thieme: an evidence-based approach to vitamins and mineralsan evidence-based approach to vitamins...

VI

Foreword

An Evidence-based Approach to Vitamins andMin-erals: Health Benefits and Intake Recommenda-tions by Dr. Jane Higdon and Dr. Victoria Drakeprovides a much needed source of authoritativeinformation on the role of micronutrients inhealth promotion and in disease prevention andtreatment. The book is especially important be-cause of the potential health benefits of tuningup people’s micronutrient metabolism, particu-larly those with inadequate diets, such as themany low-income and elderly people. A meta-bolic tune-up is likely to have enormous healthbenefits but is currently not being addressed ad-equately by the medical community.

Maximum health and life span require meta-bolic harmony. It is commonly thought thatAmericans’ intake of the more than 40 essentialmicronutrients (vitamins, minerals, and otherbiochemicals that humans require) is adequate.Classic deficiency diseases such as scurvy, beri-beri, pernicious anemia, and rickets are rare, butthe evidence suggests that metabolic damage oc-curs at intake levels between the level causingacute micronutrient deficiency diseases and therecommended dietary allowances (RDAs). Whenone input in the metabolic network is inade-quate, repercussions are felt on a large number ofsystems and can lead to degenerative disease.This may, for example, result in an increase inDNA damage (and possibly cancer), neuron decay(and possibly cognitive dysfunction), or mito-chondrial decay (and possibly accelerated agingand degenerative diseases). The optimumamount of folate or zinc that is truly “required” isthe amount that minimizes DNA damage andmaximizes a healthy life span, which is higherthan the amount to prevent acute disease. Vita-min andmetabolite requirements of older peopleare likely to differ from those of younger people,but this issue has not been seriously examined.An optimal intake of micronutrients and metab-olites will also vary with genetic constitution. Atune-up of micronutrient metabolism shouldgive a marked increase in health at little cost. It isinexcusable that anyone in theworld should have

an inadequate intake of a vitamin or mineral, atgreat cost to that person’s health, when a year’ssupply of a daily multivitamin/multimineral pillas insurance against deficiencies costs less than afew packs of cigarettes. Low-income populations,in general, are the most likely to have poor dietsand have the most to gain from multivitamin/multimineral supplementation. As Hippocratessaid: “Leave your drugs in the chemist’s pot if youcan heal the patient with food.”

Although many degenerative diseases willbenefit from optimal nutrition, and optimal nu-trition clearly involves more than adequate mi-cronutrients, there are several important reasonsfor focusing on micronutrients and health, par-ticularly DNA damage: (1) More than 20 years ofefforts to improve the American diet have notbeen notably successful, though this work mustcontinue. A parallel approach focusing on micro-nutrient intake is overdue and might be moresuccessful, since it should be easier to convincepeople to take a multivitamin/multimineral pillas insurance against ill health than to changetheir diet significantly. (2) A multivitamin/multi-mineral pill is inexpensive, is recognized as safe,and supplies the range of vitamins and mineralsthat a person requires, though not the essentialfatty acids. Fortification of food is another ap-proach that is useful, but its implementation hasbeen very slow, as with folic acid fortification.Moreover, fortification of food does not allow fordifferences between individuals. For example,menstruating women need more iron than menor postmenopausal women, who may be gettingtoo much. That is why two types of vitamin pillsare marketed, one with iron and one without.With better knowledge it seems likely that abroader variety of multivitamin/multimineralpills will be developed, reflecting such life-stagedifferences.

The above issues and many others discussedin this book highlight the need to educate thepublic about the crucial importance of optimalnutrition and the potential health benefits ofsomething as simple and affordable as a daily

aus: Higdon, An Evicdence-based Approach to Vitamins and Minerals (ISBN 9783131324528) © 2012 Georg Thieme Verlag KG

VIIForeword

multivitamin/multimineral supplement. The nu-merous advances in the science of nutrition andchanging ideas about optimal intakes of micro-nutrients make An Evidence-based Approach toVitamins and Minerals: Health Benefits and IntakeRecommendations an excellent and timely re-source. Dr. Higdon, who had a background inhealth care and nutrition science, and Dr. Drake,who has an expertise in toxicology and nutrition,have synthesized a large amount of recent scien-tific research on vitamins and nutritionally es-sential minerals into an organized volume thatincludes information on optimal micronutrientintakes to prevent and treat chronic diseases. Thebook also contains much needed and up-to-dateinformation on safety and drug interactions ofvitamins and minerals. The credibility of this

book is enhanced by the fact that it is endorsedby the Linus Pauling Institute at Oregon StateUniversity and that each chapter has been criti-cally reviewed by a recognized expert in the field.Tuning up the metabolism to maximize humanhealth will require scientists, clinicians, and edu-cators to abandon outdated paradigms of micro-nutrients merely preventing deficiency diseaseand to explore more meaningful ways to preventchronic disease and achieve optimal healththrough optimal nutrition.

Bruce N. Ames, PhDUniversity of California, BerkeleyChildren’s Hospital Oakland Research InstituteOakland, California


VIII

Preface to the Second Edition

I am honored to revise and update Dr. Jane Hig-don’s book, An Evidence-based Approach to Vita-mins and Minerals: Health Benefits and IntakeRecommendations. Since the first edition waspublished in 2003, there has been a dramatic ex-pansion of the literature on the role of micronu-trients in human health and disease. In this sec-ond edition, all 27 chapters have been revised toincorporate information from the relevant, morerecently published peer-reviewed studies, espe-cially studies with human subjects. This editionincludes the latest recommendations by the Foodand Nutrition Board (FNB) of the Institute ofMedicine: the FNB established new dietary refer-ence intakes for potassium and sodium in 2004and revised their recommendations for calciumand vitamin D in 2010. Additionally, some of theLinus Pauling Institute (LPI) recommendationshave been modified to reflect current knowledgein micronutrient research. The LPI recommenda-tions are daily intake levels aimed at the promo-tion of optimum health and prevention of chron-ic disease in healthy individuals. A large litera-ture indicates that inadequate or marginal intakeof vitamins and nutritionally essential mineralsmay increase one’s risk for a number of diseases,including cardiovascular diseases, certain can-cers and neurodegenerative diseases, and osteo-porosis. Micronutrient inadequacy can also im-pair immunity and thus increase susceptibility tocommunicable diseases like influenza. This bookreviews the present knowledge on the roles of

vitamins and minerals in disease prevention anddisease treatment, in addition to providing basicinformation on biological function, deficiency,food sources, safety, and interactions with othermicronutrients and drugs.

AcknowledgmentsI wish to thank the faculty, staff, and students ofthe Linus Pauling Institute for their editorial ad-vice and support in the revision of this book, es-pecially Balz Frei, PhD, director and endowedchair; Stephen Lawson, administrative officer;and Barbara McVicar, assistant to the director. Iam very appreciative to all of the distinguishedscientists listed in the Editorial Advisory Board,who reviewed the contents of each chapter andprovided helpful comments. I am particularlygrateful to Donald M. Mock, MD, PhD, and EvaObarzanek, PhD, for their valuable expertise inrevising the chapters on biotin and salt, respec-tively. Finally, I deeply appreciate the skillfulwork by Dr. Higdon in writing the first edition ofthis book, which has been a popular resource forboth health professionals and the public.

Victoria J. Drake, PhDManager, Micronutrient Information CenterLinus Pauling InstituteOregon State UniversityCorvallis, Oregon


IX

Preface to the First Edition

During my clinical training, I learned to approachmicronutrient nutrition from the perspective ofpreventing or treating deficiency diseases, suchas scurvy or iron-deficiency anemia. In clinicalpractice, I became increasingly interested in thepotential for micronutrients to prevent and treatchronic diseases at intakes higher than those re-quired to prevent deficiency. However, the stan-dard medical and nutrition texts of the day rarelyprovided the kind of information I was lookingfor. Today, scientific and medical research on theroles of micronutrients in health and disease isexpanding rapidly, as are, unfortunately, exag-gerated health claims from numerous supple-ment manufacturers. Keeping up with the explo-sion of contradictory information regarding thesafety and efficacy of dietary supplements hasbecome an overwhelming task for consumers aswell as health care and nutrition professionals.My goal in writing this book was to provide clini-cians and consumers with a practical evidence-based reference to the rapidly expanding field ofmicronutrient nutrition.

While my own interest in nutrition and healthled me to pursue doctoral work in nutrition andbiochemistry, such a step should not be neces-sary for health care and nutrition professionalswho want more information on the health impli-cations of dietary and supplemental micronutri-ents. With the support of the Linus Pauling Insti-tute at Oregon State University (LPI), I have syn-thesized and organized hundreds of experimen-tal, clinical, and epidemiologic studies, providingan overview of the current scientific knowledgeof the roles of vitamins and nutritionally impor-tant minerals in human health and disease. Toensure the accuracy of the information present-ed, I asked at least one recognized scientific ex-pert in the field to review each chapter. Thenames and affiliations of these scientists are list-ed in the Editorial Advisory Board.

Throughout this book, I have tried to empha-size human research published in peer-reviewedjournals. Where relevant, I have included the re-sults of experimental studies in cell culture oranimal models. Although randomized clinical tri-

als provide the strongest evidence for the effectof micronutrient intake on disease outcomes inhumans, it is not always ethical or practical toperform a double-blind, placebo-controlled trial.Observational studies can also provide useful in-formation about micronutrient intake and dis-ease outcomes. In reviewing the epidemiologicresearch, I have given more weight to the resultsof large prospective cohort studies, such as theNurses Health Study, than retrospective case–control or cross-sectional studies. When avail-able, I have included the results of systematic re-views and meta-analyses, which summarize in-formation on the findings of many similar stud-ies.

Nearly 35 years ago Linus Pauling, PhD, theonly individual ever to win two unshared NobelPrizes, concluded that micronutrients could playa significant role in enhancing human health andpreventing chronic disease, not just deficiencydisease. The basic premise that an optimum dietis the key to optimum health continues today asthe foundation of the Linus Pauling Institute atOregon State University. Scientists at the LinusPauling Institute investigate the roles that micro-nutrients and other dietary constituents play inhuman aging and chronic diseases, particularlycancer, cardiovascular diseases, and neurodegen-erative diseases. The goals of our research are tounderstand the molecular mechanisms behindthe effects of nutrition on health and to deter-mine how micronutrients and other dietary fac-tors can be used in the prevention and treatmentof diseases, thereby enhancing human health andwell-being. The Linus Pauling Institute is alsodedicated to training and supporting new re-searchers in the interdisciplinary science of nu-trition and optimum health, as well as to educat-ing the public about the science of optimum nu-trition.

