Thieme: an Evidence-Based Approach to Vitamins and Minerals

Foreword

An Evidence-based Approach to Vitamins and Min- an inadequate intake of a vitamin or mineral, at erals: Health Benefits and Intake Recommenda- great cost to that person’s health, when a year’s tions by Dr. Jane Higdon and Dr. Victoria Drake supply of a daily multivitamin/multimineral pill provides a much needed source of authoritative as insurance against deficiencies costs less than a information on the role of micronutrients in few packs of cigarettes. Low-income populations, health promotion and in disease prevention and in general, are the most likely to have poor diets treatment. The book is especially important be- and have the most to gain from multivitamin/ cause of the potential health benefits of tuning multimineral supplementation. As Hippocrates up people’s micronutrient metabolism, particu- said: “Leave your drugs in the chemist’s pot if you larly those with inadequate diets, such as the can heal the patient with food.” many low-income and elderly people. A meta- Although many degenerative diseases will bolic tune-up is likely to have enormous health benefit fromti op mal nutrition, and optimal nu- benefits but is currently not being addressed ad- trition clearly involves more than adequate mi- equately by the medical community. cronutrients, there are several important reasons Maximum health and life span require meta- for focusing on micronutrients and health, par- bolic harmony. It is commonly thought that ticularly DNA damage: (1) More than 20 years of Americans’ intake of the more than 40 essential efforts to improve the American diet have not micronutrients (vitamins, minerals, and other been notably successful, though this work must biochemicals that humans require) is adequate. continue. A parallel approach focusing on micro- Classic deficiency diseases such as scurvy, beri- nutrient intake is overdue and might be more beri, pernicious anemia, and rickets are rare, but successful, since it should be easier to convince the evidence suggests that metabolic damage oc- people to take a multivitamin/multimineral pill curs at intake levels between the level causing as insurance against ill health than to change acute micronutrient deficiency diseases and the their diet significantly. (2) A multivitamin/multi- recommended dietary allowances (RDAs). When mineral pill is inexpensive, is recognized as safe, one input in the metabolic network is inade- and supplies the range of vitamins and minerals quate, repercussions are felt on a large number of that a person requires, though not the essential systems and can lead to degenerative disease. fatty acids. Fortification of food is another ap- This may, for example, result in an increase in proach that is useful, but its implementation has DNA damage (and possibly cancer), neuron decay been very slow, as with folic acid fortification. (and possibly cognitive dysfunction), or mito- Moreover, fortification of food does not allow for chondrial decay (and possibly accelerated aging differences between individuals. For example, and degenerative diseases). The optimum menstruating women need more iron than men amount of folate or zinc that is truly “required” is or postmenopausal women, who may be getting the amount that minimizes DNA damage and too much. That is why two types of vitamin pills maximizes a healthy life span, which is higher are marketed, one with iron and one without. than the amount to prevent acute disease. Vita- With better knowledge it seems likely that a min and metabolite requirements of older people broader variety of multivitamin/multimineral are likely to differ from those of younger people, pills will be developed, reflecting such life-stage but this issue has not been seriously examined. differences. An optimal intake of micronutrients and metab- The above issues and many others discussed olites will also vary with genetic constitution. A in this book highlight the need to educate the tune-up of micronutrient metabolism should public about the crucial importance of optimal give a marked increase in health at little cost. It is nutrition and the potential health benefits of inexcusable that anyone in the world should have something as simple and affordable as a daily

aus: Higdon, An Evicdence-based Approach to Vitamins and Minerals (ISBN 9783131324528) © 2012 Georg Thieme Verlag KG Foreword VII multivitamin/multimineral supplement. The nu- book is enhanced by the fact that it is endorsed merous advances in the science of nutrition and by the Linus Pauling Institute at Oregon State changing ideas about optimal intakes of micro- University and that each chapter has been criti- nutrients make An Evidence-based Approach to cally reviewed by a recognized expert in the field. Vitamins and Minerals: Health Benefits and Intake Tuning up the metabolism to maximize human Recommendations an excellent and timely re- health will require scientists, clinicians, and edu- source. Dr. Higdon, who had a background in cators to abandon outdated paradigms of micro- health care and nutrition science, and Dr. Drake, nutrients merely preventing deficiency disease who has an expertise in toxicology and nutrition, and to explore more meaningful ways to prevent have synthesized a large amount of recent scien- chronic disease and achieve optimal health tific research on vitamins and nutritionally es- through optimal nutrition. sential minerals into an organized volume that includes information on optimal micronutrient Bruce N. Ames, PhD intakes to prevent and treat chronic diseases. The University of California, Berkeley book also contains much needed and up-to-date Children’s Hospital Oakland Research Institute information on safety and drug interactions of Oakland, California vitamins and minerals. The credibility of this

Preface to the Second Edition

I am honored to revise and update Dr. Jane Hig- vitamins and minerals in disease prevention and don’s book, An Evidence-based Approach to Vita- disease treatment, in addition to providing basic mins and Minerals: Health Benefits and Intake information on biological function, deficiency, Recommendations. Since the first edition was food sources, safety, and interactions with other published in 2003, there has been a dramatic ex- micronutrients and drugs. pansion of the literature on the role of micronutrients in human health and disease. In this second edition, all 27 chapters have been revised to Acknowledgments incorporate information from the relevant, more recently published peer-reviewed studies, espe- I wish to thank the faculty, staff, and students of cially studies with human subjects. This edition the Linus Pauling Institute for their editorial ad- includes the latest recommendations by the Food vice and support in the revision of this book, es- and Nutrition Board (FNB) of the Institute of pecially Balz Frei, PhD, director and endowed Medicine: the FNB established new dietary refer- chair; Stephen Lawson, administrative officer; ence intakes for potassium and sodium in 2004 and Barbara McVicar, assistant to the director. I and revised their recommendations for calcium am very appreciative to all of the distinguished and vitamin D in 2010. Additionally, some of the scientists listed in the Editorial Advisory Board, Linus Pauling Institute (LPI) recommendations who reviewed the contents of each chapter and have been modified to reflect current knowledge provided helpful comments. I am particularly in micronutrient research. The LPI recommenda- grateful to Donald M. Mock, MD, PhD, and Eva tions are daily intake levels aimed at the promo- Obarzanek, PhD, for their valuable expertise in tion of optimum health and prevention of chron- revising the chapters on biotin and salt, respec- ic disease in healthy individuals. A large litera- tively. Finally, I deeply appreciate the skillful ture indicates that inadequate or marginal intake work by Dr. Higdon in writing the first edition of of vitamins and nutritionally essential minerals this book, which has been a popular resource for may increase one’s risk for a number of diseases, both health professionals and the public. including cardiovascular diseases, certain can- cers and neurodegenerative diseases, and osteo- Victoria J. Drake, PhD porosis. Micronutrient inadequacy can also im- Manager, Micronutrient Information Center pair immunity and thus increase susceptibility to Linus Pauling Institute communicable diseases like influenza. This book Oregon State University reviews the present knowledge on the roles of Corvallis, Oregon

Preface to the First Edition

During my clinical training, I learned to approach als provide the strongest evidence for the effect micronutrient nutrition from the perspective of of micronutrient intake on disease outcomes in preventing or treating deficiency diseases, such humans, it is not always ethical or practical to as scurvy or iron-deficiency anemia. In clinical perform a double-blind, placebo-controlled trial. practice, I became increasingly interested in the Observational studies can also provide useful in- potential for micronutrients to prevent and treat formation about micronutrient intake and dis- chronic diseases at intakes higher than those re- ease outcomes. In reviewing the epidemiologic quired to prevent deficiency. However, the stan- research, I have given more weight to the results dard medical and nutrition texts of the day rarely of large prospective cohort studies, such as the provided the kind of information I was looking Nurses Health Study, than retrospective case– for. Today, scientific and medical research on the control or cross-sectional studies. When avail- roles of micronutrients in health and disease is able, I have included the results of systematic re- expanding rapidly, as are, unfortunately, exag- views and meta-analyses, which summarize in- gerated health claims from numerous supple- formation on the findings of many similar stud- ment manufacturers. Keeping up with the explo- ies. sion of contradictory information regarding the Nearly 35 years ago Linus Pauling, PhD, the safety and efficacy of tadie ry supplements has only individual ever to win two unshared Nobel become an overwhelming task for consumers as Prizes, concluded that micronutrients could play well as health care and nutrition professionals. a significant role in enhancing human health and My goal in writing this book was to provide clini- preventing chronic disease, not just deficiency cians and consumers with a practical evidence- disease. The basic premise that an optimum diet based reference to the rapidly expanding field of is the key to optimum health continues today as micronutrient nutrition. the foundation of the Linus Pauling Institute at While my own interest in nutrition and health Oregon State University. Scientists at the Linus led me to pursue doctoral work in nutrition and Pauling Institute investigate the roles that micro- biochemistry, such a step should not be neces- nutrients and other dietary constituents play in sary for health care and nutrition professionals human aging and chronic diseases, particularly who want more information on the health impli- cancer, cardiovascular diseases, and neurodegen- cations of dietary and supplemental micronutri- erative diseases. The goals of our research are to ents. With the support of the Linus Pauling Insti- understand the molecular mechanisms behind tute at Oregon State University (LPI), I have syn- the effects of nutrition on health and to deter- thesized and organized hundreds of experimen- mine how micronutrients and other dietary fac- tal, clinical, and epidemiologic studies, providing tors can be used in the prevention and treatment an overview of the current scientific knowledge of diseases, thereby enhancing human health and of the roles of vitamins and nutritionally impor- well-being. The Linus Pauling Institute is also tant minerals in human health and disease. To dedicated to training and supporting new re- ensure the accuracy of the information present- searchers in the interdisciplinary science of nu- ed, I asked at least one recognized scientific ex- trition and optimum health, as well as to educat- pert in the field to review each chapter. The ing the public about the science of optimum nu- names and affiliations of these scientists are list- trition. ed in the Editorial Advisory Board. As you read this book, it will become apparent Throughout this book, I have tried to empha- that the Linus Pauling Institute recommenda- size human research published in peer-reviewed tions for certain micronutrients (e.g., vitamin C) journals. Where relevant, I have included the re- differ considerably from those of Linus Pauling sults of experimental studies in cell culture or himself. Dr. Pauling, for whom the Linus Pauling animal models. Although randomized clinical tri- Institute has great respect, based his own micro-

nutrient recommendations largely on theoretical McVicar also provided much needed technical arguments. For example, in developing his rec- assistance and support. I am very grateful for the ommendations for vitamin C intake, he used support of Bruce N. Ames, PhD, who was enthusi- cross-species comparisons, evolutionary argu- astic about this project from the beginning. His ments, and the amount of vitamin C likely con- research and his eloquent foreword have been sumed in a raw plant food diet. At the Linus Paul- invaluable in laying the groundwork for this ing Institute, we base our micronutrient recom- book. mendations on current scientific evidence, much I would like to thank each of the distinguished of which was unavailable to Dr. Pauling. The scientists listed in the Editorial Advisory Board Linus Pauling Institute’s recommendation for a for taking the time to carefully review each chap- vitamin C intake of at least 200 mg/day for gener- ter of this book and provide insightful and con- ally healthy adults takes into account the cur- structive comments. I am also grateful to Aram rently available epidemiologic, biochemical, and Chobanian, MD, for reviewing the information clinical evidence. Similarly, the Linus Pauling In- presented on salt. The artist, Pat Grimaldi of the stitute’s intake recommendation for each micro- Communication Media Center at Oregon State nutrient in this book is based on the current sci- University, was both patient and skillful in creat- entific research available, while, in many cases, ing the book’s illustrations. acknowledging that the intake levels most likely This project would not have been possible to promote optimum health remain to be deter- without the generous financial support of the mined. donors to the Linus Pauling Institute, who de- serve special thanks. Finally, although I did not know him personally, I would like to thank Dr. Acknowledgments Linus Pauling for courageously stimulating scientific, medical, and popular esinter t in the roles First and foremost, I wish to thank the faculty, played by micronutrients in promoting optimum staff, and students of the Linus Pauling Institute health and preventing and treating disease. for providing me with the inspiration and the op- portunity to write this book. Specifically, Balz Jane Higdon, PhD Frei, PhD, the director, and Stephen Lawson, the Linus Pauling Institute chief administrative officer of the Linus Pauling Oregon State University Institute, provided valuable advice and editorial Corvallis, Oregon assistance throughout the project. Barbara

