The Dietary Requirement for Vitamin D: Looking Beyond Bone Bruce W. Hollis, Ph.D. Medical University of South Carolina Charleston, SC Presentation: Dr. Bruce Hollis 1
Metabolism of Vitamin D Under Conditions of Adequate Vitamin D Supply High/Normal Input of Cholecalciferol from diet or UVB METABOLITE COMPARTMENT Vitamin D 3 1 LEGEND Liver mitochondrial vit D-25-hydroxylase 1 2 2 3 Liver microsomal vit D-25-hydroxylase Renal 25(OH)D-1-hydroxylase 25(OH)D 1,25(OH) 2 D 24,25(OH) 2 D & Catabolism 4 5 Within Tissues Processing 1-OHase 6 In Plasma 3 4 5 6 Tissue (non-renal) 25(OH)D-1-hydroxylase Renal Mitochondrial 25(OH)D-24-hydroxylase Non-renal 1,25 (OH) 2 D- 24-hydroxylase An unregulated step in flow of metabolism A regulated step in the flow of metabolism 7 Catabolism and excretion When vitamin D supplies are adequate, flow of 25(OH)D through other potential pathways, including its utilization by peripheral tissues for paracrine regulation, is no longer compromised. Metabolism of Vitamin D Under Conditions of Low Vitamin D Supply METABOLITE COMPARTMENT Vitamin D 3 25(OH)D 1,25(OH) 2 D 24,25(OH) 2 D & Catabolism Low Input of Cholecalciferol from diet or UVB 1 2 4 5 Within Tissues Processing 1-OHase 6 In Plasma 3 1 2 3 4 5 6 Legend Liver mitochondrial vit D-25-hydroxylase Liver microsomal vit D-25-hydroxylase Renal 25(OH)D-1-hydroxylase Tissue (non-renal) 25(OH)D-1-hydroxylase Renal Mitochondrial 25(OH)D-24-hydroxylase Non-renal 1,25 (OH) 2 D- 24-hydroxylase An unregulated step in flow of metabolism A regulated step in the flow of metabolism 7 Catabolism and excretion The vessels represent metabolic compartments, stages in the metabolism of vitamin D. The height of the shaded portion of each vessel represents the relative concentration of each metabolite indicated in the figure. Vitamin D essentially does not occur in natural foodstuffs. Presentation: Dr. Bruce Hollis 2
Cutaneous Generation of Vitamin D How much solar exposure is required to synthesize endogenous vitamin D 3? A single initial MED dose of UVB radiation to a light-skinned individual will release approximately 20,000 IU vitamin D 3 into the circulation within 24 hrs. However, if an individual has very dark skin the exposure time for a MED could increase by 10-fold. Presentation: Dr. Bruce Hollis 3
Effect of UVB exposure time and skin colour on Vitamin D production : Yield of vitamin D White skin Very Dark skin Same capacity for vit D, different exposure-time requirements 20 min 120 min Childhood lack of vitamin D causes rickets Normal shape of female pelvis Contracted pelvis, in a case of osteomalacia (adult rickets). Normal childbirth would be impossible. Vieth 2001. Nutritional Aspects of Osteoporosis, Chapter 17, ed P Burckhardt, RP Heaney, B Dawson-Hughes; Academic Press Presentation: Dr. Bruce Hollis 4
Oral Supplementation of Vitamin D Circulating 25(OH)D as a Function of Oral Vitamin D 3 Intake 10,000 IU/d 5,000 IU/d 1,000 IU/d 400 IU/d Presentation: Dr. Bruce Hollis 5
How toxic is vitamin D? The U.S. Nutrition Guidelines state that the lowest observed adverse effect level (LOAEL) for humans is 2,000 IU vitamin D/day This statement is grossly in error and is an impediment to the health of humans Optimal Circulating Concentrations of 25(OH)D Presentation: Dr. Bruce Hollis 6
Vitamin D Status in Primates and Early Humans Serum 25(OH)D nmol/l Winter 160 43 o N 120 Latitude A 80 80 Humans 40 exposing full skin Blood 0 Old-World Primates surface to Levels Northern People Taking Normal Sunshine s when taking 4000 IU/day UVB 1000 IU/day Physiological adult intake Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000 Haddad and Chyu JCEM 1971, 33: 992-995 995 Group No. Age (years) Consumption Of D Weekly (units) Weekly Exposure to Sunlight (hours) Plasma 25 HCC (ng/ml) Normal Volunteers 40 30.2 12.9 2230 1041 8.8 6.1 27.3 11.8 Biliary Cirrhosis 4 1.5-55 2500 (est.) 6.4 2.6* Lifeguards 8 18.5 2.0 2895 677 53.0 10.3 64.4 8.7* * P <.001 + values represent mean SD Normal Vitamin D Status Should NEVER have been defined by Gaussian distribution. This is similar to defining normal estrogen levels by sampling a population of women whom are primarily postmenopausal. Presentation: Dr. Bruce Hollis 7
