Table Of Content

The Vitamins This page intentionally left blank The Vitamins Fundamental Aspects in Nutrition and Health Gerald F. Combs, Jr., Ph.D. Professor Emeritus Cornell University Ithaca, NY James P. McClung, Ph.D. Westborough, MA AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD • PARIS SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Fifth Edition Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2017, 2012, 2008, 1998, 1990 Elsevier Inc. All rights reserved. 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Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-802965-7 For information on all Academic Press publications visit our website at https://www.elsevier.com/ Publisher: Nikki Levy Acquisition Editor: Megan Ball Editorial Project Manager: Jaclyn Truesdell Production Project Manager: Caroline Johnson Designer: Miles Hitchen Typeset by TNQ Books and Journals Dedication To the students and professionals who have used this book and whose comments and suggestions have helped us produce this fifth edition –The Authors, Fifth Edition and to Barbara, ma fleur –Jerry and to Holly, Elliott, and Adeline –James This page intentionally left blank vii Contents Preface to the Fifth Edition xi How to Use This Book xiii Part I Perspectives on the Vitamins in Nutrition 1. What Is a Vitamin? 1. Thinking About Vitamins 3 2. Vitamin: A Revolutionary Concept 3 3. An Operating Definition of a Vitamin 4 4. The Recognized Vitamins 5 5. Study Questions and Exercises 5 2. Discovery of the Vitamins 1. The Emergence of Nutrition as a Science 8 2. The Process of Discovery in Nutritional Science 8 3. The Empirical Phase of Vitamin Discovery 8 4. The Experimental Phase of Vitamin Discovery 12 5. The Vitamine Theory 14 6. Elucidation of the Vitamins 18 7. Vitamin Terminology 28 8. Other Factors Sometimes Called Vitamins 28 9. Modern History of the Vitamins 29 10. Study Questions and Exercises 30 Recommended Reading 30 3. General Properties of Vitamins 1. Vitamin Nomenclature 34 2. Chemical and Physical Properties of the Vitamins 36 3. Physiological Utilization of the Vitamins 43 4. Metabolism of the Vitamins 50 5. Metabolic Functions of the Vitamins 51 6. Vitamin Bioavailability 52 7. Vitamin Analysis 52 8. Study Questions and Exercises 58 Recommended Reading 58 4. Vitamin Deficiency 1. The Concept of Vitamin Deficiency 60 2. Clinical Manifestations of Vitamin Deficiencies 61 3. Causes of Vitamin Deficiencies 65 4. Study Questions and Exercises 78 Recommended Reading 78 5. Vitamin Needs and Safety 1. Dietary Standards for Vitamins 80 2. Vitamin Allowances for Humans 87 3. Vitamin Allowances for Animals 89 4. Uses of Vitamins Above Required Levels 89 5. Hypervitaminoses 96 6. Safe Intakes of Vitamins 102 7. Study Questions and Exercises 105 Recommended Reading 105 Part II Considering the Individual Vitamins 6. Vitamin A 1. Significance of Vitamin A 110 2. Properties of Vitamin A 111 3. Sources of Vitamin A 112 4. Absorption of Vitamin A 115 5. Transport of Vitamin A 118 6. Metabolism of Vitamin A 125 7. Metabolic Functions of Vitamin A 129 8. Biomarkers of Vitamin A Status 137 9. Vitamin A Deficiency 139 10. Vitamin A in Health and Disease 147 11. Vitamin A Toxicity 153 12. Case Studies 156 13. Study Questions and Exercises 158 Recommended Reading 159 viii Contents 7. Vitamin D 1. Significance of Vitamin D 162 2. Properties of Vitamin D 163 3. Sources of Vitamin D 164 4. Enteric Absorption of Vitamin D 170 5. Transport of Vitamin D 171 6. Metabolism of Vitamin D 173 7. Metabolic Functions of Vitamin D 176 8. Biomarkers of Vitamin D Status 190 9. Vitamin D Deficiency 192 10. Vitamin D in Health and Disease 198 11. Vitamin D Toxicity 202 12. Case Studies 204 13. Study Questions and Exercises 205 Recommended Reading 205 8. Vitamin E 1. Significance of Vitamin E 208 2. Properties of Vitamin E 208 