Contents

1 Biotin ...... 1 Safety ...... 14 Function ...... 1 Toxicity...... 14 Enzyme cofactor...... 1 drug interactions ...... 14 Histone Biotinylation ...... 1 3 Niacin ...... 17 Deficiency ...... 1 Function ...... 17 Signs and Symptoms...... 1 Oxidation–reduction Predisposing conditions...... 2 (redox) reactions ...... 17 Adequate intake...... 2 Non-redox reactions ...... 17 Disease Prevention ...... 3 Deficiency ...... 18 Birth defects...... 3 Pellagra...... 18 Disease treatment...... 3 Nutrient interactions ...... 19 diabetes mellitus...... 3 recommended dietary Allowance ...... 19 Brittle Fingernails ...... 3 Disease Prevention ...... 19 Hair loss...... 4 cancer...... 19 Sources...... 4 Type 1 diabetes mellitus ...... 20 Food Sources...... 4 Disease treatment...... 21 Bacterial Synthesis ...... 4 High cholesterol and Safety ...... 4 cardiovascular disease ...... 21 Toxicity...... 4 Human Immunodeficiency Virus...... 21 Nutrient interactions...... 4 Sources...... 22 drug interactions ...... 5 Food Sources...... 22 2 Folic Acid ...... 7 Supplements...... 22 Function ...... 7 Safety ...... 22 One-carbon metabolism...... 7 Toxicity...... 22 Nutrient interactions...... 8 drug interactions ...... 23 Deficiency ...... 8 4 Pantothenic Acid...... 26 causes...... 8 Function ...... 26 Symptoms...... 9 coenzyme A...... 26 recommended dietary Allowance...... 9 Acyl-carrier Protein...... 26 dietary Folate Equivalents...... 9 Deficiency ...... 26 Genetic variation Adequate intake...... 27 in Folate requirements...... 10 Disease Prevention ...... 27 Disease Prevention ...... 10 Disease treatment...... 27 Pregnancy complications...... 10 Wound Healing ...... 27 cardiovascular diseases ...... 11 High cholesterol ...... 27 cancer ...... 12 Sources...... 28 Alzheimer disease Food Sources...... 28 and cognitive impairment ...... 13 intestinal Bacteria...... 28 Disease treatment...... 13 Supplements...... 28 Sources...... 14 Safety ...... 28 Food Sources ...... 14 Toxicity...... 28 Supplements...... 14 drug interactions ...... 29

5 Riboflavin ...... 30 Disease treatment...... 46 Function ...... 30 Pharmacological doses of retinoids ...... 46 Oxidation–reduction (redox) reactions .30 diseases of the Skin...... 46 Antioxidant Functions ...... 30 Sources...... 46 Nutrient interactions...... 31 retinol Activity Equivalents...... 46 Deficiency ...... 31 Food Sources...... 47 Risk Factors for Riboflavin Deficiency ...... 32 Supplements...... 48 recommended dietary Allowance ...... 32 Safety ...... 48 Disease Prevention ...... 33 Toxicity...... 48 cataracts...... 33 Safety in Pregnancy...... 48 Disease treatment...... 33 Effects on Bone ...... 49 migraine Headaches...... 33 drug interactions ...... 49 Sources...... 34 8 Vitamin B ...... 52 Food Sources...... 34 6 Function ...... 52 Supplements...... 34 Nervous System Function...... 52 Safety ...... 34 red Blood cell Formation and Function...52 Toxicity...... 34 Niacin Formation...... 52 drug interactions ...... 34 Hormone Function...... 52 6 thiamin ...... 36 Nucleic Acid Synthesis...... 52 Function ...... 36 Deficiency ...... 52 coenzyme Function ...... 36 recommended dietary Allowance...... 53 Deficiency ...... 36 Disease Prevention ...... 53 Causes of Thiamin Deficiency...... 37 cardiovascular diseases ...... 53 recommended dietary Allowance...... 37 immune Function...... 54 Disease Prevention ...... 38 cognitive Function ...... 54 cataracts ...... 38 Kidney Stones...... 55 Disease treatment...... 38 Disease treatment...... 55 Alzheimer disease ...... 38 Side Effects of Oral Contraceptives...... 55 congestive Heart Failure ...... 38 Premenstrual Syndrome...... 55 cancer...... 39 depression ...... 56 Sources...... 39 Nausea and vomiting in Pregnancy...... 56 Food Sources...... 39 carpal Tunnel Syndrome ...... 56 Supplements ...... 39 Sources...... 56 Safety ...... 39 Food Sources...... 56 Toxicity...... 39 Supplements ...... 56 drug interactions ...... 40 Safety ...... 57 Toxicity ...... 57 7 Vitamin A ...... 42 drug interactions ...... 57 Function ...... 42

vision...... 42 9 Vitamin B12...... 60 regulation of Gene Expression ...... 43 Function ...... 60 immunity...... 44 cofactor for methionine Synthase ...... 60 Growth and development...... 44 cofactor for methylmalonyl-coA red Blood cell Production...... 44 mutase...... 60 Nutrient interactions...... 44 Deficiency ...... 60

Deficiency ...... 44 causes of vitamin B12 Deficiency ...... 60

Vitamin A Deficiency and Vision...... 44 Other causes of vitamin B12 Deficiency...62

Vitamin A Deficiency and Infectious Symptoms of vitamin B12 Deficiency...... 62 disease...... 44 recommended dietary Allowance ...... 63 recommended dietary Allowance ...... 45 Disease Prevention ...... 64 Disease Prevention ...... 45 cardiovascular diseases ...... 64 cancer...... 45 cancer...... 64

Neural Tube defects...... 65 Disease Prevention ...... 87 Alzheimer disease and dementia...... 65 Osteoporosis...... 87 depression ...... 66 cancer...... 88 Sources...... 66 Autoimmune diseases...... 89 Food Sources...... 66 Hypertension ...... 90 Supplements...... 67 Sources ...... 90 Safety ...... 67 Sunlight...... 90 Toxicity...... 67 Food Sources...... 91 drug interactions ...... 67 Supplements...... 91 Safety...... 91 10 Vitamin C ...... 70 Toxicity...... 91 Function ...... 70 drug interactions ...... 92 Deficiency...... 70 Scurvy...... 70 12 Vitamin E...... 96 recommended dietary Allowance ...... 70 Function ...... 96 Disease Prevention ...... 70 α-Tocopherol...... 96 cardiovascular diseases ...... 71 γ-Tocopherol...... 96 cancer...... 72 Deficiency...... 97 cataracts...... 73 recommended dietary Allowance ...... 97 Gout...... 73 Disease Prevention ...... 98 lead Toxicity...... 73 cardiovascular diseases ...... 98 role in immunity...... 74 cataracts ...... 98 Disease treatment ...... 74 immune Function...... 99 cardiovascular diseases ...... 74 cancer ...... 99 cancer...... 75 Disease treatment ...... 99 diabetes mellitus...... 75 cardiovascular diseases ...... 99 common cold...... 76 diabetes mellitus...... 100 Sources ...... 76 dementia (impaired cognitive Food Sources...... 76 Function) ...... 100 Supplements...... 76 cancer...... 101 Safety...... 77 Sources ...... 101 Toxicity...... 77 Food Sources...... 101 does vitamin c Promote Oxidative Supplements ...... 102 damage under Physiological Safety...... 102 conditions?...... 78 Toxicity...... 102 Kidney Stones...... 78 vitamin E Supplementation and drug interactions ...... 78 All-cause mortality...... 103 drug interactions ...... 103 11 Vitamin D...... 83 Function ...... 83 13 Vitamin K ...... 107 Activation of vitamin d...... 83 Function ...... 107 mechanisms of Action...... 83 coagulation ...... 107 calcium Balance...... 83 Bone mineralization ...... 108 Cell Differentiation ...... 83 cell Growth ...... 108 immunity...... 84 Deficiency...... 109 insulin Secretion...... 84 controversy Surrounding vitamin K Blood Pressure regulation...... 84 Administration and Newborn infants....109 Deficiency ...... 85 Adequate intake ...... 109 Severe Vitamin D Deficiency ...... 85 Disease Prevention ...... 110 Risk Factors for Vitamin D Deficiency...... 85 Osteoporosis...... 110 Assessing vitamin d Nutritional Status ...86 Vascular Calcification and recommended dietary Allowance...... 86 cardiovascular disease...... 111

Sources ...... 112 Sources ...... 132 Food Sources...... 112 Food Sources...... 132 intestinal Bacteria...... 112 Supplements...... 132 Safety...... 112 Safety...... 132 Toxicity...... 112 Toxicity...... 132 Nutrient interactions...... 112 drug interactions ...... 133 drug interactions ...... 113 16 Copper...... 135 14 Calcium ...... 115 Function ...... 135 Function ...... 115 Energy Production...... 135 Structure...... 115 connective Tissue Formation ...... 135 cell Signaling...... 115 iron metabolism...... 135 cofactor for Enzymes and Proteins...... 115 central Nervous System ...... 135 regulation of calcium levels...... 115 melanin Formation ...... 135 Deficiency...... 116 Antioxidant Functions ...... 135 Nutrient interactions...... 116 regulation of Gene Expression ...... 136 recommended dietary Allowance...... 117 Nutrient interactions...... 136 Disease Prevention ...... 118 Deficiency...... 136 colorectal cancer ...... 118 Individuals at Risk of Deficiency ...... 137 Osteoporosis...... 118 recommended dietary Allowance ...... 137 Kidney Stones...... 119 Disease Prevention ...... 137 Pregnancy-induced Hypertension ...... 120 cardiovascular diseases ...... 137 lead Toxicity...... 120 immune System Function ...... 138 Disease treatment ...... 121 Osteoporosis...... 139 Hypertension...... 121 Sources ...... 139 Premenstrual Syndrome ...... 121 Food Sources...... 139 Sources ...... 122 Supplements...... 139 Food Sources ...... 122 Safety...... 139 Supplements...... 122 Toxicity...... 139 lead in calcium Supplements ...... 123 drug interactions ...... 140 Safety...... 123 17 Fluoride (Fluorine)...... 142 Toxicity...... 123 Function ...... 142 do High calcium intakes increase Nutrient interactions...... 142 the risk of Prostate cancer?...... 124 Deficiency...... 142 drug interactions ...... 124 Adequate intake...... 142 Nutrient interactions...... 125 Disease Prevention ...... 143 Recent Research...... 125 dental caries ...... 143 calcium and Weight loss ...... 125 Osteoporosis...... 143 15 Chromium...... 128 Disease treatment ...... 144 Function ...... 128 Osteoporosis...... 144 Nutrient interactions...... 128 Sources ...... 145 Deficiency...... 129 Water Fluoridation ...... 145 Adequate intake...... 129 Food and Beverage Sources...... 145 Disease Prevention ...... 130 Supplements ...... 145 impaired Glucose Tolerance and Toothpaste...... 146 Type 2 diabetes mellitus ...... 130 Safety...... 146 cardiovascular diseases ...... 130 Adverse Effects...... 146 Health claims...... 130 drug interactions ...... 147 Disease treatment ...... 131 Type 2 diabetes mellitus ...... 131 Gestational diabetes...... 131

18 Iodine ...... 149 inhibitors of Nonheme iron Function ...... 149 Absorption ...... 163 Deficiency...... 149 Typical dietary intake...... 163 The Effects of Iodine Deficiency by Supplements...... 163 developmental Stage...... 150 Iron Overload ...... 164 Nutrient interactions...... 151 Hereditary Hemochromatosis...... 164 Goitrogens...... 151 Hereditary Anemias...... 164 Individuals at Risk of Iodine Deficiency..152 Safety...... 164 recommended dietary Allowance ...... 152 Toxicity...... 164 Disease Prevention ...... 152 diseases Associated with iron Excess.....165 radiation-induced Thyroid cancer ...... 152 drug interactions ...... 166 Disease treatment ...... 152 20 Magnesium ...... 169 Fibrocystic Breast condition...... 152 Function ...... 169 Sources ...... 153 Energy Production...... 169 Food Sources...... 153 Synthesis of Essential Biomolecules...... 169 Supplements...... 153 Structural roles...... 169 Safety...... 153 ion Transport across cell membranes....169 Acute Toxicity...... 153 cell Signaling...... 169 iodine Excess...... 154 cell migration...... 169 drug interactions ...... 154 Nutrient interactions...... 169 19 Iron...... 157 Deficiency...... 170 Function ...... 157 recommended dietary Allowance...... 170 Oxygen Transport and Storage...... 157 Disease Prevention ...... 170 Electron Transport and Energy Hypertension...... 170 metabolism ...... 157 cardiovascular diseases ...... 171 Antioxidant and Beneficial Prooxidant Osteoporosis...... 171 Functions ...... 157 Disease treatment ...... 172 Oxygen Sensing...... 157 Hypertension ...... 172 dNA Synthesis...... 158 Pre-eclampsia–Eclampsia ...... 172 regulation of intracellular iron ...... 158 cardiovascular diseases ...... 173 Systemic regulation of iron diabetes mellitus...... 173 Homeostasis ...... 158 migraine Headaches...... 174 Nutrient interactions...... 158 Asthma ...... 174 Deficiency...... 159 Sources ...... 174 Symptoms of Iron Deficiency ...... 159 Food Sources ...... 174 individuals at increased risk of iron Supplements...... 175 Deficiency ...... 159 Safety...... 175 recommended dietary Allowance ...... 160 Toxicity...... 175 Disease Prevention ...... 161 drug interactions ...... 176 impaired intellectual development 21 Manganese...... 179 in children...... 161 Function ...... 179 lead Toxicity...... 161 Antioxidant Function...... 179 Pregnancy complications...... 161 metabolism...... 179 impaired immune Function...... 161 Bone development ...... 179 Disease treatment ...... 162 Wound Healing ...... 179 restless legs Syndrome ...... 162 Nutrient interactions...... 179 Sources ...... 162 Deficiency...... 180 Food Sources...... 162 Adequate intake ...... 180 Enhancers of Nonheme iron Absorption ...... 162

Disease Prevention ...... 180 Disease Prevention ...... 197 Osteoporosis...... 181 Stroke...... 197 diabetes mellitus...... 181 Osteoporosis...... 198 Seizure disorders...... 181 Kidney Stones...... 198 Sources ...... 181 Disease treatment ...... 199 Food Sources...... 181 Hypertension...... 199 Breast milk and infant Formulas...... 182 Sources ...... 199 Water...... 182 Food Sources...... 199 Supplements...... 182 Supplements...... 200 Safety...... 182 Safety...... 200 Toxicity...... 182 Toxicity (Excess)...... 200 individuals with increased Adverse reactions to Potassium Susceptibility to manganese Toxicity.....183 Supplements...... 200 drug interactions ...... 184 drug interactions ...... 201 High levels of manganese in Supple- 25 Selenium ...... 203 ments marketed for Bone/Joint Function ...... 203 Health...... 184 Selenoproteins ...... 203 22 Molybdenum ...... 187 Nutrient interactions...... 204 Function ...... 187 Deficiency...... 205 Nutrient interactions...... 187 individuals at increased risk of Deficiency...... 187 Selenium Deficiency...... 205 recommended dietary Allowance ...... 188 Keshan disease...... 205 Disease Prevention ...... 188 Kashin–Beck disease...... 205 Gastroesophageal cancer...... 188 recommended dietary Allowance...... 205 Sources ...... 189 Disease Prevention ...... 206 Food Sources...... 189 immune Function...... 206 Supplements...... 189 viral infection...... 206 Safety...... 189 cancer...... 206 Toxicity...... 189 cardiovascular diseases ...... 208 drug interactions ...... 189 Type 2 diabetes mellitus ...... 209 Disease treatment ...... 209 23 Phosphorus ...... 191 Hiv/AidS ...... 209 Function ...... 191 Sources ...... 209 Nutrient interactions...... 191 Food Sources...... 209 Deficiency...... 192 Supplements...... 210 recommended dietary Allowance ...... 193 Selenium-enriched vegetables...... 210 Sources ...... 193 Safety...... 210 Food Sources...... 193 Toxicity...... 210 Supplements...... 193 drug interactions ...... 211 Safety...... 193 Toxicity...... 193 26 Sodium Chloride ...... 214 drug interactions ...... 194 Function ...... 214 maintenance of membrane Potential....214 24 Potassium...... 196 Nutrient Absorption and Transport...... 215 Function ...... 196 maintenance of Blood volume and maintenance of membrane Potential....196 Blood Pressure ...... 215 cofactor for Enzymes...... 196 Deficiency...... 215 Deficiency...... 197 Hyponatremia...... 215 conditions that increase the risk of Adequate intake for Sodium ...... 216 Hypokalemia...... 197 Adequate intake...... 197

Disease Prevention (Dietary Sodium impaired immune response in and Disease)...... 216 Elderly People...... 227 Gastric cancer...... 216 Pregnancy complications ...... 227 Osteoporosis...... 216 Disease treatment ...... 228 Kidney Stones...... 217 common cold...... 228 Hypertension ...... 217 Age-related macular degeneration ...... 229 cardiovascular diseases ...... 219 diabetes mellitus ...... 229 Sources ...... 219 Hiv/AidS ...... 229 Safety...... 219 Sources ...... 229 Toxicity...... 219 Food Sources...... 229 Adverse Effects...... 220 Supplements...... 230 drug interactions ...... 221 Safety...... 230 Toxicity...... 230 27 Zinc...... 224 drug interactions ...... 230 Function ...... 224 catalytic role ...... 224 Appendix...... 235 Structural role ...... 224 Nutrient–Nutrient Interactions...... 236 regulatory role...... 224 Drug–Nutrient Interactions ...... 239 Nutrient interactions...... 224 Quick Reference to Diseases ...... 243 Deficiency...... 225 Glossary...... 248 Severe Zinc Deficiency ...... 225 The Linus Pauling Institute Mild Zinc Deficiency...... 225 Prescription for Health ...... 270 recommended dietary Allowance ...... 226 Healthy Eating...... 270 Disease Prevention ...... 226 Healthy lifestyle...... 270 impaired Growth and development...... 226 Supplements...... 270 increased Susceptibility to infectious Index ...... 273 disease in children...... 227

How To Use This Book

Chapter Organization

Information on individual vitamins, organic • References (carbon-containing) compounds that are re- In addition to the Linus Pauling Institute Rec- quired by humans in small amounts from the ommendations, the Food and Nutrition Board diet to maintain normal physiological function, (FNB) of the Institute of Medicine appoints can be found in Chapters 1 through 13, in alpha- committees of expert scientists to set Dietary betical order by vitamin. In addition to vitamins, Reference Intakes (DRIs), which are used to a number of inorganic elements (minerals) are plan and evaluate diets of apparently healthy required in the human diet to support a wide people. Three different DRIs appear regularly range of biological functions. Information on nu- throughout this book: tritionally important minerals can be found in –The Recommended Dietary Allowance (RDA) is Chapters 14 through 27, in alphabetical order by defined as the average daily dietary intake mineral. For ease of use, the information in each level of a specific nutrient sufficient to meet chapter is organized in the following manner: the requirement of nearly all (97%–98%) • Function Current scientific understanding of healthy individuals in a particular life-stage the function of the micronutrient with respect group. Because RDAs generally reflect intake to maintaining health and preventing disease. levels designed to prevent deficiency, they • Deficiency Risk factors, signs, symptoms, and are presented in the Deficiency section of physiological effects of frank deficiency of the each chapter. micronutrient. –An Adequate Intake (AI) is provided if there is • Disease Prevention Where controlled research insufficient evidence to determine an RDA. is available, information on the role(s) of the The AI is based on experimentally derived in- micronutrient in the prevention of disease. take levels or observed average intake levels • Disease treatment Where controlled research of apparently healthy people. For example, is available, information on the role(s) of the the AI of a nutrient for infants is generally micronutrient in the treatment of disease. based on the average daily intake of that nu- • Sources Information on dietary, supplemental, trient supplied by human milk in healthy, and other sources of the micronutrient. When full-term infants who are exclusively breast- available, this section includes a table of die- fed. Because AIs reflect intakeve le ls thought tary sources. to prevent deficiency, they are also presented • Safety Information on toxicity and adverse ef- in the Deficiency section of each chapter. fects of the micronutrient, as well as micronu- –The Tolerable Upper Intake Level (UL) is de- trient–drug interactions. fined as the highest level of a nutrient deter- • The Linus Pauling Institute Recommendation A mined to pose no risk of adverse effects for daily intake recommendation based on rele- almost all individuals in the general popula- vant scientific research and reflecting an intake tion. The UL is discussed in the Safety section level aimed at the prevention of chronic disease of each chapter. and the promotion of optimum health in generally healthy individuals. Recommendations for older adults (over the age of 50 years) are also addressed in this section.

Appendices

Several appendices have been included to facili- • Quick Reference to Diseases A useful chart that tate the use of this book by clinicians as well as allows the reader to locate micronutrient infor- consumers. mation by disease or health condition. • Nutrient—Nutrient Interactions A table sum- • Glossary marizing the information on nutrient—nutri- • The Linus Pauling Institute Prescription for ent interactions discussed in the book. Health A list summarizing the Linus Pauling • Drug—Nutrient Interactions A table summariz- Institute Recommendations for a healthy diet, ing the information on nutrient—drug interac- lifestyle, and supplement use. tions discussed in the book.

2 Folic Acid

The terms folic acid and folate are often used in- ceptors and donors of one-carbon units in a vari- terchangeably for this water-soluble B-complex ety of reactions critical to the metabolism of nu- vitamin. Folic acid, the more stable form, occurs cleic acids and amino acids.3 rarely in foods or the human body but is the form most often used in vitamin supplements and for- Nucleic acid metabolism. Folate coenzymes play tified foods. Naturally occurring folates exist in a vital role in DNA metabolism through two dif- many chemical forms. They are found in foods as ferent pathways (Fig. 2.1): well as in metabolically active forms in the hu- 1. The synthesis of DNA from its precursors (thy- man body.1 In the following discussion, forms midine and purines) is dependent on folate found in food or the body are referred to as fo- coenzymes. lates, whereas the form found in supplements or 2. A folate coenzyme is required for the synthe- fortified foods is referred to as folic acid. sis of methionine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). Function SAM is a methyl group (one-carbon unit) donor One-carbon Metabolism used in many biological methylation reactions, The only function of folate coenzymes in the including the methylation of a number of sites body appears to be in mediating the transfer of within DNA and RNA. Methylation of DNA may one-carbon units.2 Folate coenzymes act as ac- be important in cancer prevention.

Fig. 2.1 Folate and nucleic acid metabolism: 5,10-methy- biological methylation reactions, including dNA methyla- lene tetrahydrofolate (THF) is required for the synthesis of tion. Methylene TH-folate reductase is a flavin-dependent nucleic acids, and 5-methyl THF is required for the forma- enzyme required to catalyze the reduction of 5,10-methy- tion of methionine from homocysteine. methionine, in leneTHF to 5-methyl THF. the form of S-adenosylmethionine, is required for many

Amino acid metabolism. Folate coenzymes are cysteine (Fig. 2.2). One pathway (methionine required for the metabolism of several important synthase) synthesizes methionine from homo- amino acids. The synthesis of methionine from cysteine and depends on a folate coenzyme and a

homocysteine requires a folate coenzyme as well vitamin B12-dependent enzyme. The other path-

as a vitamin B12-dependent enzyme. Thus, folate way converts homocysteine to another amino

deficiency can result in decreased synthesis of acid, cysteine, and requires two vitamin B6-de- methionine and a build-up of homocysteine. In- pendent enzymes. Thus, the amount of homo- creased levels of homocysteine may be a risk fac- cysteine in the blood is regulated by three vita- 4 tor for heart disease as well as several other mins: folate, vitamin B12, and vitamin B6. chronic diseases. Deficiency Nutrient Interactions Causes The metabolism of homocysteine, an intermedi- ate in the metabolism of sulfur-containing amino Folate deficiency is most often caused by a di- acids, provides an example of the interrelation- etary insufficiency; however, it can occur in a ships of nutrients necessary for optimal physio- number of other situations, for example, alcohol- logical function and health. Healthy individuals ism is associated with low dietary intake and di- use two different pathways to metabolize homo- minished absorption of folate, which can lead to

Fig. 2.2 Homocysteine metabolism: S-adenosylhomo- dependent reaction that is catalyzed by methionine

cysteine is formed during S-adenosylmethionine-depen- synthase, a vitamin B12-dependent enzyme. Alternately, dent methylation reactions, and the hydrolysis of S-ade- homocysteine may be metabolized to cysteine in reac-

nosylhomocysteine results in homocysteine. Homocyste- tions catalyzed by two vitamin B6-dependent enzymes. ine may be remethylated to form methionine by a folate-

aus: Higdon, An Evicdence-based Approach to Vitamins and Minerals (ISBN 9783131324528) © 2012 Georg Thieme Verlag KG Deficiency 9 folate deficiency. In addition, certain conditions Recommended such as pregnancy or cancer result in increased Dietary Allowance rates of cell division and metabolism, causing an increase in the body’s demand for folate.5 Several Traditionally, the dietary folate requirement was medications may also contribute to deficiency defined as the amount needed to prevent a defi- (see “Drug Interactions,” p. 14). ciency severe enough to cause symptoms such as anemia. The most recent recommended dietary Symptoms allowance (RDA)(Table 2.1) was based primarily on the adequacy of red blood cell folate concen- Individuals in the early stages of folate deficiency trations at different vele ls of folate intake, as may not show obvious symptoms, but their blood judged by the absence of abnormal hematologi- levels of homocysteine may increase. Rapidly di- cal indicators. Red cell folate has been shown to viding cells are most vulnerable to the effects of correlate with liver folate stores. Maintenance of folate deficiency, so when the folate supply to the normal blood homocysteine levels, an indicator rapidly dividing cells of the bone marrow is inad- of one-carbon metabolism, was considered only equate, blood cell division becomes abnormal, as an ancillary indicator of adequate folate in- resulting in fewer but larger red blood cells. This take. As pregnancy is associated with a signifi- type of anemia is called megaloblastic or macro- cant increase in cell division and other metabolic cytic anemia, referring to the enlarged, immature processes that require folate coenzymes, the RDA red blood cells. Neutrophils, a type of white for pregnant women is considerably higher than blood cell, become hypersegmented, a change for women who are not pregnant.3 However, the that can be found by examining a blood sample prevention of neural tube defects (NTDs) was not microscopically. As normal red blood cells have a considered when setting the RDA for pregnant lifetime in the circulation of approximately 4 women. Rather, reducing the risk of NTDs was months, it can take months for folate-deficient considered in a separate recommendation for individuals to develop the characteristic megalo- women capable of becoming pregnant, because blastic anemia. Progression of such an anemia the crucial events in neural tube development leads to decreased oxygen-carrying capacity of occur before many women are aware that they the blood and may ultimately result in symptoms are pregnant.6 of fatigue, weakness, and shortness of breath.1 It is important to point out that megaloblastic ane- Dietary Folate Equivalents mia resulting from folate deficiency is identical to the megaloblastic anemia resulting from vita- When the Food and Nutrition Board (FNB) of the min B12 deficiency, and further clinical testing is Institute of Medicine set the new dietary recom- required to diagnose the true cause of megalo- mendation for folate, they introduced a new unit, blastic anemia. the dietary folate equivalent (DFE):

Table 2.1 recommended dietary allowance for folate in dFEs

Life stageAge Males (µg/day)Females (µg/day) infants0–6 months 65 (Ai) 65 (Ai) infants7–12 months 80 (Ai) 80 (Ai) children 1–3 years150 150 children 4–8 years200 200 children 9–13 years300 300 Adolescents14–18 years400 400 Adults ≥ 19 years 400 400 PregnancyAll ages– 600 Breast-feedingAll ages– 500 Ai, adequate intake; dFE, dietary folate equivalent.

Immunity At present, the health consequences of zinc deficiency on vitamin A nutritional status in humans Vitamin A is commonly known as the anti-infec- are unclear.10 tive vitamin, because it is required for normal functioning of the immune system.4 The skin and Iron. Vitamin A deficiency may exacerbate iron- mucosal cells (cells that line the airways, diges- deficiency anemia. Vitamin A supplementation tive tract, and urinary tract) function as a barrier has beneficial effects on iron-deficiency anemia and form the body’s first line offe de nse against and improves iron nutritional status among chil- infection. Retinol and its metabolites are required dren and pregnant women. The combination of to maintain the integrity and function of these supplemental vitamin A and iron seems to re- cells.5 Vitamin A and RA play a central role in the duce anemia more effectively than either supple- development and differentiation of white blood mental iron or vitamin A alone.11 Moreover, stud- cells, such as lymphocytes, which play critical ies in rats have shown that iron deficiency alters roles in the immune response. Activation of T plasma and liver levels of vitamin A.12,13 lymphocytes, the major regulatory cells of the immune system, appears to require all-trans-RA binding of RARs.3 Deficiency Vitamin A Deficiency and Vision Growth and Development Vitamin A deficiency among children in less de- Both vitamin A excess and deficiency are known veloped nations is the leading preventable cause to cause birth defects. Retinol and RA are essen- of blindness.14 The earliest evidence of vitamin A tial for embryonic development.4 During fetal deficiency is impaired dark adaptation or night development, RA functions in limb development blindness. Mild vitamin A deficiency may result and formation of the heart, eyes, and ears.6 In ad- in changes in the conjunctiva (corner of the eye) dition, RA has been found to regulate expression called Bitot spots. Severe or prolonged vitamin A of the gene for growth hormone. deficiency causes a condition called xerophthalmia (dry eye), characterized by changes in the Red Blood Cell Production cells of the cornea (clear covering of the eye) that ultimately result in corneal ulcers, scarring, and Red blood cells, similar to all blood cells, are de- blindness.4,9 rived from precursor cells called stem cells. Stem cells are dependent on retinoids for normal dif- Vitamin A Deficiency and Infectious ferentiation into red blood cells. In addition, vita- Disease min A appears to facilitate the mobilization of iron from storage sites to the developing red Vitamin A deficiency can be considered a nutri- blood cell for incorporation into hemoglobin, the tionally acquired immunodeficiency disease.15 oxygen carrier in red blood cells.2,7 Even children who are only mildly deficient in vitamin A have a higher incidence of respiratory Nutrient Interactions disease and diarrhea as well as a higher rate of mortality from infectious disease compared with Zinc. Zinc deficiency is thought to interfere with children who consume sufficient vitamin A.16 Vi- vitamin A metabolism in several ways: tamin A supplementation has been found to de- • Zinc deficiency results in decreased synthesis crease both the severity and the incidence of of retinol-binding protein (RBP), which trans- deaths related to diarrhea and measles in less ports retinol through the circulation to tissues developed countries, where vitamin A deficiency (e.g., the retina) and also protects the organism is common.17 The onset of infection reduces against the potential toxicity of retinol. blood retinol levels very rapidly. This phenome- • Zinc deficiency results in decreased activity of non is generally believed to be related to de- the enzyme that releases retinol from its stor- creased synthesis of RBP by the liver. In this man- age form, retinyl palmitate, in the liver. ner, infection stimulates a vicious cycle, because • Zinc is required for the enzyme that converts inadequate vitamin A nutritional status is related retinol into retinal.8,9 to increased severity and likelihood of death

aus: Higdon, An Evicdence-based Approach to Vitamins and Minerals (ISBN 9783131324528) © 2012 Georg Thieme Verlag KG disease Prevention 45 from infectious disease.18 However, a review of people who subsequently developed lung cancer four studies concluded that vitamin A supple- and those who did not. Only one of those studies mentation is not beneficial in reducing the found a statistically significant vein rse associa- mother-to-child transmission of HIV.19 One study tion between serum retinol and lung cancer found that HIV-infected women who were vita- risk.22 The results of the β-Carotene And Retinol min A deficient were three to four times more Efficacy Trial (CARET) suggest that high-dose likely to transmit HIV to their infants.20 supplementation of vitamin A and β-carotene should be avoided in people at high risk of lung Recommended Dietary Allowance cancer.23 About 9000 people (smokers and people with asbestos exposure) were assigned a The recommended dietary allowance (RDA) for daily regimen of 25000 IU retinol and 30 mg vitamin A was revised by the Food and Nutrition β-carotene, while a similar number of people Board (FNB) of the Institute of Medicine in 2001. were assigned a placebo. After four years of fol- The latest RDA is based on the amount needed to low-up, the incidence of lung cancer was 28% ensure adequate stores (4 months) of vitamin A higher in the supplemented group compared in the body to support normal reproductive func- with the placebo group. A possible explanation tion, immune function, gene expression, and vi- for such a finding is that the oxidative environ- sion (Table 7.1).21 ment of the lung, created by smoke or asbestos exposure, gives rise to unusual carotenoid cleav- age products, which are involved in carcinogen- Disease Prevention esis. Currently, it seems unlikely that increased retinol intake decreases the risk of lung cancer, Cancer although the effects of retinol may be different Studies in cell culture and animal models have for nonsmokers than for smokers.22 documented the capacity for natural and synthetic retinoids to reduce carcinogenesis signifi- Breast cancer. Retinol and its metabolites have cantly in skin, breast, liver, colon, prostate, and been found to reduce the growth of breast cancer other sites.2 However, the results of human stud- cells in vitro, but observational studies of dietary ies examining the relationship between the con- retinol intake in humans have not confirmed sumption of preformed vitamin A and cancer are this.24 Most epidemiological studies have failed less clear. to find significant associations between retinol intake and breast cancer risk in women,25–28 Lung cancer. At least 10 prospective studies have although one large prospective study found that compared blood retinol levels at baseline among total vitamin A intake was inversely associated

Table 7.1 recommended dietary allowance for vitamin A as preformed vitamin A (retinol)

Life stageAge Males µg/day (IU/day)Females µg/day (IU/day) infants0–6 months 400 (1333 iU) (Ai) 400 (1333 iU) (Ai) infants7–12 months 500 (1667 iU) (Ai) 500 (1667 iU) (Ai) children 1–3 years300 (1000 iU) 300 (1000 iU) children 4–8 years400 (1333 iU) 400 (1333 iU) children 9–13 years600 (2000 iU) 600 (2000 iU) Adolescents14–18 years900 (3000 iU) 700 (2333 iU) Adults ≥19 years 900 (3000 iU) 700 (2333 iU) Pregnancy ≤18 years –750 (2500 iU) Pregnancy ≥19 years –770 (2567 iU) Breast-feeding ≤18 years –1200 (4000 iU) Breast-feeding ≥19 years– 1300 (4333 iU) Ai, adequate intake.

with the risk of breast cancer in premenopausal tamin E increased the loss of retinal function by a women with a family history of breast cancer.29 small but significant amount,gg su esting that pa- Blood levels of retinol reflect the intake of both tients with common forms of retinitis pigmen- preformed vitamin A and provitamin A carot- tosa may benefit from g-lon term vitamin A sup- enoids such as β-carotene. Although a case–con- plementation but should avoid vitamin E supple- trol study found serum retinol levels and serum mentation at levels higher than those found in a antioxidant levels to be inversely related to the typical multivitamin. Up to 12 years of follow-up risk of breast cancer,30 two prospective studies in these patients did not reveal any signs of liver did not observe significant associations between toxicity as a result of excess vitamin A intake.35 blood retinol levels and subsequent risk of devel- High-dose vitamin A supplementation to slow oping breast cancer.31,32 Currently, there is little the course of retinitis pigmentosa requires medi- evidence in humans that increased intake of pre- cal supervision and must be discontinued if there formed vitamin A or retinol reduces breast can- is a possibility of pregnancy. cer risk. Acute promyelocytic leukemia. Normal differentiation of myeloid stem cells in the bone marrow Disease treatment gives rise to platelets, red blood cells, and white blood cells that are important for the immune re- Pharmacological Doses of Retinoids sponse. Altered differentiation of those stem cells Retinoids are used at pharmacological doses to results in the proliferation of immature leukemic treat several conditions, including retinitis pig- cells, giving rise to leukemia. A mutation of the mentosa, acute promyelocytic leukemia, and RAR has been discovered in patients with a spe- various skin diseases. It is important to note that cific type of leukemia called acute promyelocytic treatment with high doses of natural or synthetic leukemia (APL). Treatment with all-trans-RA or retinoids overrides the body’s own control mech- with high doses of all-trans-retinyl palmitate re- anisms, so retinoid therapies are associated with stores normal differentiation and leads to im- potential side effects and toxicities. In addition, provement in some APL patients.2,18 all of the retinoid compounds have been found to cause birth defects. Thus, women who have a Diseases of the Skin chance of becoming pregnant should avoid treatment with these medications. Retinoids tend to Both natural and synthetic retinoids have been be very long acting: side effects and birth defects used as pharmacological agents to treat disorders have been reported to occur months after discon- of the skin. Etretinate and acitretin are retinoids tinuing retinoid therapy.2 The retinoids discussed that have been useful in the treatment of psoria- below are prescription drugs and should not be sis, whereas tretinoin and isotretinoin have been used without medical supervision. used successfully to treat severe acne. Retinoids most likely affect the transcription of skin growth Retinitis pigmentosa. Retinitis pigmentosa de- factors and their receptors.2 Use of pharmaco- scribes a broad spectrum of genetic disorders logical doses of retinoids by pregnant women that result in the progressive loss of photorecep- causes birth defects. tor cells (rods and cones) in the eye’s retina.33 Early symptoms of retinitis pigmentosa include impaired dark adaptation and night blindness, Sources followed by the progressive loss of peripheral Retinol Activity Equivalents and central vision over time. The results of a randomized controlled trial in more than 600 pa- Different dietary sources of vitamin A have dif- tients with common forms of retinitis pigmen- ferent potencies; for example, β-carotene is less tosa indicated that supplementation with easily absorbed than retinol and must be con- 4500 µg (15000 IU)/day of preformed vitamin A verted to retinal and retinol by the body. The (retinol) significantly slowed the loss of retinal most recent international standard of measure function over a period of four to six years.34 In for vitamin A is retinol activity equivalents (RAE), contrast, supplementation with 400IU/day of vi- which represent vitamin A activity as retinol:

Table 7.2 retinol activity equivalent (rAE) ratios for sorbed than β-carotene, resulting in RAE ratios of β-carotene and other provitamin A carotenoids 24:1. The RAE ratios for β-carotene and other Quantity Quantity RAE ratio provitamin A carotenoids are shown in table consumed bioconverted 7.2.21 An older international standard, still com- to retinol monly used, is the international unit (IU): 1IU is 1µg dietary or 1µg retinol 1:1 equivalent to 0.3 µg retinol. supplemental vitamin A Food Sources 2µg supplemental 1µg retinol 2:1 β-carotene Free retinol is not generally found in foods. Reti- 12 µg dietary 1µg retinol 12:1 nyl palmitate, a precursor and storage form of β-carotene retinol, is found in foods from animals. Plants 24 µg dietary 1µg retinol 24:1 contain carotenoids, some of which are precur- α-carotene sors for vitamin A (e.g., α-carotene, β-carotene, 24 µg dietary 1µg retinol 24:1 and β-cryptoxanthin). Yellow and orange vegeta- β-cryptoxanthin bles contain significant quantities of carotenoids. Green vegetables also contain carotenoids, al- 2µg β-carotene in oil provided as a supplement though the pigment is masked by the green pig- can be converted by the body to 1µg retinol, ment of chlorophyll.1 A number of good food giving it an RAE ratio of 2:1. However, 12 µg sources of vitamin A are listed in Table 7.3 along β-carotene from foods are required to provide with their vitamin A content in RAEs. In those the body with 1µg retinol, giving dietary foods where retinol activity comes mainly from β-carotene an RAE ratio of 12:1. Other provita- provitamin A carotenoids, the carotenoid content min A carotenoids in foods are less easily ab- and the RAEs are presented.

Table 7.3 Food sources of vitamin A

Food Serving Vitamin A Vitamin A Retinol Retinol (µg RAE) (IU) (µg) (IU) cod liver oil 1 teaspoon 1350 4500 1350 4500 Fortified breakfast cereals 1 serving 150–230 500–767 150–230 500–767 Egg1large 91 303 89 296 Butter1tablespoon 97 323 95 317 Whole milk 1 cup (8 fluid ounces) 68 227 68 227 2% fat milk (vitamin A added) 1 cup (8 fluid ounces) 134 447 134 447 Nonfat milk (vitamin A added) 1 cup (8 fluid ounces) 149 497 149 497 Sweet potato, canned ½ cup, mashed 555 1848 00 Sweet potato, baked ½ cup961 3203 00 Pumpkin, canned ½ cup953 3177 00 carrot, raw½cup, chopped 538 1793 00 cantaloupe ½ medium melon 467 15550 0 mango 1 fruit 79 263 00 Spinach½cup, cooked 472 1572 00 Broccoli ½ cup, cooked 60 200 00 Kale ½ cup, cooked 443 1475 00 collards ½ cup, cooked 386 1285 00 Squash, butternut ½ cup, cooked 572 1907 00 rAE, retinol activity equivalent.

Index Page numbers in italics refer to illustrations or tables

A angiotensin 215 bioavailability 250 antacid interactions 140, 166, bioflavanoids 77 acetyl-CoA carboxylase 1 184, 194, 239 biotin 1–5 acetylation 26 anti-thiamin factors (ATFs) 37 adequate intake 2, 2 acne 46 anti-tuberculosis medications 57 bacterial synthesis 4 acrodermatitis enteropathica 225 antibiotic interactions 113, 230, birth defects prevention 3 acute promyelocytic leukemia 239 deficiency 1–2 (APL) 46 antibodies 248–249 disease treatment 3–4 acyl-carrier protein 26 anticoagulants 249 brittle fingernails 3–4 adequate intake (AI) 248 interactions 40, 78, 103, 113 diabetes mellitus 3 see also specific nutrients anticonvulsants 249 hair loss 4 adolescents interactions 14, 103, 231, 239 drug interactions 5 calcium recommendations 125 antidiuretic hormone (ADH) 215 food sources 4, 4 iodine deficiency 151 antigens 249 function 1 iron deficiency 159 antihistamine 249 nutrient interactions 4–5, 236 ADP-ribosyl cyclases 17–18 antioxidants 249 recommendations 5 adrenal glands 248 copper function 135–136 toxicity 4 age-related macular degeneration iron function 157 biotin-deficient facies 2 (ARMD) treatment 246 manganese function 179 biotinidase deficiency 2 zinc 229 selenium interaction 204, 211 birth defects AIDS 21, 248 statin interactions 78–79, 211 prevention 247 treatment 246 vitamin E interactions 103–104 biotin 3 selenium 209 see also specific antioxidants folic acid 10–11 zinc 229 antiplatelet drug interactions 240 vitamin A and 48 alcohol interactions 40, 49, 241 apoptosis 249 bisphosphonate interactions 176, alcoholism arginase 179 240 folate deficiency and 8–9 ariboflavinosis 31–32 Bitot spots 44 magnesium deficiency and 170 ascorbate 77 blood loss, iron deficiency and thiamin deficiency and 36, 37 see also vitamin C 159–160 aldehyde oxidase 187 ascorbyl palmitate 77 blood pressure regulation aldosterone 215 aspirin interactions 241 sodium chloride 215 allele 248 asthma 243, 249 vitamin D84–85 allopurinol 241 magnesium treatment 174 see also hypertension Alzheimer disease 243, 248 ataxia 97, 249 blood volume maintenance 215 prevention 243 atherosclerosis 111, 249 body mass index (BMI) 250 folic acid 13 prevention 244 bone development 179 vitaminB6 54–55 treatment 244 bone mineral density (BMD) 250 vitaminB12 65–66 see also cardiovascular diseases fluoride and 143–144 treatment 243 ATP 249 magnesium and 172 thiamin 38 atrial fibrillation 249 potassium and 198 vitamin E 100–101 atrophic gastritis 61–62, 249 sodium chloride and 216–217 amino acids 248 autoimmune disease 249 vitamin A effects 49 metabolism 8 prevention 243 vitamin D role 87–88 analog 248 vitamin D89–90 vitamin K and 108, 110 anaphylactic reactions 248 see also osteoporosis thiamin 39 B bone remodeling 115, 250 anemia 32, 136, 248 brain damage, iodine deficiency hemolytic 257 bacteria 249 and 149, 150 hereditary 164 biotin synthesis 4 breast cancer prevention 243 iron deficiency 159 pantothenic acid synthesis 28 folic acid 12 macrocytic 259 vitamin K synthesis 112 vitamin A 45–46 megaloblastic 9, 62, 260 balance study 249 vitamin B12 64–65 pernicious 60–61, 263 beriberi 36–37, 38 vitamin C 72 sickle cell 266 beta-carotene 42, 46–47 vitamin D88–89 sideroblastic 266 bias 249 vitamin E 99 anencephaly 248 bile 249–250 angina pectoris 248 bile acids 250 angiography 248

breast feeding treatment 243 chemotherapy 251 calcium recommendations 126 thiamin 39 children iodine deficiency and 151 vitamin C 75 calcium recommendations 125 vitamin D deficiency and 85 vitamin E 101 iodine deficiency 151 brittle fingernails, biotin treat- see also specific types of cancer iron deficiency 159 ment 3–4 carbohydrate 250 impaired intellectual deve- buffer 250 chromium interactions lopment and 161 128–129 manganese susceptibility 184 C carboxylation 250 zinc deficiency 226–227 osteocalcin 110 diarrhea susceptibility and caffeine, calcium balance and 117 carcinogen 250 227 calcidiol 83 carcinoid syndrome 250 effects on growth and deve- see also vitamin D cardiac arrhythmias 244, 249 lopment 226 calcification 250 see also cardiovascular diseases malaria susceptibility and phosphorus and 193–194 cardiomyopathy 250 227 vascular 111–112 cardiovascular diseases 250 pneumonia susceptibility calcitriol 83, 115, 241 iron excess and 165 and 227 see also vitamin D prevention 244 chloramphenicol 241 calcium 115–126 chromium 130 chlorpromazine 176, 241 deficiency 116 copper 137–138 cholecalciferol 83, 91 disease prevention 118–121 folic acid 11–12 see also vitamin D colorectal cancer 118 magnesium 171 cholestatic liver disease 251 kidney stones 119–120 niacin 21 cholesterol 251 lead toxicity 120–121 selenium 208–209 lowering 246 osteoporosis 118–119 sodium chloride reduction niacin 21 pregnancy-inducedhyper- 219 pantethine 27–28

tension 120 vitaminB6 53–54 cholesytramine 241 disease treatment 121 vitaminB12 64 chorionic villous sampling (CVS) hypertension 121 vitamin C 71–72 251–252 premenstrual syndrome 121 vitamin E 98 chromatin 252 drug interactions 124–125 vitamin K 111–112 chromium 128–133 function 115 treatment 244 adequate intake 129, 130 lead levels in supplements 123 magnesium 173 deficiency 129 nutrient interactions 116–117, vitamin C 74–75 diabetes treatment 131–132 125, 142, 147, 159, 170, 180, vitamin E 99–100 disease prevention 130 224–225, 236–238 carnitine 250, 271 cardiovascular diseases 130 phosphorus role in calcium carotenoids 42 diabetes mellitus 130 balance 117, 191, 192 carotid arteries 250 drug interactions 133 prostate cancer risk and 124 carpal tunnel syndrome treat- function 128, 129 RDA 116, 118 ment 56, 245 health claims 130–131 recommendations 125–126, cartilage 250 nutrient interactions 128–129, 271 case reports 251 236–237 regulation 115, 116 case-control study 250–251 recommendations 133 sources 122–123, 122 catabolism 251 sources 132, 132 tolerable upper intake level cataract 251 toxicity 132–133 123 prevention 245 chromosome 252 toxicity 123 riboflavin 33 chronic disease 252 vitamin D role 83, 84 thiamin 38 cirrhosis 252 weight loss and 125 vitamin C 73 clinical trial 252, 263 calcium channel blocker interac- vitamin E 98–99 coagulation 252 tions 240 catecholamines 251 calcium role 115 calmodulin 115 celiac disease 160, 245, 251 vitamin K role 107–108, 109 cancer 12, 243, 250 cell differentiation 83–84 cobalamin 60

iron excess and 165–166 cell membrane 251 see also vitamin B12 prevention 243 membrane potential 196, 196, coenzyme 252 calcium 118 214, 214 coenzyme A 26 folic acid 12 cell migration 169 cofactor 252 niacin 19–20 cell signaling 115, 169, 251 see also enzyme cofactors selenium 206–208 cerebrovascular disease 251 cognitive impairment vitamin A 45–46 ceruloplasmin 135, 136 prevention, folic acid 13

vitaminB12 64–65 cardiovascular disease and 137, iron, in children 161 vitamin C 72–73 138 vitaminB6 54–55 vitamin D 88–89 cervical intraepithelial neoplasia treatment, vitamin E 100–101 vitamin E 99 (CIN) 251 see also dementia

aus: Higdon, An Evicdence-based Approach to Vitamins and Minerals (ISBN 9783131324528) © 2012 Georg Thieme Verlag KG index 275 cohort study 252 cystic fibrosis (CF) 253 double blind 254 colchicine 241 cytochromes 157 doxorubicin 241 colestipol 241 cytochrome P450 (CYP) 253 DEXA 253 collagen 252 cytokine 253 colon 252 cytoplasmic retinoic acid-binding E colorectal cancer 252 proteins (CRABPs) 43 iron excess and 165–166 echocardiography 254 prevention 243 D eclampsia 32, 247 calcium 118 magnesium treatment folic acid 12 daily value (DV) 254 172–173, 247 vitamin D88 decarboxylation 253 ecological study 254 common cold treatment 245 dementia 253 electroencephalogram (EEG) 254 vitamin C 76 prevention 245 electrolytes 254

zinc 228 vitaminB12 62, 65–66 electron transport 157, 255 intranasal preparations 228, treatment 245 endocrine system 255 230 vitamin E 100–101 endothelial dysfunction, magne- lozenges 228 vascular 269 sium treatment 173 complement 252 see also Alzheimer disease energy metabolism 157 congestive heart failure 244, 252 dental caries 142, 253 energy production 135, 169 thiamin treatment 38–39 prevention 143, 245 enzyme 255 see also cardiovascular diseases dental fluorosis 142, 146–147 enzyme cofactors connective tissue formation, depletion–repletion study 253 biotin 1 copper function 135 depression 245 calcium 115 copper 135–140 prevention 66, 245 potassium 196

deficiency 136–137, 230 treatment 56, 245 vitamin B12 60 individuals at risk 137 dermatitis 132, 253 epilepsy 255 disease prevention 137–139 diabetes mellitus 253–254 see also seizure cardiovascular diseases iron excess and 166 ergocalciferol 83 137–138 prevention 245 see also vitamin D immune system function chromium 130 erythropoietin 255 138–139 manganese 181 esophagus 255 osteoporosis 139 niacin 20 see also gastroesophageal drug interactions 140 selenium 209 cancer function 135–136 vitamin D 89 estimated average requirement antioxidant functions treatment 245 (EAR) 254 135–136 biotin 3 estrogen 52, 255 central nervous system 135 chromium 131–132 see also oral contraceptives connective tissue formation magnesium treatment 135 173–174 F energy production 135 treatment 229 gene expression regulation vitamin C 75–76 familial adenomatous polyposis 135 vitamin E 100 255 iron metabolism 135 zinc 229 fatty acid 255 melanin formation 135 diabetic ketoacidosis 254 ferritin 158, 165, 166 nutrient interactions 136, 158, dialysis 100, 254 ferroxidase 135 187, 224, 230, 237–238 peritoneal 262–263 fetal development RDA 137, 137 diarrhea 44, 175, 227 folic acid benefits 10–11, 15 recommendations 140 diastolic blood pressure 254 iodine deficiency 150 sources 139, 139 dietary folate equivalents (DFEs) vitamin A and 44, 48 tolerable upper intake level 140 9–10 see also pregnancy toxicity 139–140 dietary reference intake (DRI) fiber, magnesium status and 169 cornea 252 254 fibroblastic breast condition 255 coronary artery 252 diethylenetriamine pentaacetate iodine treatment 152–153 coronary heart disease (CHD) (DPTA) 241 fish oil 271 244, 252 digoxin 241 flavin adenine dinucleotide (FAD) see also cardiovascular diseases diuretic 254 30, 31 creatine phosphate 252–253 interactions 40, 231, 240 flavin mononucleotide (FMN) 30 cretinism 150, 253 diverticulitis 254 flavocoenzymes 30 Crohn disease 253 DNA 254 flavoproteins 30 cross-sectional study 253 damage 132–133 fluoride (fluorine) 142–147 crossover trial 253 metabolism 7 adequate intake 142, 143 cyanocobalamin 60, 67 methylation 63 adverse effects 146–147

see also vitamin B12 synthesis 158 deficiency 142 cycloserine 241 transcription 268

disease prevention 143–144 chromium supplementation vitamin A effects on transmis- dental caries 143 131–132 sion 45 osteoporosis 143–144 gluconeogenesis 256 HMG-CoA reductase inhibitors drug interactions 147 glucose 256 see statins function 142 glucose tolerance impairment holocarboxylase synthetase nutrient interactions 142, 237 258 (HCS) 1 osteoporosis treatment 144 chromium and 128, 130 deficiency 2 recommendations 147 see also diabetes mellitus homocysteine 8, 31, 244, 257 sources 145–146, 145, 146 glucoside 256 Alzheimer disease and 65–66 fluorosis glutamate 179 cardiovascular diseases and dental 142, 146–147 glutamine synthetase 179 11–12, 53–54, 64 skeletal 147 glutathione 256 metabolism 8, 8, 54, 61 5-fluorouracil 24, 241 glutathione peroxidase 30, 203, homopantothenate 26 folic acid 7–15 203 hormone 257 deficiency 8–9, 62 glutathione reductase 30, 203 hydrolysis 257 dietary folate equivalents glycogen 256 hydroxyapatite 115, 142, 191, 257 (DFEs) 9–10 glycoside 256 hydroxylation 257 disease prevention 10–13 glycosyltransferases 179 hypercalcemia 91–92, 123 Alzheimer disease and cogni- goiter 149, 151, 154, 256 hypercalciuria 123, 198–199 tive impairment 13 goitrogens 151–152, 256 hypercholesterolemia 21, 27–28, cancer 12 gout 256 246 cardiovascular diseases prevention, vitamin C 73 hyperglycemia 257 11–12 growth retardation 246 hyperkalemia 194–195, 200, 201 pregnancy complications zinc deficiency and 226 hypermagnesemia 175 10–11, 15 GTP (guanosine triphosphate) hypernatremia 220 drug interactions 14–15 257 hyperparathyroidism 257–258 function 7–8, 7 secondary 85 genetic variation in require- H hyperphosphatemia 193–194 ments 10 hypertension 74–75, 258

nutrient interactions 8, 225, H2-receptor antagonist interac- prevention 246 236 tions 166, 240 calcium 120 RDA 9, 9 hair loss, biotin and 1, 4 magnesium 170–171 recommendations 15 hallucination 2 pregnancy-inducedhyper- sources 13, 14 Hartnup disease 19, 257 tension 120 toxicity 14 healthy eating 270 vitamin D90

food-bound vitamin B12 malab- healthy lifestyle 270 sodium and 217–219 sorption 61 heart disease see cardiovascular clinical trials 217–219 fortification 255 diseases salt sensitivity 218 fractures see osteoporosis Helicobacter pylori infection 62, target organ damage 219 free radical 255 72–73, 160, 216 treatment 246 fructose 256 heme 257 calcium 121 copper interaction 136 hemodialysis 257 magnesium 172 phosphorus interaction 191 hemoglobin 52, 157, 159, 257 potassium 199 function 7–8, 7 glycated 256 see also cardiovascular diseases hemolysis 97, 257 hyperthyroidism 258 G hemorrhage 257 iodine-induced (IHH) 154 vitamin E and 102–103 hypervitaminosis A 48 G-proteins 17 hepatitis 257 hypervitaminosis D91 gallbladder 256 liver cancer and 207 hypoglycemia 258 gallstones 256 niacin and 22–23 hypokalemia 197, 201 Gas6 protein 108 hepatocellular carcinoma 165, hypomagnesemia 170, 173–174 gastric bypass surgery 160 257 hyponatremia 215 gastric cancer 243 hepatotoxicity, niacin 22–23 prolonged endurance exercise salt consumption and 216 hepcidin 158 and 215–216 gastroesophageal cancer 243 hereditary hemochromatosis hypoparathyroidism 258 molybdenum 188–189 164, 257 hypophosphatemia 192 gastroesophageal reflux disease hereditary spherocytosis 257 hypothalamus 258 (GERD) 256 histone 257 hypothyroidism 149, 151, 258 gene expression 256 biotinylation 1 congenital 150, 252 copper role 136 HIV infection 257 hypoxia 157 retinoic acid role 43, 43 treatment 246 hypoxia inducible factors (HIFs) gestation 256 niacin 21 157 see also pregnancy selenium 209 gestation diabetes 247 zinc 229

