Thieme: An Evidence-based Approach to Vitamins and MineralsAn Evidence-based Approach to Vitamins and Min- erals: Health Benefits and IntakeRecommenda- tions by Dr.JaneHigdonandDr.VictoriaDrake
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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
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
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
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-
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
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 treatment ......................................46Pharmacological doses of retinoids .......46diseases of the Skin.................................46
Safety ..........................................................48Toxicity....................................................48Safety in Pregnancy.................................48Effects on Bone .......................................49drug interactions ....................................49
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
14 Calcium ...................................................115Function ..................................................115Structure...............................................115cell Signaling.........................................115cofactor for Enzymes and Proteins........115regulation of calcium levels.................115
Deficiency................................................136Individuals at Risk of Deficiency ............137recommended dietary Allowance .......137
Disease Prevention ................................137cardiovascular diseases ........................137immune System Function .....................138Osteoporosis.........................................139
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 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
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
24 Potassium................................................196Function ..................................................196maintenance of membrane Potential ....196cofactor for Enzymes ............................196
Deficiency................................................197conditions that increase the risk ofHypokalemia .........................................197Adequate intake....................................197
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
27 Zinc..........................................................224Function ..................................................224catalytic role ........................................224Structural role ......................................224regulatory role.....................................224Nutrient interactions.............................224
Disease Prevention .................................226impaired Growth and development......226increased Susceptibility to infectiousdisease in children................................227
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.
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.
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.
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.
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
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
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)
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:
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
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
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
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
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
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
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
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