As you read this book, it will become apparentthat the Linus Pauling Institute recommenda-tions for certain micronutrients (e.g., vitamin C)differ considerably from those of Linus Paulinghimself. Dr. Pauling, for whom the Linus PaulingInstitute has great respect, based his own micro-


X Preface to the First Edition

nutrient recommendations largely on theoreticalarguments. For example, in developing his rec-ommendations for vitamin C intake, he usedcross-species comparisons, evolutionary argu-ments, and the amount of vitamin C likely con-sumed in a raw plant food diet. At the Linus Paul-ing Institute, we base our micronutrient recom-mendations on current scientific evidence, muchof which was unavailable to Dr. Pauling. TheLinus Pauling Institute’s recommendation for avitamin C intake of at least 200mg/day for gener-ally healthy adults takes into account the cur-rently available epidemiologic, biochemical, andclinical evidence. Similarly, the Linus Pauling In-stitute’s intake recommendation for each micro-nutrient in this book is based on the current sci-entific research available, while, in many cases,acknowledging that the intake levels most likelyto promote optimum health remain to be deter-mined.

AcknowledgmentsFirst and foremost, I wish to thank the faculty,staff, and students of the Linus Pauling Institutefor providingmewith the inspiration and the op-portunity to write this book. Specifically, BalzFrei, PhD, the director, and Stephen Lawson, thechief administrative officer of the Linus PaulingInstitute, provided valuable advice and editorialassistance throughout the project. Barbara

McVicar also provided much needed technicalassistance and support. I am very grateful for thesupport of Bruce N. Ames, PhD, whowas enthusi-astic about this project from the beginning. Hisresearch and his eloquent foreword have beeninvaluable in laying the groundwork for thisbook.

I would like to thank each of the distinguishedscientists listed in the Editorial Advisory Boardfor taking the time to carefully review each chap-ter of this book and provide insightful and con-structive comments. I am also grateful to AramChobanian, MD, for reviewing the informationpresented on salt. The artist, Pat Grimaldi of theCommunication Media Center at Oregon StateUniversity, was both patient and skillful in creat-ing the book’s illustrations.

This project would not have been possiblewithout the generous financial support of thedonors to the Linus Pauling Institute, who de-serve special thanks. Finally, although I did notknow him personally, I would like to thank Dr.Linus Pauling for courageously stimulating scien-tific, medical, and popular interest in the rolesplayed by micronutrients in promoting optimumhealth and preventing and treating disease.

Jane Higdon, PhDLinus Pauling InstituteOregon State UniversityCorvallis, Oregon


XIII

Contents

1 Biotin .............................................................1Function ........................................................1

Enzyme cofactor.......................................1Histone Biotinylation ................................1

Deficiency .....................................................1Signs and Symptoms.................................1Predisposing conditions............................2Adequate intake........................................2

Disease Prevention .......................................3Birth defects .............................................3

Disease treatment ........................................3diabetes mellitus.......................................3Brittle Fingernails ......................................3Hair loss....................................................4

Sources ..........................................................4Food Sources.............................................4Bacterial Synthesis ....................................4

Safety ............................................................4Toxicity......................................................4Nutrient interactions.................................4drug interactions ......................................5

2 Folic Acid .......................................................7Function ........................................................7

One-carbon metabolism............................7Nutrient interactions.................................8

Deficiency .....................................................8causes.......................................................8Symptoms.................................................9recommended dietary Allowance ............9dietary Folate Equivalents.........................9Genetic variationin Folate requirements ...........................10

Disease Prevention .....................................10Pregnancy complications........................10cardiovascular diseases ..........................11cancer ....................................................12Alzheimer diseaseand cognitive impairment ......................13

Disease treatment ......................................13Sources ........................................................14

Food Sources ..........................................14Supplements...........................................14

Safety ..........................................................14Toxicity....................................................14drug interactions ...................................14

3 Niacin ..........................................................17Function ......................................................17

Oxidation–reduction(redox) reactions ...................................17Non-redox reactions ...............................17

Deficiency ...................................................18Pellagra ...................................................18Nutrient interactions ..............................19recommended dietary Allowance .........19

Disease Prevention ....................................19cancer.....................................................19Type 1 diabetes mellitus .........................20

Disease treatment ......................................21High cholesterol andcardiovascular disease ...........................21Human Immunodeficiency Virus .............21

Sources ........................................................22Food Sources...........................................22Supplements...........................................22

Safety ..........................................................22Toxicity....................................................22drug interactions ....................................23

4 Pantothenic Acid.........................................26Function ......................................................26

coenzyme A............................................26Acyl-carrier Protein..................................26

Deficiency ...................................................26Adequate intake......................................27

Disease Prevention .....................................27Disease treatment ......................................27

Wound Healing .......................................27High cholesterol .....................................27

Sources ........................................................28Food Sources...........................................28intestinal Bacteria ...................................28Supplements...........................................28



XIV contents

5 Riboflavin ....................................................30Function ......................................................30

Oxidation–reduction (redox) reactions .30Antioxidant Functions .............................30Nutrient interactions...............................31

Deficiency ...................................................31Risk Factors for Riboflavin Deficiency ......32recommended dietary Allowance .........32

Disease Prevention .....................................33cataracts.................................................33

Disease treatment ......................................33migraine Headaches................................33



6 thiamin .......................................................36Function ......................................................36

coenzyme Function ................................36Deficiency ...................................................36

Causes of Thiamin Deficiency..................37recommended dietary Allowance ..........37

Disease Prevention .....................................38cataracts ................................................38

Disease treatment ......................................38Alzheimer disease ..................................38congestive Heart Failure .........................38cancer.....................................................39

Sources ........................................................39Food Sources...........................................39Supplements ..........................................39

Safety ..........................................................39Toxicity....................................................39drug interactions ...................................40

7 Vitamin A ....................................................42Function ......................................................42

vision ......................................................42regulation of Gene Expression ................43immunity ................................................44Growth and development.......................44red Blood cell Production.......................44Nutrient interactions...............................44

Deficiency ...................................................44Vitamin A Deficiency and Vision..............44Vitamin A Deficiency and Infectiousdisease....................................................44recommended dietary Allowance .........45

Disease Prevention .....................................45cancer.....................................................45

Disease treatment ......................................46Pharmacological doses of retinoids .......46diseases of the Skin.................................46

Sources ........................................................46retinol Activity Equivalents .....................46Food Sources...........................................47Supplements...........................................48

Safety ..........................................................48Toxicity....................................................48Safety in Pregnancy.................................48Effects on Bone .......................................49drug interactions ....................................49

8 Vitamin B6 ...................................................52Function ......................................................52

Nervous System Function........................52red Blood cell Formation and Function...52Niacin Formation.....................................52Hormone Function..................................52Nucleic Acid Synthesis.............................52

Deficiency ...................................................52recommended dietary Allowance ..........53

Disease Prevention .....................................53cardiovascular diseases ..........................53immune Function....................................54cognitive Function ..................................54Kidney Stones .........................................55

Disease treatment ......................................55Side Effects of Oral Contraceptives..........55Premenstrual Syndrome..........................55depression ..............................................56Nausea and vomiting in Pregnancy.........56carpal Tunnel Syndrome .........................56

Sources ........................................................56Food Sources...........................................56Supplements ..........................................56

Safety ..........................................................57Toxicity ...................................................57drug interactions ...................................57

9 Vitamin B12..................................................60Function ......................................................60

cofactor for methionine Synthase ...........60cofactor for methylmalonyl-coAmutase ....................................................60

Deficiency ...................................................60causes of vitamin B12 Deficiency ............60Other causes of vitamin B12 Deficiency...62Symptoms of vitamin B12 Deficiency.......62recommended dietary Allowance .........63

Disease Prevention .....................................64cardiovascular diseases ..........................64cancer.....................................................64


XVcontents

Neural Tube defects................................65Alzheimer disease and dementia............65depression ..............................................66



10 Vitamin C ..................................................70Function ....................................................70Deficiency..................................................70Scurvy .....................................................70recommended dietary Allowance .........70

Disease Prevention ...................................70cardiovascular diseases ..........................71cancer.....................................................72cataracts.................................................73Gout........................................................73lead Toxicity ...........................................73role in immunity.....................................74

Disease treatment ....................................74cardiovascular diseases ..........................74cancer.....................................................75diabetes mellitus.....................................75common cold.........................................76

Sources ......................................................76Food Sources...........................................76Supplements...........................................76

Safety.........................................................77Toxicity....................................................77does vitamin c Promote Oxidativedamage under Physiologicalconditions? .............................................78Kidney Stones .........................................78drug interactions ....................................78

11 Vitamin D ..................................................83Function ....................................................83Activation of vitamin d...........................83mechanisms of Action.............................83calcium Balance......................................83Cell Differentiation ..................................83immunity ................................................84insulin Secretion......................................84Blood Pressure regulation.......................84

Deficiency ...................................................85Severe Vitamin D Deficiency ...................85Risk Factors for Vitamin D Deficiency ......85Assessing vitamin d Nutritional Status ...86recommended dietary Allowance ..........86

Disease Prevention .....................................87Osteoporosis...........................................87cancer.....................................................88Autoimmune diseases.............................89Hypertension .........................................90

Sources ......................................................90Sunlight...................................................90Food Sources...........................................91Supplements...........................................91

Safety.........................................................91Toxicity....................................................91drug interactions ....................................92

12 Vitamin E...................................................96Function ....................................................96α-Tocopherol ...........................................96γ-Tocopherol............................................96

Deficiency..................................................97recommended dietary Allowance .........97

Disease Prevention ...................................98cardiovascular diseases ..........................98cataracts ................................................98immune Function....................................99cancer ....................................................99

Disease treatment ....................................99cardiovascular diseases ..........................99diabetes mellitus...................................100dementia (impaired cognitiveFunction) ..............................................100cancer...................................................101

Sources ....................................................101Food Sources.........................................101Supplements ........................................102

Safety.......................................................102Toxicity..................................................102vitamin E Supplementation andAll-cause mortality ................................103drug interactions .................................103

13 Vitamin K ................................................107Function ..................................................107coagulation ..........................................107Bone mineralization ..............................108cell Growth ...........................................108

Deficiency................................................109controversy Surrounding vitamin KAdministration and Newborn infants ....109Adequate intake ...................................109

Disease Prevention .................................110Osteoporosis.........................................110Vascular Calcification andcardiovascular disease ..........................111


XVI contents

Sources ....................................................112Food Sources.........................................112intestinal Bacteria .................................112

Safety.......................................................112Toxicity..................................................112Nutrient interactions.............................112drug interactions ..................................113

14 Calcium ...................................................115Function ..................................................115Structure...............................................115cell Signaling.........................................115cofactor for Enzymes and Proteins........115regulation of calcium levels.................115

Deficiency................................................116Nutrient interactions.............................116recommended dietary Allowance ........117

Disease Prevention .................................118colorectal cancer .................................118Osteoporosis.........................................118Kidney Stones .......................................119Pregnancy-induced Hypertension ........120lead Toxicity .........................................120

Disease treatment ..................................121Hypertension ........................................121Premenstrual Syndrome .......................121

Sources ...................................................122Food Sources ........................................122Supplements.........................................122lead in calcium Supplements ...............123

Safety.......................................................123Toxicity..................................................123do High calcium intakes increasethe risk of Prostate cancer? ..................124drug interactions ..................................124Nutrient interactions.............................125

Recent Research ......................................125calcium and Weight loss ......................125

15 Chromium ...............................................128Function ..................................................128Nutrient interactions.............................128

Deficiency................................................129Adequate intake....................................129

Disease Prevention .................................130impaired Glucose Tolerance andType 2 diabetes mellitus .......................130cardiovascular diseases ........................130Health claims........................................130

Disease treatment ..................................131Type 2 diabetes mellitus .......................131Gestational diabetes .............................131

Sources ....................................................132Food Sources.........................................132Supplements.........................................132

Safety.......................................................132Toxicity..................................................132drug interactions ..................................133

16 Copper.....................................................135Function ..................................................135Energy Production.................................135connective Tissue Formation ................135iron metabolism....................................135central Nervous System........................135melanin Formation ................................135Antioxidant Functions ...........................135regulation of Gene Expression ..............136Nutrient interactions.............................136

Deficiency................................................136Individuals at Risk of Deficiency ............137recommended dietary Allowance .......137

Disease Prevention ................................137cardiovascular diseases ........................137immune System Function .....................138Osteoporosis.........................................139



17 Fluoride (Fluorine)..................................142Function ..................................................142Nutrient interactions.............................142

Deficiency................................................142Adequate intake....................................142

Disease Prevention ................................143dental caries ........................................143Osteoporosis.........................................143

Disease treatment ..................................144Osteoporosis.........................................144

Sources ....................................................145Water Fluoridation ................................145Food and Beverage Sources...................145Supplements ........................................145Toothpaste ............................................146

Safety.......................................................146Adverse Effects......................................146drug interactions ..................................147


XVIIcontents

18 Iodine ......................................................149Function ..................................................149Deficiency................................................149The Effects of Iodine Deficiency bydevelopmental Stage............................150Nutrient interactions.............................151Goitrogens ............................................151Individuals at Risk of Iodine Deficiency..152recommended dietary Allowance .......152

Disease Prevention .................................152radiation-induced Thyroid cancer ........152

Disease treatment ..................................152Fibrocystic Breast condition..................152


Safety.......................................................153Acute Toxicity........................................153iodine Excess .........................................154drug interactions ..................................154

19 Iron ..........................................................157Function ..................................................157Oxygen Transport and Storage..............157Electron Transport and Energymetabolism ..........................................157Antioxidant and Beneficial ProoxidantFunctions ..............................................157Oxygen Sensing ....................................157dNA Synthesis.......................................158regulation of intracellular iron ..............158Systemic regulation of ironHomeostasis .........................................158Nutrient interactions.............................158

Deficiency................................................159Symptoms of Iron Deficiency ................159individuals at increased risk of ironDeficiency .............................................159recommended dietary Allowance .......160

Disease Prevention .................................161impaired intellectual developmentin children.............................................161lead Toxicity .........................................161Pregnancy complications......................161impaired immune Function...................161

Disease treatment ..................................162restless legs Syndrome ........................162

Sources ....................................................162Food Sources.........................................162Enhancers of Nonheme ironAbsorption ............................................162

inhibitors of Nonheme ironAbsorption ............................................163Typical dietary intake............................163Supplements.........................................163

Iron Overload ..........................................164Hereditary Hemochromatosis ...............164Hereditary Anemias ..............................164

Safety.......................................................164Toxicity..................................................164diseases Associated with iron Excess.....165drug interactions ..................................166

20 Magnesium .............................................169Function ..................................................169Energy Production.................................169Synthesis of Essential Biomolecules.......169Structural roles .....................................169ion Transport across cell membranes....169cell Signaling.........................................169cell migration........................................169Nutrient interactions.............................169

Deficiency................................................170recommended dietary Allowance ........170

Disease Prevention .................................170Hypertension ........................................170cardiovascular diseases ........................171Osteoporosis.........................................171

Disease treatment ..................................172Hypertension .......................................172Pre-eclampsia–Eclampsia .....................172cardiovascular diseases ........................173diabetes mellitus...................................173migraine Headaches..............................174Asthma .................................................174

Sources ....................................................174Food Sources ........................................174Supplements.........................................175


21 Manganese..............................................179Function ..................................................179Antioxidant Function.............................179metabolism...........................................179Bone development ...............................179Wound Healing .....................................179Nutrient interactions.............................179

Deficiency................................................180Adequate intake ...................................180


XVIII contents

Disease Prevention ................................180Osteoporosis.........................................181diabetes mellitus...................................181Seizure disorders ..................................181

Sources ....................................................181Food Sources.........................................181Breast milk and infant Formulas ............182Water ....................................................182Supplements.........................................182

Safety.......................................................182Toxicity..................................................182individuals with increasedSusceptibility to manganese Toxicity.....183drug interactions ..................................184High levels of manganese in Supple-ments marketed for Bone/JointHealth ...................................................184

22 Molybdenum ..........................................187Function ..................................................187Nutrient interactions.............................187

Deficiency................................................187recommended dietary Allowance .......188

Disease Prevention .................................188Gastroesophageal cancer......................188



23 Phosphorus .............................................191Function ..................................................191Nutrient interactions.............................191

Deficiency................................................192recommended dietary Allowance .......193



24 Potassium................................................196Function ..................................................196maintenance of membrane Potential ....196cofactor for Enzymes ............................196

Deficiency................................................197conditions that increase the risk ofHypokalemia .........................................197Adequate intake....................................197

Disease Prevention .................................197Stroke....................................................197Osteoporosis.........................................198Kidney Stones .......................................198

Disease treatment ..................................199Hypertension ........................................199


Safety.......................................................200Toxicity (Excess) ....................................200Adverse reactions to PotassiumSupplements.........................................200drug interactions ..................................201

25 Selenium .................................................203Function ..................................................203Selenoproteins ......................................203Nutrient interactions.............................204

Deficiency................................................205individuals at increased risk ofSelenium Deficiency..............................205Keshan disease......................................205Kashin–Beck disease .............................205recommended dietary Allowance ........205

Disease Prevention .................................206immune Function..................................206viral infection........................................206cancer...................................................206cardiovascular diseases ........................208Type 2 diabetes mellitus .......................209

Disease treatment ..................................209Hiv/AidS ...............................................209

Sources ....................................................209Food Sources.........................................209Supplements.........................................210Selenium-enriched vegetables ..............210


26 Sodium Chloride .....................................214Function ..................................................214maintenance of membrane Potential ....214Nutrient Absorption and Transport .......215maintenance of Blood volume andBlood Pressure ......................................215

Deficiency................................................215Hyponatremia .......................................215Adequate intake for Sodium .................216


XIXcontents

Disease Prevention (Dietary Sodiumand Disease) ............................................216Gastric cancer .......................................216Osteoporosis.........................................216Kidney Stones .......................................217Hypertension ........................................217cardiovascular diseases ........................219

Sources ....................................................219Safety.......................................................219Toxicity..................................................219Adverse Effects......................................220drug interactions ..................................221

27 Zinc..........................................................224Function ..................................................224catalytic role ........................................224Structural role ......................................224regulatory role.....................................224Nutrient interactions.............................224

Deficiency................................................225Severe Zinc Deficiency ..........................225Mild Zinc Deficiency ..............................225recommended dietary Allowance .......226

Disease Prevention .................................226impaired Growth and development......226increased Susceptibility to infectiousdisease in children................................227

impaired immune response inElderly People........................................227Pregnancy complications .....................227

Disease treatment ..................................228common cold.......................................228Age-related macular degeneration .......229diabetes mellitus ..................................229Hiv/AidS ...............................................229



Appendix.........................................................235Nutrient–Nutrient Interactions ..............236Drug–Nutrient Interactions ...................239Quick Reference to Diseases ..................243Glossary...................................................248The Linus Pauling InstitutePrescription for Health ...........................270Healthy Eating.......................................270Healthy lifestyle....................................270Supplements.........................................270

Index ...............................................................273


XX

How To Use This Book

Chapter Organization

Information on individual vitamins, organic(carbon-containing) compounds that are re-quired by humans in small amounts from thediet to maintain normal physiological function,can be found in Chapters 1 through 13, in alpha-betical order by vitamin. In addition to vitamins,a number of inorganic elements (minerals) arerequired in the human diet to support a widerange of biological functions. Information on nu-tritionally important minerals can be found inChapters 14 through 27, in alphabetical order bymineral. For ease of use, the information in eachchapter is organized in the following manner:• Function Current scientific understanding ofthe function of the micronutrient with respectto maintaining health and preventing disease.

• Deficiency Risk factors, signs, symptoms, andphysiological effects of frank deficiency of themicronutrient.

• Disease Prevention Where controlled researchis available, information on the role(s) of themicronutrient in the prevention of disease.

• Disease treatment Where controlled researchis available, information on the role(s) of themicronutrient in the treatment of disease.

• Sources Information on dietary, supplemental,and other sources of the micronutrient. Whenavailable, this section includes a table of die-tary sources.

• Safety Information on toxicity and adverse ef-fects of the micronutrient, as well as micronu-trient–drug interactions.

• The Linus Pauling Institute Recommendation Adaily intake recommendation based on rele-vant scientific research and reflecting an intakelevel aimed at the prevention of chronic diseaseand the promotion of optimum health in gen-erally healthy individuals. Recommendationsfor older adults (over the age of 50 years) arealso addressed in this section.

• ReferencesIn addition to the Linus Pauling Institute Rec-ommendations, the Food and Nutrition Board(FNB) of the Institute of Medicine appointscommittees of expert scientists to set DietaryReference Intakes (DRIs), which are used toplan and evaluate diets of apparently healthypeople. Three different DRIs appear regularlythroughout this book:– The Recommended Dietary Allowance (RDA) isdefined as the average daily dietary intakelevel of a specific nutrient sufficient to meetthe requirement of nearly all (97%–98%)healthy individuals in a particular life-stagegroup. Because RDAs generally reflect intakelevels designed to prevent deficiency, theyare presented in the Deficiency section ofeach chapter.

– An Adequate Intake (AI) is provided if there isinsufficient evidence to determine an RDA.The AI is based on experimentally derived in-take levels or observed average intake levelsof apparently healthy people. For example,the AI of a nutrient for infants is generallybased on the average daily intake of that nu-trient supplied by human milk in healthy,full-term infants who are exclusively breast-fed. Because AIs reflect intake levels thoughtto prevent deficiency, they are also presentedin the Deficiency section of each chapter.

– The Tolerable Upper Intake Level (UL) is de-fined as the highest level of a nutrient deter-mined to pose no risk of adverse effects foralmost all individuals in the general popula-tion. The UL is discussed in the Safety sectionof each chapter.


XXIAppendices

Appendices

Several appendices have been included to facili-tate the use of this book by clinicians as well asconsumers.• Nutrient—Nutrient Interactions A table sum-marizing the information on nutrient—nutri-ent interactions discussed in the book.

• Drug—Nutrient Interactions A table summariz-ing the information on nutrient—drug interac-tions discussed in the book.

• Quick Reference to Diseases A useful chart thatallows the reader to locate micronutrient infor-mation by disease or health condition.

• Glossary• The Linus Pauling Institute Prescription forHealth A list summarizing the Linus PaulingInstitute Recommendations for a healthy diet,lifestyle, and supplement use.


7

2 Folic Acid

The terms folic acid and folate are often used in-terchangeably for this water-soluble B-complexvitamin. Folic acid, the more stable form, occursrarely in foods or the human body but is the formmost often used in vitamin supplements and for-tified foods. Naturally occurring folates exist inmany chemical forms. They are found in foods aswell as in metabolically active forms in the hu-man body.1 In the following discussion, formsfound in food or the body are referred to as fo-lates, whereas the form found in supplements orfortified foods is referred to as folic acid.

FunctionOne-carbonMetabolismThe only function of folate coenzymes in thebody appears to be in mediating the transfer ofone-carbon units.2 Folate coenzymes act as ac-

ceptors and donors of one-carbon units in a vari-ety of reactions critical to the metabolism of nu-cleic acids and amino acids.3

Nucleic acid metabolism. Folate coenzymes playa vital role in DNA metabolism through two dif-ferent pathways (Fig. 2.1):1. The synthesis of DNA from its precursors (thy-

midine and purines) is dependent on folatecoenzymes.

2. A folate coenzyme is required for the synthe-sis of methionine, and methionine is requiredfor the synthesis of S-adenosylmethionine(SAM).

SAM is a methyl group (one-carbon unit) donorused in many biological methylation reactions,including the methylation of a number of siteswithin DNA and RNA. Methylation of DNA maybe important in cancer prevention.

Fig. 2.1 Folate and nucleic acid metabolism: 5,10-methy-lene tetrahydrofolate (THF) is required for the synthesis ofnucleic acids, and 5-methyl THF is required for the forma-tion of methionine from homocysteine. methionine, inthe form of S-adenosylmethionine, is required for many

biological methylation reactions, including dNA methyla-tion. Methylene TH-folate reductase is a flavin-dependentenzyme required to catalyze the reduction of 5,10-methy-lene THF to 5-methyl THF.


8 2 Folic Acid

Amino acid metabolism. Folate coenzymes arerequired for the metabolism of several importantamino acids. The synthesis of methionine fromhomocysteine requires a folate coenzyme as wellas a vitamin B12-dependent enzyme. Thus, folatedeficiency can result in decreased synthesis ofmethionine and a build-up of homocysteine. In-creased levels of homocysteine may be a risk fac-tor for heart disease as well as several otherchronic diseases.

Nutrient Interactions

The metabolism of homocysteine, an intermedi-ate in the metabolism of sulfur-containing aminoacids, provides an example of the interrelation-ships of nutrients necessary for optimal physio-logical function and health. Healthy individualsuse two different pathways to metabolize homo-

cysteine (Fig. 2.2). One pathway (methioninesynthase) synthesizes methionine from homo-cysteine and depends on a folate coenzyme and avitamin B12-dependent enzyme. The other path-way converts homocysteine to another aminoacid, cysteine, and requires two vitamin B6-de-pendent enzymes. Thus, the amount of homo-cysteine in the blood is regulated by three vita-mins: folate, vitamin B12, and vitamin B6.4

DeficiencyCausesFolate deficiency is most often caused by a di-etary insufficiency; however, it can occur in anumber of other situations, for example, alcohol-ism is associated with low dietary intake and di-minished absorption of folate, which can lead to

Fig. 2.2 Homocysteine metabolism: S-adenosylhomo-cysteine is formed during S-adenosylmethionine-depen-dent methylation reactions, and the hydrolysis of S-ade-nosylhomocysteine results in homocysteine. Homocyste-ine may be remethylated to form methionine by a folate-

dependent reaction that is catalyzed by methioninesynthase, a vitamin B12-dependent enzyme. Alternately,homocysteine may be metabolized to cysteine in reac-tions catalyzed by two vitamin B6-dependent enzymes.


9Deficiency

folate deficiency. In addition, certain conditionssuch as pregnancy or cancer result in increasedrates of cell division and metabolism, causing anincrease in the body’s demand for folate.5 Severalmedications may also contribute to deficiency(see “Drug Interactions,” p. 14).

Symptoms

Individuals in the early stages of folate deficiencymay not show obvious symptoms, but their bloodlevels of homocysteine may increase. Rapidly di-viding cells are most vulnerable to the effects offolate deficiency, so when the folate supply to therapidly dividing cells of the bone marrow is inad-equate, blood cell division becomes abnormal,resulting in fewer but larger red blood cells. Thistype of anemia is called megaloblastic or macro-cytic anemia, referring to the enlarged, immaturered blood cells. Neutrophils, a type of whiteblood cell, become hypersegmented, a changethat can be found by examining a blood samplemicroscopically. As normal red blood cells have alifetime in the circulation of approximately 4months, it can take months for folate-deficientindividuals to develop the characteristic megalo-blastic anemia. Progression of such an anemialeads to decreased oxygen-carrying capacity ofthe blood andmay ultimately result in symptomsof fatigue, weakness, and shortness of breath.1 Itis important to point out that megaloblastic ane-mia resulting from folate deficiency is identicalto the megaloblastic anemia resulting from vita-min B12 deficiency, and further clinical testing isrequired to diagnose the true cause of megalo-blastic anemia.

RecommendedDietary Allowance

Traditionally, the dietary folate requirement wasdefined as the amount needed to prevent a defi-ciency severe enough to cause symptoms such asanemia. The most recent recommended dietaryallowance (RDA) (Table 2.1) was based primarilyon the adequacy of red blood cell folate concen-trations at different levels of folate intake, asjudged by the absence of abnormal hematologi-cal indicators. Red cell folate has been shown tocorrelate with liver folate stores. Maintenance ofnormal blood homocysteine levels, an indicatorof one-carbon metabolism, was considered onlyas an ancillary indicator of adequate folate in-take. As pregnancy is associated with a signifi-cant increase in cell division and other metabolicprocesses that require folate coenzymes, the RDAfor pregnant women is considerably higher thanfor women who are not pregnant.3 However, theprevention of neural tube defects (NTDs) was notconsidered when setting the RDA for pregnantwomen. Rather, reducing the risk of NTDs wasconsidered in a separate recommendation forwomen capable of becoming pregnant, becausethe crucial events in neural tube developmentoccur before many women are aware that theyare pregnant.6

Dietary Folate Equivalents

When the Food and Nutrition Board (FNB) of theInstitute of Medicine set the new dietary recom-mendation for folate, they introduced a new unit,the dietary folate equivalent (DFE):

Table 2.1 recommended dietary allowance for folate in dFEs

Life stage Age Males (µg/day) Females (µg/day)

infants 0–6 months 65 (Ai) 65 (Ai)

infants 7–12 months 80 (Ai) 80 (Ai)

children 1–3 years 150 150



Adolescents 14–18 years 400 400

Adults ≥ 19 years 400 400

Pregnancy All ages – 600

Breast-feeding All ages – 500

Ai, adequate intake; dFE, dietary folate equivalent.


44 7 vitamin A

Immunity

Vitamin A is commonly known as the anti-infec-tive vitamin, because it is required for normalfunctioning of the immune system.4 The skin andmucosal cells (cells that line the airways, diges-tive tract, and urinary tract) function as a barrierand form the body’s first line of defense againstinfection. Retinol and itsmetabolites are requiredto maintain the integrity and function of thesecells.5 Vitamin A and RA play a central role in thedevelopment and differentiation of white bloodcells, such as lymphocytes, which play criticalroles in the immune response. Activation of Tlymphocytes, the major regulatory cells of theimmune system, appears to require all-trans-RAbinding of RARs.3

Growth and Development

Both vitamin A excess and deficiency are knownto cause birth defects. Retinol and RA are essen-tial for embryonic development.4 During fetaldevelopment, RA functions in limb developmentand formation of the heart, eyes, and ears.6 In ad-dition, RA has been found to regulate expressionof the gene for growth hormone.

Red Blood Cell Production

Red blood cells, similar to all blood cells, are de-rived from precursor cells called stem cells. Stemcells are dependent on retinoids for normal dif-ferentiation into red blood cells. In addition, vita-min A appears to facilitate the mobilization ofiron from storage sites to the developing redblood cell for incorporation into hemoglobin, theoxygen carrier in red blood cells.2,7

Nutrient Interactions

Zinc. Zinc deficiency is thought to interfere withvitamin A metabolism in several ways:• Zinc deficiency results in decreased synthesisof retinol-binding protein (RBP), which trans-ports retinol through the circulation to tissues(e.g., the retina) and also protects the organismagainst the potential toxicity of retinol.

• Zinc deficiency results in decreased activity ofthe enzyme that releases retinol from its stor-age form, retinyl palmitate, in the liver.

• Zinc is required for the enzyme that convertsretinol into retinal.8,9

At present, the health consequences of zinc defi-ciency on vitamin A nutritional status in humansare unclear.10

Iron. Vitamin A deficiency may exacerbate iron-deficiency anemia. Vitamin A supplementationhas beneficial effects on iron-deficiency anemiaand improves iron nutritional status among chil-dren and pregnant women. The combination ofsupplemental vitamin A and iron seems to re-duce anemiamore effectively than either supple-mental iron or vitamin A alone.11Moreover, stud-ies in rats have shown that iron deficiency altersplasma and liver levels of vitamin A.12,13

DeficiencyVitamin A Deficiency and VisionVitamin A deficiency among children in less de-veloped nations is the leading preventable causeof blindness.14 The earliest evidence of vitamin Adeficiency is impaired dark adaptation or nightblindness. Mild vitamin A deficiency may resultin changes in the conjunctiva (corner of the eye)called Bitot spots. Severe or prolonged vitamin Adeficiency causes a condition called xerophthal-mia (dry eye), characterized by changes in thecells of the cornea (clear covering of the eye) thatultimately result in corneal ulcers, scarring, andblindness.4,9

Vitamin A Deficiency and InfectiousDiseaseVitamin A deficiency can be considered a nutri-tionally acquired immunodeficiency disease.15Even children who are only mildly deficient invitamin A have a higher incidence of respiratorydisease and diarrhea as well as a higher rate ofmortality from infectious disease compared withchildren who consume sufficient vitamin A.16 Vi-tamin A supplementation has been found to de-crease both the severity and the incidence ofdeaths related to diarrhea and measles in lessdeveloped countries, where vitamin A deficiencyis common.17 The onset of infection reducesblood retinol levels very rapidly. This phenome-non is generally believed to be related to de-creased synthesis of RBP by the liver. In this man-ner, infection stimulates a vicious cycle, becauseinadequate vitamin A nutritional status is relatedto increased severity and likelihood of death


45disease Prevention

from infectious disease.18 However, a review offour studies concluded that vitamin A supple-mentation is not beneficial in reducing themother-to-child transmission of HIV.19 One studyfound that HIV-infected women who were vita-min A deficient were three to four times morelikely to transmit HIV to their infants.20

Recommended Dietary Allowance

The recommended dietary allowance (RDA) forvitamin A was revised by the Food and NutritionBoard (FNB) of the Institute of Medicine in 2001.The latest RDA is based on the amount needed toensure adequate stores (4 months) of vitamin Ain the body to support normal reproductive func-tion, immune function, gene expression, and vi-sion (Table 7.1).21

Disease PreventionCancerStudies in cell culture and animal models havedocumented the capacity for natural and syn-thetic retinoids to reduce carcinogenesis signifi-cantly in skin, breast, liver, colon, prostate, andother sites.2 However, the results of human stud-ies examining the relationship between the con-sumption of preformed vitamin A and cancer areless clear.

Lung cancer. At least 10 prospective studies havecompared blood retinol levels at baseline among

people who subsequently developed lung cancerand those who did not. Only one of those studiesfound a statistically significant inverse associa-tion between serum retinol and lung cancerrisk.22 The results of the β-Carotene And RetinolEfficacy Trial (CARET) suggest that high-dosesupplementation of vitamin A and β-caroteneshould be avoided in people at high risk of lungcancer.23 About 9000 people (smokers andpeople with asbestos exposure) were assigned adaily regimen of 25000 IU retinol and 30mgβ-carotene, while a similar number of peoplewere assigned a placebo. After four years of fol-low-up, the incidence of lung cancer was 28%higher in the supplemented group comparedwith the placebo group. A possible explanationfor such a finding is that the oxidative environ-ment of the lung, created by smoke or asbestosexposure, gives rise to unusual carotenoid cleav-age products, which are involved in carcinogen-esis. Currently, it seems unlikely that increasedretinol intake decreases the risk of lung cancer,although the effects of retinol may be differentfor nonsmokers than for smokers.22

Breast cancer. Retinol and its metabolites havebeen found to reduce the growth of breast cancercells in vitro, but observational studies of dietaryretinol intake in humans have not confirmedthis.24 Most epidemiological studies have failedto find significant associations between retinolintake and breast cancer risk in women,25–28although one large prospective study found thattotal vitamin A intake was inversely associated

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

Life stage Age Males µg/day (IU/day) Females µg/day (IU/day)

infants 0–6 months 400 (1333 iU) (Ai) 400 (1333 iU) (Ai)

infants 7–12 months 500 (1667 iU) (Ai) 500 (1667 iU) (Ai)

children 1–3 years 300 (1000 iU) 300 (1000 iU)



Adolescents 14–18 years 900 (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.


46 7 vitamin A

with the risk of breast cancer in premenopausalwomen with a family history of breast cancer.29Blood levels of retinol reflect the intake of bothpreformed vitamin A and provitamin A carot-enoids such as β-carotene. Although a case–con-trol study found serum retinol levels and serumantioxidant levels to be inversely related to therisk of breast cancer,30 two prospective studiesdid not observe significant associations betweenblood retinol levels and subsequent risk of devel-oping breast cancer.31,32 Currently, there is littleevidence in humans that increased intake of pre-formed vitamin A or retinol reduces breast can-cer risk.

Disease treatmentPharmacological Doses of RetinoidsRetinoids are used at pharmacological doses totreat several conditions, including retinitis pig-mentosa, acute promyelocytic leukemia, andvarious skin diseases. It is important to note thattreatment with high doses of natural or syntheticretinoids overrides the body’s own control mech-anisms, so retinoid therapies are associated withpotential side effects and toxicities. In addition,all of the retinoid compounds have been found tocause birth defects. Thus, women who have achance of becoming pregnant should avoid treat-ment with these medications. Retinoids tend tobe very long acting: side effects and birth defectshave been reported to occurmonths after discon-tinuing retinoid therapy.2 The retinoids discussedbelow are prescription drugs and should not beused without medical supervision.

Retinitis pigmentosa. Retinitis pigmentosa de-scribes a broad spectrum of genetic disordersthat result in the progressive loss of photorecep-tor cells (rods and cones) in the eye’s retina.33Early symptoms of retinitis pigmentosa includeimpaired dark adaptation and night blindness,followed by the progressive loss of peripheraland central vision over time. The results of a ran-domized controlled trial in more than 600 pa-tients with common forms of retinitis pigmen-tosa indicated that supplementation with4500µg (15 000 IU)/day of preformed vitamin A(retinol) significantly slowed the loss of retinalfunction over a period of four to six years.34 Incontrast, supplementation with 400 IU/day of vi-

tamin E increased the loss of retinal function by asmall but significant amount, suggesting that pa-tients with common forms of retinitis pigmen-tosa may benefit from long-term vitamin A sup-plementation but should avoid vitamin E supple-mentation at levels higher than those found in atypical multivitamin. Up to 12 years of follow-upin these patients did not reveal any signs of livertoxicity as a result of excess vitamin A intake.35High-dose vitamin A supplementation to slowthe course of retinitis pigmentosa requires medi-cal supervision andmust be discontinued if thereis a possibility of pregnancy.

Acute promyelocytic leukemia. Normal differen-tiation of myeloid stem cells in the bone marrowgives rise to platelets, red blood cells, and whiteblood cells that are important for the immune re-sponse. Altered differentiation of those stem cellsresults in the proliferation of immature leukemiccells, giving rise to leukemia. A mutation of theRAR has been discovered in patients with a spe-cific type of leukemia called acute promyelocyticleukemia (APL). Treatment with all-trans-RA orwith high doses of all-trans-retinyl palmitate re-stores normal differentiation and leads to im-provement in some APL patients.2,18

Diseases of the Skin

Both natural and synthetic retinoids have beenused as pharmacological agents to treat disordersof the skin. Etretinate and acitretin are retinoidsthat have been useful in the treatment of psoria-sis, whereas tretinoin and isotretinoin have beenused successfully to treat severe acne. Retinoidsmost likely affect the transcription of skin growthfactors and their receptors.2 Use of pharmaco-logical doses of retinoids by pregnant womencauses birth defects.

SourcesRetinol Activity EquivalentsDifferent dietary sources of vitamin A have dif-ferent potencies; for example, β-carotene is lesseasily absorbed than retinol and must be con-verted to retinal and retinol by the body. Themost recent international standard of measurefor vitamin A is retinol activity equivalents (RAE),which represent vitamin A activity as retinol:


47Sources

2µg β-carotene in oil provided as a supplementcan be converted by the body to 1 µg retinol,giving it an RAE ratio of 2:1. However, 12µgβ-carotene from foods are required to providethe body with 1µg retinol, giving dietaryβ-carotene an RAE ratio of 12:1. Other provita-min A carotenoids in foods are less easily ab-

sorbed than β-carotene, resulting in RAE ratios of24:1. The RAE ratios for β-carotene and otherprovitamin A carotenoids are shown in table7.2.21 An older international standard, still com-monly used, is the international unit (IU): 1 IU isequivalent to 0.3 µg retinol.

Food Sources

Free retinol is not generally found in foods. Reti-nyl palmitate, a precursor and storage form ofretinol, is found in foods from animals. Plantscontain carotenoids, some of which are precur-sors for vitamin A (e.g., α-carotene, β-carotene,and β-cryptoxanthin). Yellow and orange vegeta-bles contain significant quantities of carotenoids.Green vegetables also contain carotenoids, al-though the pigment is masked by the green pig-ment of chlorophyll.1 A number of good foodsources of vitamin A are listed in Table 7.3 alongwith their vitamin A content in RAEs. In thosefoods where retinol activity comes mainly fromprovitamin A carotenoids, the carotenoid contentand the RAEs are presented.

Table 7.2 retinol activity equivalent (rAE) ratios forβ-carotene and other provitamin A carotenoids

Quantityconsumed

Quantitybioconvertedto retinol

RAE ratio

1µg dietary orsupplementalvitamin A

1µg retinol 1:1

2 µg supplementalβ-carotene

1µg retinol 2:1

12 µg dietaryβ-carotene

1µg retinol 12:1

24 µg dietaryα-carotene

1µg retinol 24:1

24 µg dietaryβ-cryptoxanthin

1µg retinol 24:1

Table 7.3 Food sources of vitamin A

Food Serving Vitamin A(µg RAE)

Vitamin A(IU)

Retinol(µg)

Retinol(IU)

cod liver oil 1 teaspoon 1350 4500 1350 4500

Fortified breakfast cereals 1 serving 150–230 500–767 150–230 500–767

Egg 1 large 91 303 89 296

Butter 1 tablespoon 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 0 0

Sweet potato, baked ½ cup 961 3203 0 0

Pumpkin, canned ½ cup 953 3177 0 0

carrot, raw ½ cup, chopped 538 1793 0 0

cantaloupe ½ medium melon 467 1555 0 0

mango 1 fruit 79 263 0 0

Spinach ½ cup, cooked 472 1572 0 0

Broccoli ½ cup, cooked 60 200 0 0

Kale ½ cup, cooked 443 1475 0 0

collards ½ cup, cooked 386 1285 0 0

Squash, butternut ½ cup, cooked 572 1907 0 0

rAE, retinol activity equivalent.


273

IndexPage numbers in italics refer to illustrations or tables

Aacetyl-CoA carboxylase 1acetylation 26acne 46acrodermatitis enteropathica 225acute promyelocytic leukemia(APL) 46

acyl-carrier protein 26adequate intake (AI) 248see also specific nutrients

adolescentscalcium recommendations 125iodine deficiency 151iron deficiency 159

ADP-ribosyl cyclases 17–18adrenal glands 248age-related macular degeneration(ARMD) treatment 246zinc 229

AIDS21, 248treatment 246selenium 209zinc 229

alcohol interactions 40, 49, 241alcoholismfolate deficiency and 8–9magnesium deficiency and 170thiamin deficiency and 36, 37

aldehyde oxidase 187aldosterone 215allele 248allopurinol 241Alzheimer disease 243, 248prevention 243folic acid 13vitamin B6 54–55vitamin B12 65–66

treatment 243thiamin 38vitamin E 100–101

amino acids 248metabolism 8

analog 248anaphylactic reactions 248thiamin 39

anemia 32, 136, 248hemolytic 257hereditary 164iron deficiency 159macrocytic 259megaloblastic 9, 62, 260pernicious 60–61, 263sickle cell 266sideroblastic 266

anencephaly 248angina pectoris 248angiography 248

angiotensin 215antacid interactions 140, 166,184, 194, 239

anti-thiamin factors (ATFs) 37anti-tuberculosis medications 57antibiotic interactions 113, 230,239

antibodies 248–249anticoagulants 249interactions 40, 78, 103, 113

anticonvulsants 249interactions 14, 103, 231, 239

antidiuretic hormone (ADH) 215antigens 249antihistamine 249antioxidants 249copper function 135–136iron function 157manganese function 179selenium interaction 204, 211statin interactions 78–79, 211vitamin E interactions 103–104see also specific antioxidants

antiplatelet drug interactions 240apoptosis 249arginase 179ariboflavinosis 31–32ascorbate 77see also vitamin C

ascorbyl palmitate 77aspirin interactions 241asthma 243, 249magnesium treatment 174

ataxia 97, 249atherosclerosis 111, 249prevention 244treatment 244see also cardiovascular diseases

ATP 249atrial fibrillation 249atrophic gastritis 61–62, 249autoimmune disease 249prevention 243vitamin D89–90

Bbacteria 249biotin synthesis 4pantothenic acid synthesis 28vitamin K synthesis 112

balance study 249beriberi 36–37, 38beta-carotene 42, 46–47bias 249bile 249–250bile acids 250

bioavailability 250bioflavanoids 77biotin 1–5adequate intake 2, 2bacterial synthesis 4birth defects prevention 3deficiency 1–2disease treatment 3–4brittle fingernails 3–4diabetes mellitus 3hair loss 4

drug interactions 5food sources 4, 4function 1nutrient interactions 4–5, 236recommendations 5toxicity 4

biotin-deficient facies 2biotinidase deficiency 2birth defectsprevention 247biotin 3folic acid 10–11

vitamin A and 48bisphosphonate interactions 176,240

Bitot spots 44blood loss, iron deficiency and159–160

blood pressure regulationsodium chloride 215vitamin D84–85see also hypertension

blood volume maintenance 215body mass index (BMI) 250bone development 179bone mineral density (BMD) 250fluoride and 143–144magnesium and 172potassium and 198sodium chloride and 216–217vitamin A effects 49vitamin D role 87–88vitamin K and 108, 110see also osteoporosis

bone remodeling 115, 250brain damage, iodine deficiencyand 149, 150

breast cancer prevention 243folic acid 12vitamin A 45–46vitamin B12 64–65vitamin C 72vitamin D88–89vitamin E 99


274 index

breast feedingcalcium recommendations 126iodine deficiency and 151vitamin D deficiency and 85

brittle fingernails, biotin treat-ment 3–4

buffer 250

Ccaffeine, calcium balance and 117calcidiol 83see also vitamin D

calcification 250phosphorus and 193–194vascular 111–112

calcitriol 83, 115, 241see also vitamin D

calcium 115–126deficiency 116disease prevention 118–121colorectal cancer 118kidney stones 119–120lead toxicity 120–121osteoporosis 118–119pregnancy-induced hyper-tension 120

disease treatment 121hypertension 121premenstrual syndrome 121

drug interactions 124–125function 115lead levels in supplements 123nutrient interactions 116–117,125, 142, 147, 159, 170, 180,224–225, 236–238phosphorus role in calciumbalance 117, 191, 192

prostate cancer risk and 124RDA 116, 118recommendations 125–126,271

regulation 115, 116sources 122–123, 122tolerable upper intake level123

toxicity 123vitamin D role 83, 84weight loss and 125

calcium channel blocker interac-tions 240

calmodulin 115cancer 12, 243, 250iron excess and 165–166prevention 243calcium 118folic acid 12niacin 19–20selenium 206–208vitamin A 45–46vitamin B12 64–65vitamin C 72–73vitamin D 88–89vitamin E 99

treatment 243thiamin 39vitamin C 75vitamin E 101

see also specific types of cancercarbohydrate 250chromium interactions128–129

carboxylation 250osteocalcin 110

carcinogen 250carcinoid syndrome 250cardiac arrhythmias 244, 249see also cardiovascular diseases

cardiomyopathy 250cardiovascular diseases 250iron excess and 165prevention 244chromium 130copper 137–138folic acid 11–12magnesium 171niacin 21selenium 208–209sodium chloride reduction219

vitamin B6 53–54vitamin B12 64vitamin C 71–72vitamin E 98vitamin K 111–112

treatment 244magnesium 173vitamin C 74–75vitamin E 99–100

carnitine 250, 271carotenoids 42carotid arteries 250carpal tunnel syndrome treat-ment 56, 245

cartilage 250case reports 251case-control study 250–251catabolism 251cataract 251prevention 245riboflavin 33thiamin 38vitamin C 73vitamin E 98–99

catecholamines 251celiac disease 160, 245, 251cell differentiation 83–84cell membrane 251membrane potential 196, 196,214, 214

cell migration 169cell signaling 115, 169, 251cerebrovascular disease 251ceruloplasmin 135, 136cardiovascular disease and 137,138

cervical intraepithelial neoplasia(CIN) 251

chemotherapy 251childrencalcium recommendations 125iodine deficiency 151iron deficiency 159impaired intellectual deve-lopment and 161

manganese susceptibility 184zinc deficiency 226–227diarrhea susceptibility and227

effects on growth and deve-lopment 226

malaria susceptibility and227

pneumonia susceptibilityand 227

chloramphenicol 241chlorpromazine 176, 241cholecalciferol 83, 91see also vitamin D

cholestatic liver disease 251cholesterol 251lowering 246niacin 21pantethine 27–28

cholesytramine 241chorionic villous sampling (CVS)251–252

chromatin 252chromium 128–133adequate intake 129, 130deficiency 129diabetes treatment 131–132disease prevention 130cardiovascular diseases 130diabetes mellitus 130

drug interactions 133function 128, 129health claims 130–131nutrient interactions 128–129,236–237

recommendations 133sources 132, 132toxicity 132–133

chromosome 252chronic disease 252cirrhosis 252clinical trial 252, 263coagulation 252calcium role 115vitamin K role 107–108, 109

cobalamin 60see also vitamin B12

coenzyme 252coenzyme A 26cofactor 252see also enzyme cofactors

cognitive impairmentprevention, folic acid 13iron, in children 161vitamin B6 54–55

treatment, vitamin E 100–101see also dementia


275index

cohort study 252colchicine 241colestipol 241collagen 252colon 252colorectal cancer 252iron excess and 165–166prevention 243calcium 118folic acid 12vitamin D88

common cold treatment 245vitamin C 76zinc 228intranasal preparations 228,230

lozenges 228complement 252congestive heart failure 244, 252thiamin treatment 38–39see also cardiovascular diseases

connective tissue formation,copper function 135

copper 135–140deficiency 136–137, 230individuals at risk 137

disease prevention 137–139cardiovascular diseases137–138

immune system function138–139

osteoporosis 139drug interactions 140function 135–136antioxidant functions135–136

central nervous system 135connective tissue formation135

energy production 135gene expression regulation135

iron metabolism 135melanin formation 135

nutrient interactions 136, 158,187, 224, 230, 237–238

RDA 137, 137recommendations 140sources 139, 139tolerable upper intake level 140toxicity 139–140

cornea 252coronary artery 252coronary heart disease (CHD)244, 252see also cardiovascular diseases

creatine phosphate 252–253cretinism 150, 253Crohn disease 253cross-sectional study 253crossover trial 253cyanocobalamin 60, 67see also vitamin B12

cycloserine 241

cystic fibrosis (CF) 253cytochromes 157cytochrome P450 (CYP) 253

cytokine 253cytoplasmic retinoic acid-bindingproteins (CRABPs) 43

Ddaily value (DV) 254decarboxylation 253dementia 253prevention 245vitamin B12 62, 65–66

treatment 245vitamin E 100–101

vascular 269see also Alzheimer disease

dental caries 142, 253prevention 143, 245

dental fluorosis 142, 146–147depletion–repletion study 253depression 245prevention 66, 245treatment 56, 245

dermatitis 132, 253diabetes mellitus 253–254iron excess and 166prevention 245chromium 130manganese 181niacin 20selenium 209vitamin D 89

treatment 245biotin 3chromium 131–132magnesium treatment173–174

treatment 229vitamin C 75–76vitamin E 100zinc 229

diabetic ketoacidosis 254dialysis 100, 254peritoneal 262–263

diarrhea 44, 175, 227diastolic blood pressure 254dietary folate equivalents (DFEs)9–10

dietary reference intake (DRI)254

diethylenetriamine pentaacetate(DPTA) 241

digoxin 241diuretic 254interactions 40, 231, 240

diverticulitis 254DNA 254damage 132–133metabolism 7methylation 63synthesis 158transcription 268

double blind 254doxorubicin 241DEXA 253

Eechocardiography 254eclampsia 32, 247magnesium treatment172–173, 247

ecological study 254electroencephalogram (EEG) 254electrolytes 254electron transport 157, 255endocrine system 255endothelial dysfunction, magne-sium treatment 173

energy metabolism 157energy production 135, 169enzyme 255enzyme cofactorsbiotin 1calcium 115potassium 196vitamin B12 60

epilepsy 255see also seizure

ergocalciferol 83see also vitamin D

erythropoietin 255esophagus 255see also gastroesophagealcancer

estimated average requirement(EAR) 254

estrogen 52, 255see also oral contraceptives

Ffamilial adenomatous polyposis255

fatty acid 255ferritin 158, 165, 166ferroxidase 135fetal developmentfolic acid benefits 10–11, 15iodine deficiency 150vitamin A and 44, 48see also pregnancy

fiber, magnesium status and 169fibroblastic breast condition 255iodine treatment 152–153

fish oil 271flavin adenine dinucleotide (FAD)30, 31

flavin mononucleotide (FMN) 30flavocoenzymes 30flavoproteins 30fluoride (fluorine) 142–147adequate intake 142, 143adverse effects 146–147deficiency 142


276 index

disease prevention 143–144dental caries 143osteoporosis 143–144

drug interactions 147function 142nutrient interactions 142, 237osteoporosis treatment 144recommendations 147sources 145–146, 145, 146

fluorosisdental 142, 146–147skeletal 147

5-fluorouracil 24, 241folic acid 7–15deficiency 8–9, 62dietary folate equivalents(DFEs) 9–10

disease prevention 10–13Alzheimer disease and cogni-tive impairment 13

cancer 12cardiovascular diseases11–12

pregnancy complications10–11, 15

drug interactions 14–15function 7–8, 7genetic variation in require-ments 10

nutrient interactions 8, 225,236

RDA 9, 9recommendations 15sources 13, 14toxicity 14

food-bound vitamin B12 malab-sorption 61

fortification 255fractures see osteoporosisfree radical 255fructose 256copper interaction 136phosphorus interaction 191

function 7–8, 7

GG-proteins 17gallbladder 256gallstones 256Gas6 protein 108gastric bypass surgery 160gastric cancer 243salt consumption and 216

gastroesophageal cancer 243molybdenum 188–189

gastroesophageal reflux disease(GERD) 256

gene expression 256copper role 136retinoic acid role 43, 43

gestation 256see also pregnancy

gestation diabetes 247

chromium supplementation131–132

gluconeogenesis 256glucose 256glucose tolerance impairment258chromium and 128, 130see also diabetes mellitus

glucoside 256glutamate 179glutamine synthetase 179glutathione 256glutathione peroxidase 30, 203,203

glutathione reductase 30, 203glycogen 256glycoside 256glycosyltransferases 179goiter 149, 151, 154, 256goitrogens 151–152, 256gout 256prevention, vitamin C 73

growth retardation 246zinc deficiency and 226

GTP (guanosine triphosphate)257

HH2-receptor antagonist interac-tions 166, 240

hair loss, biotin and 1, 4hallucination 2Hartnup disease 19, 257healthy eating 270healthy lifestyle 270heart disease see cardiovasculardiseases