3. Sources of Vitamin E 210 4. Absorption of Vitamin E 212 5. Transport of Vitamin E 214 6. Metabolism of Vitamin E 219 7. Metabolic Functions of Vitamin E 221 8. Biomarkers of Vitamin E Status 227 9. Vitamin E Deficiency 229 10. Vitamin E in Health and Disease 231 11. Vitamin E Toxicity 239 12. Case Studies 240 13. Study Questions and Exercises 241 Recommended Reading 241 9. Vitamin K 1. The Significance of Vitamin K 244 2. Properties of Vitamin K 244 3. Sources of Vitamin K 245 4. Absorption of Vitamin K 249 5. Transport of Vitamin K 249 6. Metabolism of Vitamin K 250 7. Metabolic Functions of Vitamin K 253 8. Biomarkers of Vitamin K Status 258 9. Vitamin K Deficiency 259 10. Vitamin K Health and Disease 262 11. Vitamin K Toxicity 262 12. Case Studies 263 13. Study Questions and Exercises 264 Recommended Reading 265 10. Vitamin C 1. The Significance of Vitamin C 268 2. Properties of Vitamin C 268 3. Sources of Vitamin C 269 4. Absorption of Vitamin C 272 5. Transport of Vitamin C 272 6. Metabolism of Vitamin C 274 7. Metabolic Functions of Vitamin C 275 8. Biomarkers of Vitamin C Status 283 9. Vitamin C Deficiency 284 10. Vitamin C in Health and Disease 286 11. Vitamin C Toxicity 292 12. Case Studies 293 13. Study Questions and Exercises 295 Recommended Reading 295 11. Thiamin 1. The Significance of Thiamin 298 2. Properties of Thiamin 298 3. Sources of Thiamin 299 4. Absorption of Thiamin 301 5. Transport of Thiamin 302 6. Metabolism of Thiamin 303 7. Metabolic Functions of Thiamin 304 8. Biomarkers of Thiamin Status 308 9. Thiamin Deficiency 309 10. Role of Thiamin in Health and Disease 312 11. Thiamin Toxicity 313 12. Case Studies 313 13. Study Questions and Exercises 314 Recommended Reading 314 12. Riboflavin 1. The Significance of Riboflavin 316 2. Properties of Riboflavin 316 3. Sources of Riboflavin 317 4. Absorption of Riboflavin 318 5. Transport of Riboflavin 319 6. Metabolism of Riboflavin 320 7. Metabolic Functions of Riboflavin 322 8. Biomarkers of Riboflavin Status 323 9. Riboflavin Deficiency 323 10. Riboflavin in Health and Disease 327 11. Riboflavin Toxicity 328 12. Case Study 328 13. Study Questions and Exercises 329 Recommended Reading 329 13. Niacin 1. The Significance of Niacin 332 2. Properties of Niacin 332 3. Sources of Niacin 333 4. Absorption of Niacin 334 5. Transport of Niacin 335 6. Metabolism of Niacin 336 7. Metabolic Functions of Niacin 340 Contents ix 8. Biomarkers of Niacin Status 342 9. Niacin Deficiency 343 10. Niacin in Health and Disease 344 11. Niacin Toxicity 348 12. Case Study 348 13. Study Questions and Exercises 349 Recommended Reading 349 14. Vitamin B6 1. The Significance of Vitamin B6 352 2. Properties of Vitamin B6 352 3. Sources of Vitamin B6 352 4. Absorption of Vitamin B6 353 5. Transport of Vitamin B6 355 6. Metabolism of Vitamin B6 356 7. Metabolic Functions of Vitamin B6 358 8. Biomarkers of Vitamin B6 Status 365 9. Vitamin B6 Deficiency 366 10. Vitamin B6 in Health and Disease 367 11. Vitamin B6 Toxicity 369 12. Case Studies 369 13. Study Questions and Exercises 370 Recommended Reading 370 15. Biotin 1. The Significance of Biotin 372 2. Properties of Biotin 372 3. Sources of Biotin 372 4. Absorption of Biotin 374 5. Transport of Biotin 374 6. Metabolism of Biotin 376 7. Metabolic Functions of Biotin 376 8. Biomarkers of Biotin Status 380 9. Biotin Deficiency 380 10. Biotin in Health and Disease 382 11. Biotin Toxicity 383 12. Case Study 383 13. Study Questions and Exercises 384 Recommended Reading 384 16. Pantothenic Acid 1. The Significance of Pantothenic Acid 388 2. Properties of Pantothenic Acid 388 3. Sources of Pantothenic Acid 388 4. Absorption of Pantothenic Acid 389 5. Transport of Pantothenic Acid 390 6. Metabolism of Pantothenic Acid 391 7. Metabolic Functions of Pantothenic Acid 393 8. Biomarkers of Pantothenic Acid Status 395 9. