MargiAnne Isaia, MD MPH Advanced Nutrition Vitamin D

VITAMIN D Resurgence of interest in vitamin D, reasons: Vitamin D deficiency is a worldwide problem with health consequences Rickets Current research indicating Vitamin D deficiency plays a role in causing varieties of Cancer, Heart Disease, Stroke, Autoimmune Diseases, Diabetes, Depression, Chronic Pain, Osteoarthritis, Osteoporosis, muscle weakness, muscle wasting, birth defects, Periodontal Disease. 1billion people worldwide have Vitamin D deficiency of insufficiency. VITAMINS & MINERALS

VITAMIN D - not really a vitamin in the strictest sense (our body manufactures it) - must be regarded as a pro-hormone Two forms: - D 2 Ergocalciferol, Found in wild mushrooms or formed by irradiation of Ergosterol in yeast; - D 3 Cholecalciferol, Found in animal sources, or formed under condition of adequate UV irradiation of 7-Dehydrocholesterol (skin). VITAMINS & MINERALS

VITAMIN DFunctions BONE HEALTH Maintains normal blood levels of Calcium and Phosphorus (absorption of calcium) (Without Vitamin D, only 10 to 15 % of dietary Calcium and about 60% of Phosphorus are absorbed) Promotes bone mineralization REGULATION OF IMMUNE FUNCTION REGULATION OF CELL GROWTH

VITAMIN D VITAMINS & MINERALS

VITAMIN D SOURCES Exposure to sunlight (UV exposure affected by season, latitude, time of day, cloud cover, smog, sunscreen etc) Food sources (cod liver oil, salmon, cooked, egg, wild mushrooms) Fortification (milk is fortified with 10 mcg=400 IU D 3 per quart)

VITAMINS & MINERALS VITAMIN D Latitude and Vitamin D production in the skin Except during the summer months, the skin makes little if any vitamin D from the sun at latitudes above 37 degrees north (in the United States, the shaded region in the map) or below 37 degrees south of the equator. People who live in these areas are at relatively greater risk for vitamin D deficiency.

VITAMINS & MINERALS VITAMIN D BIOCHEMICAL TRANSFORMATION Conversion to active form - Liver 25-hydroxylase a 25-(OH) D3 - Kidneys 1 a-hydroxylase a 1, 25-(OH) 2 D 3 24-hydroxylase - Activated by 1, 25-(OH) 2 D 3 - Involved in catabolism of 1, 25-(OH) 2 D 3 to water-soluble biologically inactive Calcitroic Acid Active form (hormone): 1, 25-(OH) 2 D 3 Major circulating form: 25-(OH) D 3 [assessment of Vitamin D status] Rate limiting enzyme: 25-hydroxycalciferol-1-hydroxylase - stimulated by low serum P and low serum Ca - stimulated by PTH and other factors (fibroblast growth factors 23, FGF-23)

VITAMINS & MINERALS VITAMIN D

Beneficial circulating level of 25-(OH) D 3 Reference range: ng/ml (preferred range: ng/ml) Deficiency: 150ng/ml Level for healthy bones: 30 ng/ml Optimal health: ng/ml Cancer prevention: ng/ml Very controversial data regarding the recommended level Importance: Vitamin D plasma status level must be on the annual check- up In the absence of adequate sun exposure IU Vitamin D/day (90 % of our Vitamin D in the blood is related with sun exposure) Vitamin D 2 equally effective with Vitamin D 3 in maintaining circulating level of 25-(OH) D 3 VITAMINS & MINERALS VITAMIN D

Actions of 1, 25 – (OH) 2 D 3  Calcium absorption in small intestine - by interacting with the Vitamin D receptor-retinoic acid x-receptor complex (VDR-RXR) to:  Expression of the epithelial Calcium channel protein  Expression of the Calcium-Binding Protein (CaBP)  Calcium resorption  Expression of the Receptor Activator of Nuclear factor-kB ligand (RANKL) Involved in inducing preosteoclasts to become mature osteoclastes Mature osteoclasts remove Ca 2+ and HPO 4 2- from bone, maintaining Ca and P levels in the blood Adequate Ca and P levels promote mineralization of the skeleton VITAMINS & MINERALS VITAMIN D

VITAMINS & MINERALS VITAMIN D

VITAMINS & MINERALS VITAMIN D AND NON-SKELETAL FUNCTIONS - Maintains normal cell proliferation Tissues in the body, including brain, prostate, breast, colon, and others have the enzymatic machinery to locally produce 1, 25-(OH) 2 D. It controls more than 200 genes responsible for the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis. - Potent immune-modulator Monocytes and macrophages exposed to a lipopolysaccharide or to M. tuberculosis up-regulate the vitamin D receptor gene and 25-(OH) D-1a- hydroxylase gene. Increased production of active Vit D results in synthesis of Cathelicidin (bactericidal protein, able of destroying M. tuberculosis and other infectious agents). When there is vitamin D deficiency, the monocytes and macrophages are prevented from initiating this innate immune response. - Inhibits Rennin synthesis - Increases Insulin production Increases myocardial contractility

VITAMINS & MINERALS VITAMIN D

Regulation of plasma Calcium Parathyroid gland -Drop in serum Ca results in h PTH Role of PTH  Formation of active Vitamin D  Re-absorption of Ca by kidney  Bone resorption Role of Vitamin D  Calcium absorption  Re-absorption of Ca by kidney  Bone resorption VITAMINS & MINERALS VITAMIN D

Clinical significance Vitamin D deficiency: Children: Rickets Adults: Osteomalacia (bone pain including, associated with joints pain, muscle pain and weakness). Muscle weakness is associated with Vitamin D deficiency (proximal muscles). Misdiagnosed as Fybromyalgia, degenerative joint disease, arthritis, chronic fatigue syndrome, etc. Osteoporosis Increased risk for common cancers (colon, prostate, breast), autoimmune diseases, hypertension, infectious diseases (tuberculosis), depression. VITAMINS & MINERALS VITAMIN D

VITAMINS & MINERALS VITAMIN D Recommendations: Sun exposure: ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen Adequate Intake AI: Children, birth to 13 years: 200 IU 14 to 18 years: 200 IU Adults, 19 to 50 years: 200 IU 51 to 70 years: 400 IU 71 + years: 600 IU

VITAMINS & MINERALS Causes of Vitamin D Deficiency Reduced skin synthesis: Sunscreen use- absorption of UVB radiation by sunscreen Skin pigment- absorption of UVB by melanin Aging- reduction of 7-dehydrocholesterol in the skin Season, latitude, and time of the day Patients with skin grafts for burns Decreased bioavailability Mal-absorption- reduction in fat absorption resulting from cystic fibrosis, celiac disease, by-pass surgery, medication that reduce cholesterol absorption, other. Obesity-sequestration of Vitamin D in body fat

VITAMINS & MINERALS Causes of Vitamin D Deficiency Increased catabolism Anticonvulsants, glucocorticoids, HAART (AIDS treatment), etc Breast-feeding-poor Vitamin content in human milk Decreased synthesis of 25-(OH) D –liver failure Increases urinary loss of 25-(OH) D – nephritic syndrome Decreased synthesis of 1, 25 – (OH) 2 D Chronic kidney disease-stages 2 and 3 -stages 4 and 5 Heritable disorders-rickets Acquired disorders: tumors, hyperthyroidism, sarcoidosis, etc.

Vitamin D supplementation to prevent deficiency: - infants who are exclusively breastfed - older adults - persons with limited sun exposure - persons with greater melanin skin content - persons with fat malabsorption VITAMINS & MINERALS VITAMIN D

Current issues and controversies about Vitamin D Vitamin D and Osteoporosis Vitamin D and Cancer Vitamin D and steroids Vitamin D and Alzheimer’s disease Vitamin D and caffeine Caffeine may inhibit Vitamin D receptors, limiting absorption VITAMINS & MINERALS VITAMIN D

Vitamin D toxicity Public Health concern for The US: High intake of Vitamin D in supplements Never get toxic level from sun exposure: excessive exposure to sunlight degrades pre-vitamin D 3 and Vitamin D 3 into inactive photoproducts. Can cause: nausea, vomiting, poor appetite, constipation, weakness, weight loss. Raise blood levels of Calcium (mental status changes, heart rhythm abnormalities) VITAMINS & MINERALS VITAMIN D

LIPIDS REFERENCES 1. Shils M et al, Modern Nutrition in Health and Disease, 10 th Edition 2. www. Pubmed.org

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