Helicobacter pylori infection 62,72–73, 160, 216

heme 257hemodialysis 257hemoglobin 52, 157, 159, 257glycated 256

hemolysis 97, 257hemorrhage 257vitamin E and 102–103

hepatitis 257liver cancer and 207niacin and 22–23

hepatocellular carcinoma 165,257

hepatotoxicity, niacin 22–23hepcidin 158hereditary hemochromatosis164, 257

hereditary spherocytosis 257histone 257biotinylation 1

HIV infection 257treatment 246niacin 21selenium 209zinc 229

vitamin A effects on transmis-sion 45

HMG-CoA reductase inhibitorssee statins

holocarboxylase synthetase(HCS) 1deficiency 2

homocysteine 8, 31, 244, 257Alzheimer disease and 65–66cardiovascular diseases and11–12, 53–54, 64

metabolism 8, 8, 54, 61homopantothenate 26hormone 257hydrolysis 257hydroxyapatite 115, 142, 191, 257hydroxylation 257hypercalcemia 91–92, 123hypercalciuria 123, 198–199hypercholesterolemia 21, 27–28,246

hyperglycemia 257hyperkalemia 194–195, 200, 201hypermagnesemia 175hypernatremia 220hyperparathyroidism 257–258secondary 85

hyperphosphatemia 193–194hypertension 74–75, 258prevention 246calcium 120magnesium 170–171pregnancy-induced hyper-tension 120

vitamin D90sodium and 217–219clinical trials 217–219salt sensitivity 218target organ damage 219

treatment 246calcium 121magnesium 172potassium 199

see also cardiovascular diseaseshyperthyroidism 258iodine-induced (IHH) 154

hypervitaminosis A 48hypervitaminosis D91hypoglycemia 258hypokalemia 197, 201hypomagnesemia 170, 173–174hyponatremia 215prolonged endurance exerciseand 215–216

hypoparathyroidism 258hypophosphatemia 192hypothalamus 258hypothyroidism 149, 151, 258congenital 150, 252

hypoxia 157hypoxia inducible factors (HIFs)157


277index

Iimmune function 246copper role 138–139iron role 161–162selenium role 206vitamin A role 44vitamin B6 role 54vitamin C role 74vitamin D role 84vitamin E role 99

infectious diseaseiron and 161–162selenium protective role 206vitamin A protective role 44deficiency effects 44–45

zinc and, children 227diarrhea 227malaria 227pneumonia 227

see also immune function;specific diseases

inflammation 258inflammatory bowel disease 258vitamin D deficiency and 86

insulin 258chromium function 128, 129resistance 258secretion 84

insulin-like growth factor-1(IGF-1) 118

intervention trial 258iodine 149–155deficiency 149–150developmental stage and150–151

individuals at risk 152drug interactions 154–155fibrocystic breast conditiontreatment 152–153

function 149nutrient interactions 151–152,204, 236–238

radiation-induced thyroidcancer prevention 152

RDA 151, 152recommendations 155sources 153, 153tolerable upper intake level154

toxicity 153–154iodine-induced hyperthyroidism(IHH) 154

iodothyronine deiodinases 204ion channel 258ion transport 169iron 157–166copper role in iron metabolism135

deficiency 159individuals at risk 159–160symptoms 159

disease prevention 161–162immune function 161–162impaired intellectual deve-lopment 161

lead toxicity 161pregnancy complications 161

diseases associated with ironexcess 165–166cancer 165–166cardiovascular diseases 165diabetes and metabolic syn-drome 166

neurodegenerative disease166

drug interactions 166function 157–158antioxidant and prooxidantfunctions 157

DNA synthesis 158electron transport and ener-gy metabolism 157

oxygen sensing 157oxygen transport and storage157

nonheme iron absorption162–163enhancers 162inhibitors 163

nutrient interactions 31, 44,125, 128, 136, 158–159,179–180, 224, 236–238

overload 164RDA 160, 160recommendations 166, 270regulation 158restless legs syndrome treat-ment 162

sources 162–163, 163tolerable upper intake level 165toxicity 164–165

iron regulatory proteins (IRPs)158

isoniazid 24, 241

Jjaundice 259

KKashin–Beck disease 205Keshan disease 205ketoconazole 241ketone bodies 259kidney failure 133kidney stones 259prevention 246calcium 119–120potassium 198–199vitamin B6 55

sodium and 217vitamin C and 78

Korsakoff psychosis 36

lL-carnitine 271lactation see breast feedinglaxative interactions 184, 240

leadin calcium supplements 123toxicity prevention 246calcium 120–121iron 161vitamin C 73–74

left ventricular hypertrophy(LVH) 259

lethargy 2leukemia 243, 259acute promyelocytic (APL) 46childhood, vitamin K relation-ship 109

leukocytes 259levodopa 241levothyroxine 241licorice 197lipids 259peroxidation 259

lipoic acid 259, 271lipoproteins 259lithium 242liver diseasebiotin deficiency and 2cancerhepatitis infection and 207iron excess and 165selenium protective effect207–208

cholestatic 251manganese susceptibility and183

lovastatin 242niacin interaction 23see also statins

low birth weights 11lung cancer 132prevention 243selenium 207vitamin A 45vitamin C 72vitamin E 99

lymphocytes 259lysyl oxidase 139

Mmacular degeneration 246zinc treatment 229

magnesium 169–176deficiency 116, 170disease prevention 170–172cardiovascular diseases 171hypertension 170–171osteoporosis 171–172

disease treatment 172–174asthma 174cardiovascular diseases 173diabetes mellitus 173–174hypertension 172migraine headaches 174pre-eclampsia and eclampsia172–173

drug interactions 176function 169


278 Index

nutrient interactions 125, 142,169–170, 180, 236–238

RDA 170, 171recommendations 176, 271sources 174–175, 175tolerable upper intake level 175toxicity 175–176

malabsorption syndrome 62, 260malaria 260susceptibility in children, zincand 227

manganese 179–184adequate intake 180, 180deficiency 180disease prevention 180–181diabetes mellitus 181osteoporosis 181seizure disorders 181

drug interactions 184function 179individuals with increasedsusceptibility 183–184

nutrient interactions 179–180,237–238

recommendations 184sources 181–182, 182tolerable upper intake level 184toxicity 182–183ingested manganese 183inhaled manganese 182–183intravenous manganese 183methylcyclopentadienylmanganese tricarbonyl(MMT) 183

manganese superoxide dismutase(MnSOD) 179

manganism 182matrix Gla protein (MGP) 108megaloblastic anemia 9, 62melanin formation, copper func-tion 135

membrane potential 214, 260potassium function 196, 196sodium chloride function 214,214

menaquinones 107, 112see also vitamin K

Menkes disease 138menstruation 260meta-analysis 260metabolic syndrome 260iron excess and 166

metabolism 260metabolite 260metallothionein 136, 224metformin 242methionine 8, 260methionine synthase 60impaired activity 62

methionine-R-sulfoxide reduc-tase 204

methotrexate 242folic acid interaction 14

methylation 260

methylcrotonyl-CoA carboxy-lase 1

methylcyclopentadienyl manga-nese tricarbonyl (MMT) 183

methyldopa 242methylene tetrahydrofolatereductase (MTHFR) 31, 31polymorphism 10, 12, 31

methylmalonic acid (MMA) 62methylmalonyl-CoA mutase 60impaired activity 62

migraine headache 260treatment 246magnesium 174riboflavin 33

milk alkali syndrome 123mineral 260miscarriage 11mitochondria 260–261molybdenum 187–190deficiency 187–188drug interactions 189function 187gastroesophageal cancer pre-vention 188–189

nutrient interactions 187RDA 188, 188recommendations 190sources 189tolerable upper intake level 189toxicity 189

mono-ADP-ribosyltrans-ferases 17

multiple sclerosis (MS) 261prevention 247vitamin D89–90

multivitamin supplements 270muscle mass 130–131mutation 261myelin 261copper function 135

myocardial infarction 261prevention 245treatment 245magnesium 173

see also cardiovascular diseasesmyocarditis 261myoglobin 157, 159, 261

Nnatural killer (NK) cells 261nausea and vomiting in preg-nancy treatment 56, 247

necrosis 261neomycin 242neural tube defect (NTD) 261prevention 247folic acid 9, 10vitamin B12 65

neurodegenerative disease 261iron and 166

neurotransmitters 261copper function 135

neutropenia 136, 138neutrophils 9, 261newborn infantsiodine deficiency 150–151manganese susceptibility183–184

vitamin K deficiency 109niacin 17–24, 17deficiency 18causes of 19

disease prevention 19–20cancer 19–20diabetes (type 1) 20

disease treatment 21cardiovascular disease 21HIV infection 21

drug interactions 23–24formation 52function 17–18HIV infection and 21nutrient interactions 19, 236RDA 19, 19recommendations 24sources 22, 22tolerable upper intake level 23toxicity 22–23

nicotinamideinsulin sensitivity and 20, 23toxicity 23

nicotinamide adenine dinucleoti-de (NAD) 17, 31cancer and 19–20synthesis 18

nicotinamide adenine dinucleoti-de phosphate (NADP) 17, 31

nicotinic acid see niacinnitric oxide 261nitrous oxide 67, 242nonsteroidal anti-inflammatorydrug (NSAID) interactions 14,103, 240

nucleic acids 261metabolism 7, 7synthesis 52, 63see also DNA; RNA

nucleotides 262nutrient absorption 215

Oobesity 262vitamin D deficiency and 86

older adults, recommendationsbiotin 5chromium 133copper 140fluoride 147folic acid 15iodine 155iron 166magnesium 176manganese 184molybdenum 190niacin 24


279index

pantothenic acid 29phosphorus 195potassium 201riboflavin 35selenium 211sodium chloride 221thiamin 40vitamin A 49vitamin B6 58vitamin B12 68vitamin C 79vitamin D92vitamin E 104vitamin K 113zinc 231immune function and 227

olestra 242oral contraceptivesinteractions 15, 24, 29, 34, 240side effects treatment 55

orlistat 242osteoarthritis 262osteoblasts 116, 262osteocalcin 108vitamin K-dependentcarboxylation 110

osteoclasts 115osteomalacia 85, 262osteoporosis 115, 262copper and 136–137, 139prevention 246calcium 118–119copper 139fluoride 143–144manganese 181potassium 198vitamin D87–88vitamin K 110–111

sodium chloride and 216–217treatment 246vitamin A and 49

oxalate 122oxidation–reduction reactions17, 30, 30, 265

oxygen sensing 157oxygen transport and storage157

Ppancreas 262pantethine 27–29pantothenic acid 26–29adequate intake 27, 27deficiency 26–27disease treatment 27–28drug interactions 29function 26nutrient interactions 236recommendations 29sources 28, 28toxicity 28–29

parathyroid glands 262

parathyroid hormone (PTH) 115magnesium deficiency and 170phosphorus and 191–192

Parkinson disease 262pellagra 18penicillamine 140, 231, 242peptic ulcer disease 262peripheral neuropathy 36, 97,262

peripheral vascular disease 262pernicious anemia 60–61phenothiazine derivative interac-tions 240

phenylketonuria (PKU) 263phenytoin 242phlebotomy 263phosphorus 191–195bone health and 191–192calcium balance and 117, 191,192

deficiency 192drug interactions 194–195function 191nutrient interactions 191–192,238

RDA 193, 193recommendations 195sources 193, 194tolerable upper intake level194

toxicity 193–194phosphorylation 263phylloquinone 107, 112see also vitamin K

phytic acid 122, 163pituitary 263placebo 263placenta 263–264placental abruption 11, 264plasma 264Plasmodium falciparum 227Plummer-Vinson syndrome 159pneumonia 264susceptibility in children, zincand 227

poly-ADP-ribose polymerases(PARPs) 17

polymorphism 264polyp 264polyphenols 163potassium 196–201adequate intake 197, 197deficiency 197disease prevention 197–199kidney stones 198–199osteoporosis 198stroke 197–198

drug interaction 201, 201function 196hypertension treatment 199nutrient interactions 238recommendations 201sources 199–200, 200toxicity 200adverse reaction to supple-ments 200

potassium iodide 153pre-eclampsia 32, 264prevention 247calcium 120folate 11

riboflavin deficiency and 32treatment 247magnesium 172–173

pregnancy 246–247biotin deficiency and 2, 3calcium recommendations 126folic acid benefits 10–11, 15gestational diabetes 131–132iodine deficiency 151iron deficiency 159pregnancy complications and161

nausea and vomiting treatment56

pregnancy-induced hypertensi-on, calcium and 120

vitamin A safety 48–49zinc deficiency 227–228

premature delivery 11premenstrual syndrome (PMS)treatmentcalcium 121vitamin B6 55–56, 247

prooxidant 264iron function 157

propionyl-CoA carboxylase 1prostaglandins 208, 264prostate 264prostate cancercalcium and 124prevention 243selenium 207, 208vitamin D89vitamin E 99

prostate-specific antigen (PSA)264

protein 264acetylation 26calcium balance and 117, 237magnesium absorption and169

protein S 108proteoglycan 264–265proton pump inhibitor interac-tions 166, 240

psoriasis 46, 265pyridoxal 5'-phosphate (PLP) 52see also vitamin B6

pyridoxine glucoside 56pyruvate carboxylase 1, 179pyruvate kinase deficiency 265

Qquinacrine 242

RR proteins 60radiation-induced thyroid cancerprevention 152


280 index

randomized controlled trial (RCT)265

RDA (recommended dietaryallowance) 265see also specific nutrients

reactive nitrogen species 265reactive oxygen species (ROS)157, 265see also antioxidants

receptor 265red blood cell productionvitamin A role 44vitamin B6 role 52

redox reactions 17, 30, 30, 265renal dialysis 100, 254renin–angiotensin–aldosteronesystem 215

resorption 265response element 265restless legs syndrome (RLS) 162,247

retina 42, 265retinal 42retinitis pigmentosa 46, 97retinoic acid (RA) 42, 44gene expression regulation 43,43

retinoic acid response elements(RAREs) 43

retinoids 42drug interactions 240pharmacological doses 46see also vitamin A

retinol 42–43, 44breast cancer and 45–46see also vitamin A

retinol activity equivalents (RAE)46–47, 47

retrospective study 266rhabdomyolysis 23rheumatoid arthritis (RA) 266prevention 247vitamin D90

riboflavin 30–35cataract prevention 33deficiency 31–32risk factors 32

drug interactions 34function 30migraine treatment 33nutrient interactions 31,236–237

RDA 32, 32recommendations 34–35sources 34, 34toxicity 34

ribonucleotide 266rickets 85, 266rifampin 242RNA 266translation 268

SS-adenosylmethionine (SAM) 7,66

salt see sodium chloridescurvy 70, 266seizure 266prevention 247manganese and 181vitamin B6 deficiency and52–53

selenium 203–211deficiency 205individuals at increased risk205

disease prevention 206–209cancer 206–208cardiovascular diseases208–209

diabetes mellitus 209immune function 206viral infection 206

drug interactions 211function 203–204HIV/AIDS treatment 209nutrient interactions 151, 204,236–238

RDA 205, 206recommendations 211sources 209–210, 210toxicity 210–211

selenophosphate synthetase 204selenoproteins 203–204selenosis 210sensory neuropathy 57Sep15 204serotonin 266synthesis 52

serum 266short bowel syndrome 266sickle cell anemia 266simvastatinantioxidant interactions 78–79,211

niacin interaction 23vitamin E interaction 103–104see also statins

skeletal fluorosis 147skin diseases, retinoid treatment46see also specific diseases

smoking 207sodium chloride 214–221adequate intake 216, 216adverse effects 220–221calcium balance and 116–117deficiency 215–216disease prevention 216–219cardiovascular diseases 219gastric cancer 216hypertension 217–219kidney stones 217osteoporosis 216–217

drug interactions 221

function 214–215blood volume and pressure215

membrane potential 214nutrient absorption 215

nutrient interactions 237, 238recommendations 221sources 219, 220tolerable upper intake level221

toxicity 219–220soy protein, iron absorption and163

spina bifida 266sprue 266–267statinsantioxidant interactions 78–79,211

niacin interactions 23vitamin E interaction 104–105

steroid 267steroid hormone receptor 267steroid hormones 52stomach cancer prevention, vita-min C 72–73

stroke 267hemorrhagic 257ischemic 258prevention 245, 247potassium 197–198vitamin C 72

see also cardiovascular diseasessucralfate 242sulfasalazine 242sulfinpyrazone 23–24, 242sulfite oxidase 187deficiency 187–188

sunlight, as vitamin D source 90superoxide dismutase (SOD)135–136

systematic review 267systolic blood pressure 267

ttannins 267testosterone 52tetany 267thalassemia 164major 164, 267minor 164, 268

thiamin 36–40cataract prevention 38deficiency 36–37causes of 37

disease treatment 38–39Alzheimer disease 38cancer 39congestive heart failure38–39

drug interactions 40function 36RDA 37, 38recommendations 40sources 39, 40toxicity 39


281index

thiomolybdates 187thioredoxin reductase 203threshold 268thyroid 268function 149, 150

thyroid cancer 154follicular 268papillary 268prevention 243iodine 152

thyroid hormones 149deiodinases 204

thyroid-stimulating hormone(TSH) 149, 154

thyrotropin-releasing hormone(TRH) 149

tocopherol 96alpha-tocopherol 96, 99supplements 102

gamma-tocopherol 96–97supplements 102

see also vitamin Etolerable upper intake level (UL)268–269see also specific nutrients

transcription factor 268transferrin 128receptor 158

transient ischemic attack (TIA)268

transketolase 36triamterene 242tricyclic antidepressant interac-tions 240

triglycerides 268trimethoprim 242troponin C 115tryptophan, niacin interaction19, 236

tuberculosis (TB) 268typhoid 268

Uulcerative colitis 268

Vvascular calcification 111–112vasodilation, vitamin C treatment74

vegetariansiron deficiency 160zinc deficiency 225

venous thromboembolism, vita-min E and 98

virus 269viral infection 206

vision 42, 42vitamin A function 42–43deficiency effects 44

vitamin 269

vitamin A 42–49bone mineral density (BMD)effects 49

cancer prevention 45–46deficiency 44–45disease treatment 46drug interactions 49function 42–44gene expression regulation43, 43

growth and development 44immunity 44red blood cell production 44vision 42–43, 43

nutrient interactions 44,112–113, 158, 225, 236–238

RDA 45, 45recommendations 49, 270safety in pregnancy 48–49sources 46–48, 47tolerable upper intake level 48toxicity 48

vitamin B1 see thiaminvitamin B2 see riboflavinvitamin B3 see niacinvitamin B5 see pantothenic acidvitamin B6 52–58deficiency 52–53disease prevention 53–55cardiovascular diseases53–54

cognitive function 54–55immune function 54kidney stones 55

disease treatment 55–56carpal tunnel syndrome 56depression 56nausea and vomiting in preg-nancy 56

oral contraceptive side effects55

premenstrual syndrome55–56

drug interactions 57function 52nutrient interactions 31, 236RDA 53, 53recommendations 57–58sources 56–57, 56tolerable upper level 57toxicity 57

vitamin B12 60–68deficiency 60–62causes 60–62symptoms 62

disease prevention 64–66cancer 64–65cardiovascular diseases 64dementia 65–66depression 66neural tube defects 65

drug interactions 67folic acid interaction 14function 60

nutrient interactions 236RDA 63, 63recommendations 67–68sources 66–67, 66toxicity 67

vitamin C 70–79deficiency 70disease prevention 70–74cancer 72–73cardiovascular diseases71–72

cataracts 73gout 73lead toxicity 73–74role in immunity 74

disease treatment 74–76cancer 75cardiovascular diseases74–75

common cold 76diabetes mellitus 75–76

drug interactions 78–79function 70nutrient interactions 128, 136,162, 236–238

RDA 70, 71recommendations 79, 270sources 76–77, 76tolerable upper intake level 77toxicity 77kidney stones 78oxidative damage promotion78

with bioflavanoids 77vitamin D83–92activation 83deficiency 85risk factors 85–86

disease prevention 87–90autoimmune disease 89–90cancer 88–89hypertension 90osteoporosis 87–88

drug interactions 92function 83blood pressure regulation84–85

calcium balance 83, 84, 116cell differentiation 83–84immunity 84insulin secretion 84

mechanisms of action 83nutrient interactions 170, 191,236–238

nutritional status assessment86

RDA 86, 87recommendations 92, 270sources 90–91, 91tolerable upper intake level 91toxicity 91–92

vitamin D receptor (VDR) 83, 85vitamin D response elements(VDREs) 83


282 index

vitamin E 96–104deficiency 97disease prevention 98–99cancer 99cardiovascular diseases 98cataracts 98–99immune function 99

disease treatment 99–101cancer 101cardiovascular diseases99–100

dementia 100–101diabetes mellitus 100

drug interactions 103–104function 96–97alpha-tocopherol 96, 99gamma-tocopherol 96–97


RDA 97, 98recommendations 104, 270sources 101–102, 101supplementation related tomortality 103

tolerable upper intake level 103toxicity 102–103

vitamin K 107–113adequate intake 109, 110childhood leukemia and 109deficiency 109disease prevention 110–112cardiovascular disease111–112

osteoporosis 110–111

drug interactions 113function 107–108bone mineralization 108cell growth 108coagulation 107–108


premature infant doses 109recommendations 113sources 112, 112toxicity 112warfarin interaction 107, 108

Wwarfarin 242fracture risk and 110–111interactions 78, 103, 107, 108,110–111, 113

water fluoridation 145weight losscalcium and 125chromium and 131

Wernicke encephalopathy 36Wernicke–Korsakoff syndrome(WKS) 36–37

Wilson disease 140wound healing 27, 179

Xxanthine oxidase 30, 187xerophthalmia 44

Zzinc 224–231deficiency 225individuals at risk 225

disease prevention 226–228immune function in elderlypeople 227

impaired growth and deve-lopment 226

infectious disease in children227

pregnancy complications227–228

disease treatment 228–229age-related macular degene-ration 229

common cold 228diabetes mellitus 229HIV/AIDS229

drug interactions 230–231function 224nutrient interactions 44, 136,158, 169, 224–225, 236–238

RDA 226, 226recommendations 231sources 229–230, 231tolerable upper intake level230

toxicity 230zinc finger motif 224Zollinger–Ellison syndrome 269


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