compaction ● Genome stability ● Suppression of homologous recombination between repeats ● Genome defense
  38. 38. Sun vs Sustenance ● Most of the dietary intake of vitamin D comes from fortified milk products and other fortified foods such as breakfast cereals and orange juice (Institute of Medicine 1997). ● Both vitamin D2 and D3 are used in nonprescription vitamin D supplements, but vitamin D2 is the form available by prescription in the United States (Holick 2007).
  39. 39. Factors Influencing Synthesis ● Under conditions of regular sun exposure, dietary vitamin D intake is of minor importance. ● However, latitude, season, aging, sunscreen use, and skin pigmentation influence the production of vitamin D3 by the skin (Institute of Medicine 1997).
  40. 40. Vitamin D Analogs ● Vitamin D3 is photosynthesized in the skin of vertebrates by the action of solar ultraviolet (UV) B radiation on 7- dehydrocholesterol (Fieser 1959). ● Vitamin D2 is produced by UV irradiation of ergosterol, which occurs in molds, yeast, and higher-order plants.
  41. 41. Factors Affecting Skin Production of Vitamin D
  42. 42. Skin Type: Melanin Content ● Type I skin always burns, never tans, and is extremely fair. ● Type II skin always burns, occasionally tans, and is considered fair. ● Type III skin occasionally burns, gradually tans, and is considered medium. ● Type IV skin rarely burns, always tense, and is considered Olive. ● Type V skin seldom burdens, always tense, and is considered medium to dark. ● Type VI skin never burns, always tends darkly, and is considered dark.
  43. 43. The Ultraviolet Index
  44. 44. UV Index Whoever wishes to investigate medicine properly should proceed thus: in the first place consider the seasons of the year … Hippocrates (circa 400 B.C.)
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  47. 47. Global Latitude
  48. 48. Vitamin D Winter
  49. 49. Degree of Obesity
  50. 50. Aging
  51. 51. Air Quality
  52. 52. Sunblock
  53. 53. Sunblock SPF 15 blocks 95% of UVB
  54. 54. Clothing
  55. 55. How to Raise your Clinical Suspicions
  56. 56. Raised Clinical Suspicion ● Age ● Bone Pain ● Race ● Muscle Pain ● Skin Color ● Girdle Muscles ● Posture ● Tender Tibias ● Chronic Diseases ● Tender Stermun ● Recurring Infections ● Tender Ilia ● Tender Heels ● Fatigue
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  58. 58. Clinical Assessment ● Vitamin D deficiency affects persons of all ages. ● Common manifestations of vitamin D deficiency are symmetric low back pain, proximal muscle weakness, muscle aches, and throbbing bone pain elicited with pressure over the sternum or tibia. Am Fam Physician. 2009 Oct 15;80(8):841-6.
  59. 59. Think Osteomalacia ● Osteomalacia is a disorder in which the structural and metabolic functions of the skeleton are impaired because newly formed bone matrix fails to mineralize. ● It usually results from vitamin D deficiency.
  60. 60. Think Osteomalacia ● Patients often complain of aching bones and muscle discomfort. ● Such patients are often misdiagnosed with fibromyalgia, chronic fatigue syndrome, myositis, or other nonspecific collagen vascular diseases. ● It is estimated that 40-60% of patients with fibromyalgia may have some component of vitamin D deficiency and osteomalacia. American Journal of Clinical Nutrition, Vol. 80, No. 6, 1678S-1688S, December 2004
  61. 61. Osteomalacia Mechanism ● ...vitamin D deficiency causes a mineralization defect of the collagen matrix that is laid down by osteoblasts. ● The rubbery matrix does not provide structural support, which increases the risk of fracture. ● Collagen matrix that is not properly mineralized becomes hydrated, causing an outward expansion on the periosteal covering, which is highly innervated with sensory pain fibers. American Journal of Clinical Nutrition, Vol. 80, No. 6, 1678S-1688S, December 2004
  62. 62. Index of Suspicion for Osteomalacia ● Bone pain, deformities, myalgias, weakness, and fragility fractures ● Back pain similar to that of osteoporotic vertebral compression fractures Weakness may be profound in severe osteomalacia and may be attributable to absence of direct stimulatory effects of vitamin D on muscle cell function and to the low levels of Ca and phosphorus.
  63. 63. Think Vitamin D Deficiency ● More than 90% of 150 children and adults 10–65 y of age who presented with nonspecific muscle aches and bone aches and pains at a Minnesota hospital were found to be vitamin D deficient. American Journal of Clinical Nutrition, Vol. 80, No. 6, 1678S-1688S, December 2004
  64. 64. It's Bigger than Rickets
  65. 65. There's an Epidemic But What are the Numbers?
  66. 66. It Depends ... If you set the reference interval too low, then there is no problem statistically or epidemiologically. If you set the reference interval too high, then there is a very big problem statistically and epidemiologically.
  67. 67. How to Lie with Statistics Lisa-Anne Bero, PhD Pharmacology University of California, San Francisco
  68. 68. A Word about Reference Intervals A reference interval does NOT indicate a normal or optimal range of function.
  69. 69. What is the “Normal Range”? ● No common definition exists for adequate vitamin D status measured as 25(OH)D serum concentrations (Dawson- Hughes 2005). ● The Institute of Medicine (1997) defined vitamin D deficiency as serum 25(OH)D concentrations of less than 11 ng/mL (27.5 nmol/L) for neonates, infants, and young children.
  70. 70. No consistent Definition ● There were no consistent definitions of hypovitaminosis D; values corresponding to vitamin D deficiency ranged from less than 5 ng/mL to less than 12 ng/mL, and those for vitamin D insufficiency ranged from less than 10 ng/mL to less than 32 ng/mL. Arch Pediatr Adolesc Med. 2008 Jun;162(6):513-9.
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  74. 74. Is there a problem?
  75. 75. A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitamin D nutritional status, and shows considerable variation. Serum 25(OH)D nmol/L 160 120 140 130 80  100 70 40 40 0 Primates Old-World Primates Humans Humans with UV Canadians Canadian Winter 1000 IU Canadian + 25 ug/d 4000 IU Canadian + 100 ug/d in sun in winter supplement supplement
  76. 76. Prevalence of Deficiency ● Breastfed infants in winter who did not receive vitamin D supplementation were the most severely vitamin D deficient (78%). ● Estimates of the prevalence of hypovitaminosis D ranged from 1% to 78%. Arch Pediatr Adolesc Med. 2008 Jun;162(6):513-9.
  77. 77. A Deficient Definition ● Because the lower limit of the normal range can be as low as 8 ng/mL (20 nmol/L) and as high as 15 ng/mL (37.5 nmol/L), depending on the geographic location, vitamin D deficiency has been defined as a concentration of less than 12 ng/mL (mid-range between 8 and 15 ng/ mL) for adults (Institute of Medicine 1997).
  78. 78. Revising the “Normal Range” ● More recently, some scientists have suggested that the criteria used to define adequate status should be revised upwards; serum 25(OH)D concentrations between 20 ng/mL (50 nmol/L) and 32 ng/mL (80 nmol/L) have been defined as sufficient (Hollis 2005; Dawson-Hughes 2005; Bischoff-Ferrari 2006; Norman 2007). Cedric Garland, DrPH
  79. 79. An Evidence-Based Range ● 0-14.9 ng/mL = Severely deficient ● 15.0-31.9 ng/mL = Mildly deficient ● 32.0-100.0 ng/mL = Optimal ● >100.0 ng/mL = Michael Hollick, MD, PhD Toxicity possible
  80. 80. New Emerging Serum Vitamin D Norms Vitamin D status (ng/dL) (nmol/L) Deficient <20 <50 (high risk) Insufficient 20-29 50-72 (moderate risk) Adequate 30 or higher 73 or higher (low risk) Serum vitamin D test results (25-Hydroxyvitamin D) are shown in these two units.
  81. 81. Practice Guidance Lacking ● ...little evidence guides clinicians on when to screen for vitamin D deficiency or effective treatment options. J Am Board Fam Med. 2009 Nov-Dec;22(6):698-706.
  82. 82. Vitamin D and Your Skin An MED (Minimum Erythemic Dose) yields approximately 20,000 IU.
  83. 83. Vitamin D and Your Skin ● The skin produces approximately 10,000 IU vitamin D in response 20–30 minutes summer sun exposure—50 times more than the US government's recommendation of 200 IU per day!