Biomarkers for Vitamin D Sufficiency 25(OH)D Intact PTH Bone Mineral Density (BMD) Intestinal Calcium Absorption Mobility responsiveness Insulin sensitivity Beta cell function Immune function Circulating cytokines Activation of human TLR2/1 triggers a vitamin D receptor-dependent antimicrobial response Philip T. Liu* 1, Steffen Stenger* 2, Huiying Li 3, Linda Wenzel 2, Belinda H. Tan 1, Stephan Krutzik 1, Maria Teresa Ochoa 1, Jürgen Schauber 4, Kent Wu 1, Christoph Meinken 2, Manfred Wagner 5, Robert Bals 6, Andreas Steinmeyer 7, Ulrich Zügel 8, Richard L. Gallo 4, David Eisenberg 3, Martin Hewison 9, Bruce W. Hollis 10, John S. Adams 7, Barry R. Bloom 9 and Robert L. Modlin 1,11. 1 Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles (UCLA), California, USA. 2 Institut für Klinische Mikrobiologie, Immunologie, und Hygiene, Universität Erlangen, 91054 Erlangen, Germany. 3 Department of Chemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-Department of Energy Institute of Genomics and Proteomics, UCLA. 4 Division of Dermatology, University of California San Diego, and VA San Diego Healthcare Center, San Diego, California, USA. 5 Klinikum Nürnberg, Medizinische Klinik 3, Germany. 6 Pneumologie, Universität Marburg, Germany. 7 Medicinal Chemistry, Schering AG, Berlin, Germany. 8 CRBA Dermatology, Schering AG, Berlin, Germany. 9 Department of Medicine, Division of Endocrinology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048. 10 Departments of Pediatrics, Biochemistry, and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425. 9 Office of the Dean, Harvard School of Public Health, Boston, MA 02115, USA. 11 Division of Dermatology, Department of Medicine, David Geffen School of Medicine at UCLA. *These authors contributed equally to this work. Vitamin D and the Innate Immune System In 1903, Niels Ryberg Finsen was awarded the Nobel Prize for his work, demonstrating that UV light was beneficial to patients with Lupus vulgaris. The beneficial effects of UV exposure to tuberculosis patients is also known. Presentation: Dr. Bruce Hollis 8
Rickets and Infection Rickets is not only associated with skeletal abnormalities but also respiratory infections. In 1994 a brief study demonstrated that respiratory infections in children with elevated alkaline phosphatase levels were eliminated by supplementing them with 60,000 IU vitamin D/wk for a period of 6 wks. Addition of 25D3 restores ability of sera from African American individuals to support TLR2/1L mediated induction of cathelicidin mrna Fold Change 8 7 6 5 4 3 2 1 Cath. mrna 25D3 TLR2/1L -- + -- + -- -- + + rickets/osteomalacia osteoporosis normal 0 25 50 75 100 125 150 (nmol/l) Presentation: Dr. Bruce Hollis 9
Future Implications Cancer Autoimmune diseases Immune dysfunction Cardiac health Brain (91) Melanoma (skin) (441) Multiple myeloma (97) Bladder (382) Lung (418) Advanced prostate (461) Non-Hodgkin s lymphoma (330) Kidney (176) Colorectal (691) Stomach (78) Multivariable RR and 95% CI for a 25 nmol/l increment in predicted plasma 25(OH) vitamin D level HPFS (1986-2000) Pancreas (170) Leukemia (82) Esophagus (93) Oral / pharyngeal (51) 0 0.5 1.0 1.5 2.0 2.5 // It is a well known fact that human milk is a poor source of vitamin D for the nursing infant. This is an absolutely false and absurd statement. Presentation: Dr. Bruce Hollis 10
Maternal Supplementation with 400 IU vitamin D /day 3 & Infant Supplementation with 300 IU/day (n=6) Visit (months) V 0 V 1 V 2 V 3 V 4 V 5 V 6 Vitamin D 3 (ng/ml ± SD) Mother 2.4 ± 2.8 2.8 ± 1.5 3.5 ± 1.2 2.8 ± 1.9 3.7 ± 2.3 5.3 ± 3.5 12 ± 15 25(OH)D Mother (ng/ml ± SD) Baby 35 ± 10 13 ± 8 35 ± 7 35 ± 4 30 ± 4 33 ± 6 26 ± 9 35 ± 5 38 ± 8 43 ± 7 Milk Activity (IU/L) 62 ± 17 71 ± 36 79 ± 33 54 ± 18 68 ± 36 70 ± 25 147 ± 138 Maternal Supplementation with 6,400 IU Vitamin D 3 /day only (n=6) Visit (months) V 0 V 1 V 2 V 3 V 4 V 5 V 6 Vitamin D 3 (ng/ml ± SD) 25(OH)D Mother (ng/ml ± SD) Baby Mother 4.6 ± 3.9 36 ± 12 14 ± 6 32 ± 12 48 ± 12 38 ± 9 50 ± 10 39 ± 27 52 ± 13 36 ± 8 52 ± 15 51 ± 9 44 ± 15 53 ± 10 47 ± 19 57 ± 14 46 ± 10 Milk Activity (IU/L) 90 ± 27 403 ± 173 419 ± 214 379 ± 202 597 ± 329 623 ± 408 782 ± 428 Conclusions Based on biomarkers of nutritional vitamin D status (PTH, BMC, intestinal calcium absorption, insulin sensitivity, beta cell function, and innate immune function), circulating levels of 25(OH)D <32 ng/ml should be considered deficient. What an optimum level is remains to be determined. A 400 IU DRI for vitamin D is irrelevant with respect to the adult population in general. Solar exposure as a means to ensure adequate vitamin D status is problematic. Guidelines stating that the lowest observed adverse effect level for humans is 2,000 IU vitamin D/day are incorrect. In actuality, the e AI for adults may be 2,000 IU/day and in some cases such as pregnancy and a lactation higher. It is almost certain that chronic nutritional vitamin D deficiency cy puts populations at risk for developing debilitating, long latency chronic diseases such as cancer and autoimmune disease. Presentation: Dr. Bruce Hollis 11
Thank you Presentation: Dr. Bruce Hollis 12