I lead toxicity 161 lead pregnancy complications 161 in calcium supplements 123 immune function 246 diseases associated with iron toxicity prevention 246 copper role 138–139 excess 165–166 calcium 120–121 iron role 161–162 cancer 165–166 iron 161 selenium role 206 cardiovascular diseases 165 vitamin C 73–74 vitamin A role 44 diabetes and metabolic syn- left ventricular hypertrophy vitamin B6 role 54 drome 166 (LVH) 259 vitamin C role 74 neurodegenerative disease lethargy 2 vitamin D role 84 166 leukemia 243, 259 vitamin E role 99 drug interactions 166 acute promyelocytic (APL) 46 infectious disease function 157–158 childhood, vitamin K relation- iron and 161–162 antioxidant and prooxidant ship 109 selenium protective role 206 functions 157 leukocytes 259 vitamin A protective role 44 DNA synthesis 158 levodopa 241 deficiency effects 44–45 electron transport and ener- levothyroxine 241 zinc and, children 227 gy metabolism 157 licorice 197 diarrhea 227 oxygen sensing 157 lipids 259 malaria 227 oxygen transport and storage peroxidation 259 pneumonia 227 157 lipoic acid 259, 271 see also immune function; nonheme iron absorption lipoproteins 259 specificdiseases 162–163 lithium 242 inflammation 258 enhancers 162 liver disease inflammatory bowel disease 258 inhibitors 163 biotin deficiency and 2 vitamin D deficiency and 86 nutrient interactions 31, 44, cancer insulin 258 125, 128, 136, 158–159, hepatitis infection and 207 chromium function 128, 129 179–180, 224, 236–238 iron excess and 165 resistance 258 overload 164 selenium protective effect secretion 84 RDA 160, 160 207–208 insulin-like growth factor-1 recommendations 166, 270 cholestatic 251 (IGF-1) 118 regulation 158 manganese susceptibility and intervention trial 258 restless legs syndrome treat- 183 iodine 149–155 ment 162 lovastatin 242 deficiency 149–150 sources 162–163, 163 niacin interaction 23 developmental stage and tolerable upper intake level 165 see also statins 150–151 toxicity 164–165 low birth weights 11 individuals at risk 152 iron regulatory proteins (IRPs) lung cancer 132 drug interactions 154–155 158 prevention 243 fibrocystic breast condition isoniazid 24, 241 selenium 207 treatment 152–153 vitamin A 45 function 149 J vitamin C 72 nutrient interactions 151–152, vitamin E 99 204, 236–238 jaundice 259 lymphocytes 259 radiation-induced thyroid lysyl oxidase 139 cancer prevention 152 RDA 151, 152 K M recommendations 155 Kashin–Beck disease 205 sources 153, 153 Keshan disease 205 macular degeneration 246 tolerable upper intake level ketoconazole 241 zinc treatment 229 154 ketone bodies 259 magnesium 169–176 toxicity 153–154 kidney failure 133 deficiency 116, 170 iodine-induced hyperthyroidism kidney stones 259 disease prevention 170–172 (IHH) 154 prevention 246 cardiovascular diseases 171 iodothyronine deiodinases 204 calcium 119–120 hypertension 170–171 ion channel 258 potassium 198–199 osteoporosis 171–172 ion transport 169 vitaminB6 55 disease treatment 172–174 iron 157–166 sodium and 217 asthma 174 copper role in iron metabolism vitamin C and 78 cardiovascular diseases 173 135 Korsakoff psychosis 36 diabetes mellitus 173–174 deficiency 159 hypertension 172 individuals at risk 159–160 l migraine headaches 174 symptoms 159 pre-eclampsia and eclampsia disease prevention 161–162 L-carnitine 271 172–173 immune function 161–162 lactation see breast feeding drug interactions 176 impaired intellectual deve- laxative interactions 184, 240 function 169 lopment 161

nutrient interactions 125, 142, methylcrotonyl-CoA carboxy- neutropenia 136, 138 169–170, 180, 236–238 lase 1 neutrophils 9, 261 RDA 170, 171 methylcyclopentadienyl manga- newborn infants recommendations 176, 271 nese tricarbonyl (MMT) 183 iodinedeficiency 150–151 sources 174–175, 175 methyldopa 242 manganese susceptibility tolerable upper intake level 175 methylene tetrahydrofolate 183–184 toxicity 175–176 reductase (MTHFR) 31, 31 vitaminKdeficiency 109 malabsorption syndrome 62, 260 polymorphism 10, 12, 31 niacin 17–24, 17 malaria 260 methylmalonic acid (MMA) 62 deficiency 18 susceptibility in children, zinc methylmalonyl-CoA mutase 60 causes of 19 and 227 impaired activity 62 disease prevention 19–20 manganese 179–184 migraine headache 260 cancer 19–20 adequate intake 180, 180 treatment 246 diabetes (type 1) 20 deficiency 180 magnesium 174 disease treatment 21 disease prevention 180–181 riboflavin33 cardiovascular disease 21 diabetes mellitus 181 milk alkali syndrome 123 HIV infection 21 osteoporosis 181 mineral 260 drug interactions 23–24 seizure disorders 181 miscarriage 11 formation 52 drug interactions 184 mitochondria 260–261 function 17–18 function 179 molybdenum 187–190 HIV infection and 21 individuals with increased deficiency 187–188 nutrient interactions 19, 236 susceptibility 183–184 drug interactions 189 RDA 19, 19 nutrient interactions 179–180, function 187 recommendations 24 237–238 gastroesophageal cancer pre- sources 22, 22 recommendations 184 vention 188–189 tolerable upper intake level 23 sources 181–182, 182 nutrient interactions 187 toxicity 22–23 tolerable upper intake level 184 RDA 188, 188 nicotinamide toxicity 182–183 recommendations 190 insulin sensitivity and 20, 23 ingested manganese 183 sources 189 toxicity 23 inhaled manganese 182–183 tolerable upper intake level 189 nicotinamide adenine dinucleoti- intravenous manganese 183 toxicity 189 de (NAD) 17, 31 methylcyclopentadienyl mono-ADP-ribosyltrans- cancer and 19–20 manganese tricarbonyl ferases 17 synthesis 18 (MMT) 183 multiple sclerosis (MS) 261 nicotinamide adenine dinucleoti- manganese superoxide dismutase prevention 247 de phosphate (NADP) 17, 31 (MnSOD) 179 vitamin D89–90 nicotinic acid see niacin manganism 182 multivitamin supplements 270 nitric oxide 261 matrix Gla protein (MGP) 108 muscle mass 130–131 nitrous oxide 67, 242 megaloblastic anemia 9, 62 mutation 261 nonsteroidal anti-inflammatory melanin formation, copper func- myelin 261 drug (NSAID) interactions 14, tion 135 copper function 135 103, 240 membrane potential 214, 260 myocardial infarction 261 nucleic acids 261 potassium function 196, 196 prevention 245 metabolism 7, 7 sodium chloride function 214, treatment 245 synthesis 52, 63 214 magnesium 173 see also DNA; RNA menaquinones 107, 112 see also cardiovascular diseases nucleotides 262 see also vitamin K myocarditis 261 nutrient absorption 215 Menkes disease 138 myoglobin 157, 159, 261 menstruation 260 O meta-analysis 260 N metabolic syndrome 260 obesity 262 iron excess and 166 natural killer (NK) cells 261 vitaminDdeficiency and86 metabolism 260 nausea and vomiting in preg- older adults, recommendations metabolite 260 nancy treatment 56, 247 biotin 5 metallothionein 136, 224 necrosis 261 chromium 133 metformin 242 neomycin 242 copper 140 methionine 8, 260 neural tube defect (NTD) 261 fluoride 147 methionine synthase 60 prevention 247 folic acid 15 impaired activity 62 folic acid 9, 10 iodine 155

methionine-R-sulfoxide reduc- vitaminB12 65 iron 166 tase 204 neurodegenerative disease 261 magnesium 176 methotrexate 242 iron and 166 manganese 184 folic acid interaction 14 neurotransmitters 261 molybdenum 190 methylation 260 copper function 135 niacin 24

pantothenic acid 29 parathyroid hormone (PTH) 115 potassium iodide 153 phosphorus 195 magnesium deficiency and 170 pre-eclampsia 32, 264 potassium 201 phosphorus and 191–192 prevention 247 riboflavin 35 Parkinson disease 262 calcium 120 selenium 211 pellagra 18 folate 11 sodium chloride 221 penicillamine 140, 231, 242 riboflavin deficiency and 32 thiamin 40 peptic ulcer disease 262 treatment 247 vitamin A 49 peripheral neuropathy 36, 97, magnesium 172–173

vitamin B6 58 262 pregnancy 246–247 vitamin B12 68 peripheral vascular disease 262 biotin deficiency and 2, 3 vitamin C 79 pernicious anemia 60–61 calcium recommendations 126 vitaminD92 phenothiazine derivative interac- folic acid benefits 10–11, 15 vitamin E 104 tions 240 gestational diabetes 131–132 vitamin K 113 phenylketonuria (PKU) 263 iodine deficiency 151 zinc 231 phenytoin 242 iron deficiency 159 immune function and 227 phlebotomy 263 pregnancy complications and olestra 242 phosphorus 191–195 161 oral contraceptives bone health and 191–192 nausea and vomiting treatment interactions 15, 24, 29, 34, 240 calcium balance and 117, 191, 56 side effects treatment 55 192 pregnancy-induced hypertensi- orlistat 242 deficiency 192 on, calcium and 120 osteoarthritis 262 drug interactions 194–195 vitamin A safety 48–49 osteoblasts 116, 262 function 191 zinc deficiency 227–228 osteocalcin 108 nutrient interactions 191–192, premature delivery 11 vitamin K-dependent 238 premenstrual syndrome (PMS) carboxylation 110 RDA 193, 193 treatment osteoclasts 115 recommendations 195 calcium 121 osteomalacia 85, 262 sources 193, 194 vitamin B6 55–56, 247 osteoporosis 115, 262 tolerable upper intake level prooxidant 264 copper and 136–137, 139 194 iron function 157 prevention 246 toxicity 193–194 propionyl-CoA carboxylase 1 calcium 118–119 phosphorylation 263 prostaglandins 208, 264 copper 139 phylloquinone 107, 112 prostate 264 fluoride 143–144 see also vitamin K prostate cancer manganese 181 phytic acid 122, 163 calcium and 124 potassium 198 pituitary 263 prevention 243 vitamin D87–88 placebo 263 selenium 207, 208 vitamin K 110–111 placenta 263–264 vitamin D89 sodium chloride and 216–217 placental abruption 11, 264 vitamin E 99 treatment 246 plasma 264 prostate-specific antigen (PSA) vitamin A and 49 Plasmodium falciparum 227 264 oxalate 122 Plummer-Vinson syndrome 159 protein 264 oxidation–reduction reactions pneumonia 264 acetylation 26 17, 30, 30, 265 susceptibility in children, zinc calcium balance and 117, 237 oxygen sensing 157 and 227 magnesium absorption and oxygen transport and storage poly-ADP-ribose polymerases 169 157 (PARPs) 17 protein S108 polymorphism 264 proteoglycan 264–265 P polyp 264 proton pump inhibitor interac- polyphenols 163 tions 166, 240 pancreas 262 potassium 196–201 psoriasis 46, 265 pantethine 27–29 adequate intake 197, 197 pyridoxal 5'-phosphate (PLP) 52 pantothenic acid 26–29 deficiency 197 see also vitamin B6 adequate intake 27, 27 disease prevention 197–199 pyridoxine glucoside 56 deficiency 26–27 kidney stones 198–199 pyruvate carboxylase 1, 179 disease treatment 27–28 osteoporosis 198 pyruvate kinase deficiency 265 drug interactions 29 stroke 197–198 function 26 drug interaction 201, 201 Q nutrient interactions 236 function 196 recommendations 29 hypertension treatment 199 quinacrine 242 sources 28, 28 nutrient interactions 238 toxicity 28–29 recommendations 201 R parathyroid glands 262 sources 199–200, 200 toxicity 200 R proteins 60 adverse reaction to supple- radiation-induced thyroid cancer ments 200 prevention 152

randomized controlled trial (RCT) S function 214–215 265 blood volume and pressure RDA (recommended dietary S-adenosylmethionine (SAM) 7, 215 allowance) 265 66 membrane potential 214 see also specific nutrients salt see sodium chloride nutrient absorption 215 reactive nitrogen species 265 scurvy 70, 266 nutrient interactions 237, 238 reactive oxygen species (ROS) seizure 266 recommendations 221 157, 265 prevention 247 sources 219, 220 see also antioxidants manganese and 181 tolerable upper intake level receptor 265 vitaminB6deficiency and 221 red blood cell production 52–53 toxicity 219–220 vitamin A role 44 selenium 203–211 soy protein, iron absorption and deficiency 205 vitamin B6 role 52 163 redox reactions 17, 30, 30, 265 individuals at increased risk spina bifida 266 renal dialysis 100, 254 205 sprue 266–267 renin–angiotensin–aldosterone disease prevention 206–209 statins system 215 cancer 206–208 antioxidant interactions 78–79, resorption 265 cardiovascular diseases 211 response element 265 208–209 niacin interactions 23 restless legs syndrome (RLS) 162, diabetes mellitus 209 vitamin E interaction 104–105 247 immune function 206 steroid 267 retina 42, 265 viral infection 206 steroid hormone receptor 267 retinal 42 drug interactions 211 steroid hormones 52 retinitis pigmentosa 46, 97 function 203–204 stomach cancer prevention, vita- retinoic acid (RA) 42, 44 HIV/AIDS treatment 209 min C 72–73 gene expression regulation 43, nutrient interactions 151, 204, stroke 267 43 236–238 hemorrhagic 257 retinoic acid response elements RDA 205, 206 ischemic 258 (RAREs) 43 recommendations 211 prevention 245, 247 retinoids 42 sources 209–210, 210 potassium 197–198 drug interactions 240 toxicity 210–211 vitamin C 72 pharmacological doses 46 selenophosphate synthetase 204 see also cardiovascular diseases see also vitamin A selenoproteins 203–204 sucralfate 242 retinol 42–43, 44 selenosis 210 sulfasalazine 242 breast cancer and 45–46 sensory neuropathy 57 sulfinpyrazone 23–24, 242 see also vitamin A Sep15 204 sulfite oxidase 187 retinol activity equivalents (RAE) serotonin 266 deficiency 187–188 46–47, 47 synthesis 52 sunlight, as vitamin D source 90 retrospective study 266 serum 266 superoxide dismutase (SOD) rhabdomyolysis 23 short bowel syndrome 266 135–136 rheumatoid arthritis (RA) 266 sickle cell anemia 266 systematic review 267 prevention 247 simvastatin systolic blood pressure 267 vitamin D90 antioxidant interactions 78–79, 211 riboflavin 30–35 t cataract prevention 33 niacin interaction 23 deficiency 31–32 vitamin E interaction 103–104 tannins 267 risk factors 32 see also statins testosterone 52 drug interactions 34 skeletal fluorosis 147 tetany 267 function 30 skin diseases, retinoid treatment thalassemia 164 migraine treatment 33 46 major 164, 267 nutrient interactions 31, see also specificdiseases minor 164, 268 236–237 smoking 207 thiamin 36–40 RDA 32, 32 sodium chloride 214–221 cataract prevention 38 recommendations 34–35 adequate intake 216, 216 deficiency 36–37 sources 34, 34 adverse effects 220–221 causes of 37 toxicity 34 calcium balance and 116–117 disease treatment 38–39 ribonucleotide 266 deficiency 215–216 Alzheimer disease 38 rickets 85, 266 disease prevention 216–219 cancer 39 rifampin 242 cardiovascular diseases 219 congestive heart failure RNA 266 gastric cancer 216 38–39 translation 268 hypertension 217–219 drug interactions 40 kidney stones 217 function 36 osteoporosis 216–217 RDA 37, 38 drug interactions 221 recommendations 40 sources 39, 40 toxicity 39

aus: Higdon, An Evicdence-based Approach to Vitamins and Minerals (ISBN 9783131324528) © 2012 Georg Thieme Verlag KG index 281 thiomolybdates 187 vitamin A 42–49 nutrient interactions 236 thioredoxin reductase 203 bone mineral density (BMD) RDA 63, 63 threshold 268 effects 49 recommendations 67–68 thyroid 268 cancer prevention 45–46 sources 66–67, 66 function 149, 150 deficiency 44–45 toxicity 67 thyroid cancer 154 disease treatment 46 vitamin C 70–79 follicular 268 drug interactions 49 deficiency 70 papillary 268 function 42–44 disease prevention 70–74 prevention 243 gene expression regulation cancer 72–73 iodine 152 43, 43 cardiovascular diseases thyroid hormones 149 growth and development 44 71–72 deiodinases 204 immunity 44 cataracts 73 thyroid-stimulating hormone red blood cell production 44 gout 73 (TSH) 149, 154 vision 42–43, 43 lead toxicity 73–74 thyrotropin-releasing hormone nutrient interactions 44, role in immunity 74 (TRH) 149 112–113, 158, 225, 236–238 disease treatment 74–76 tocopherol 96 RDA 45, 45 cancer 75 alpha-tocopherol 96, 99 recommendations 49, 270 cardiovascular diseases supplements 102 safety in pregnancy 48–49 74–75 gamma-tocopherol 96–97 sources 46–48, 47 common cold 76 supplements 102 tolerable upper intake level 48 diabetes mellitus 75–76 see also vitamin E toxicity 48 drug interactions 78–79 tolerable upper intake level (UL) vitamin B1 see thiamin function 70 268–269 vitamin B2 see riboflavin nutrient interactions 128, 136, see also specific nutrients vitamin B3 see niacin 162, 236–238 transcription factor 268 vitamin B5 see pantothenic acid RDA 70, 71 transferrin 128 vitamin B6 52–58 recommendations 79, 270 receptor 158 deficiency 52–53 sources 76–77, 76 transient ischemic attack (TIA) disease prevention 53–55 tolerable upper intake level 77 268 cardiovascular diseases toxicity 77 transketolase 36 53–54 kidney stones 78 triamterene 242 cognitive function 54–55 oxidative damage promotion tricyclic antidepressant interac- immune function 54 78 tions 240 kidney stones 55 with bioflavanoids 77 triglycerides 268 disease treatment 55–56 vitaminD83–92 trimethoprim 242 carpal tunnel syndrome 56 activation 83 troponin C 115 depression 56 deficiency 85 tryptophan, niacin interaction nausea and vomiting in preg- risk factors 85–86 19, 236 nancy 56 disease prevention 87–90 tuberculosis (TB) 268 oral contraceptive side effects autoimmune disease 89–90 typhoid 268 55 cancer 88–89 premenstrual syndrome hypertension 90 U 55–56 osteoporosis 87–88 drug interactions 57 drug interactions 92 ulcerative colitis 268 function 52 function 83 nutrient interactions 31, 236 blood pressure regulation V RDA 53, 53 84–85 recommendations 57–58 calcium balance 83, 84, 116 vascular calcification 111–112 sources 56–57, 56 cell differentiation 83–84 vasodilation, vitamin C treatment tolerable upper level 57 immunity 84 74 toxicity 57 insulin secretion 84 vegetarians vitamin B12 60–68 mechanisms of action 83 iron deficiency 160 deficiency 60–62 nutrient interactions 170, 191, zinc deficiency 225 causes 60–62 236–238 venous thromboembolism, vita- symptoms 62 nutritional status assessment min E and 98 disease prevention 64–66 86 virus 269 cancer 64–65 RDA 86, 87 viral infection 206 cardiovascular diseases 64 recommendations 92, 270 vision 42, 42 dementia 65–66 sources 90–91, 91 vitamin A function 42–43 depression 66 tolerable upper intake level 91 deficiency effects 44 neural tube defects 65 toxicity 91–92 vitamin 269 drug interactions 67 vitamin D receptor (VDR) 83, 85 folic acid interaction 14 vitamin D response elements function 60 (VDREs) 83

vitamin E 96–104 drug interactions 113 Z deficiency 97 function 107–108 disease prevention 98–99 bone mineralization 108 zinc 224–231 cancer 99 cell growth 108 deficiency 225 cardiovascular diseases 98 coagulation 107–108 individuals at risk 225 cataracts 98–99 nutrient interactions 112–113, disease prevention 226–228 immune function 99 236–237 immune function in elderly disease treatment 99–101 premature infant doses 109 people 227 cancer 101 recommendations 113 impaired growth and deve- cardiovascular diseases sources 112, 112 lopment 226 99–100 toxicity 112 infectious disease in children dementia 100–101 warfarin interaction 107, 108 227 diabetes mellitus 100 pregnancy complications 227–228 drug interactions 103–104 W function 96–97 disease treatment 228–229 alpha-tocopherol 96, 99 warfarin 242 age-related macular degene- gamma-tocopherol 96–97 fracture risk and 110–111 ration 229 nutrient interactions 112–113, interactions 78, 103, 107, 108, common cold 228 236–238 110–111, 113 diabetes mellitus 229 RDA 97, 98 water fluoridation 145 HIV/AIDS 229 recommendations 104, 270 weight loss drug interactions 230–231 sources 101–102, 101 calcium and 125 function 224 supplementation related to chromium and 131 nutrient interactions 44, 136, mortality 103 Wernicke encephalopathy 36 158, 169, 224–225, 236–238 tolerable upper intake level 103 Wernicke–Korsakoff syndrome RDA 226, 226 toxicity 102–103 (WKS) 36–37 recommendations 231 vitamin K 107–113 Wilson disease 140 sources 229–230, 231 adequate intake 109, 110 wound healing 27, 179 tolerable upper intake level childhood leukemia and 109 230 toxicity 230 deficiency 109 X disease prevention 110–112 zinc finger motif 224 cardiovascular disease xanthine oxidase 30, 187 Zollinger–Ellison syndrome 269 111–112 xerophthalmia 44 osteoporosis 110–111