  84. 84. Tanning Beds ● A UV lamp that emits ultraviolet radiation similar to sunlight and thus produces vitamin D(3) in the skin is an excellent alternative for patients who suffer from vitamin D deficiency due to fat malabsorption, especially during the winter months when natural sunlight is unable to produce vitamin D3 in the skin. Photodermatol Photoimmunol Photomed. 2007 Oct;23(5):179-85.
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  86. 86. Proper Protective Eyewear
  87. 87. Vitamin D Supplementation ● Children under 100# ● 1,000 to 2,000 IU/day Vitamin D ● Adults 100# to 150# ● 2,000 to 3,000 IU/day Vitamin D ● Adults over 150# ● 3,000 to 5,000IU/day Vitamin D
  88. 88. Supplementation in Illness ● In those with serious illnesses associated with vitamin D deficiency, such as cancer, heart disease, multiple sclerosis, diabetes, autism, and a host of other illnesses, oral doses of 10,000IU should be sufficient to maintain year-round 25(OH)D levels between 55 -70 ng per mL. Altern Med Rev. 2008 Mar;13(1):6-20.
  89. 89. Supplementation Suggestion ● Treatment of vitamin D deficiency in otherwise healthy patients with 2,000-7,000 IU vitamin D per day should be sufficient to maintain year-round 25(OH)D levels between 40-70 ng per mL. Altern Med Rev. 2008 Mar;13(1):6-20.
  90. 90. Supplementation in Illness ● Vitamin D-deficient patients with serious illness should not only be supplemented more aggressively than the well, they should have more frequent monitoring of serum 25(OH)D and serum calcium. ● Vitamin D should always be adjuvant/adjunctive treatment in patients with serious illnesses and never replace standard treatment. Altern Med Rev. 2008 Mar;13(1):6-20.
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  92. 92. Seasonal Deficiency Odds
  93. 93. Racial Deficiency Odds
  94. 94. BMI vs Plasma Concentration
  95. 95. Physical Activity Odds
  96. 96. Toxicity ● Vitamin D is fat soluble, and accumulation (from diet) in the body can be toxic. ● The long-term safe dose of vitamin D is not known, however, 10,000 IU /day is safe in healthy adults ● All known cases of vitamin D toxicity have involved intake of or over 40,000 IU/day. ● The LD50 in man is unknown – there are no reported deaths from acute toxicity.
  97. 97. What about Toxicity? ● A common definition for high serum vitamin D concentrations is also lacking. ● The Institute of Medicine (1997) used serum calcium concentrations greater than 11 milligrams per deciliter (mg/dL) for assessing the potential for increased risk of harm associated with high vitamin D intakes. ● To date, however, no evidence has surfaced of adverse effects with serum 25(OH)D concentrations as high as 56 ng/mL (140 nmol/L) in healthy individuals (Vieth 1999).
  98. 98. 10,000 IU/day is Safe ● Even prolonged physiologic- replacement intake of 10,000 IU per day of vitamin D3 would pose no known risk of adverse effects in virtually all adults (25).
  99. 99. How Much is That? ● 1 IU is the biological equivalent of 0.025μg of cholecalciferol or ergocalciferol. ● 10,000IUs is 250μg ● 250μg is 0.25mg
  100. 100. D Toxicity Reduced by A ● These data suggest that 9-cis RA mitigated 1,25(OH)(2)D3- induced renal calcification by modifying the 1,25(OH)(2)D3- induced increase in Matrix gamma-Carboxyglutamic Acid. J Nutr. 2008 Dec;138(12):2337-41.
  101. 101. D Toxicity Blunted by K ● Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. ● An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. Thromb Haemost. 2008 Oct;100(4):593-603
  102. 102. What is this “D” Thang? ● We no longer see vitamin D as a "vitamin" important only in childhood, but as a complex hormone that is involved not only in calcium homeostasis but also in the integrity of the innate immune system. ● Vitamin D deficiency is linked to inflammatory and long-latency diseases such as multiple sclerosis, rheumatoid arthritis, tuberculosis, diabetes, and various cancers, to name a few.” Breastfeed Med. 2008 Dec;3(4):239-50.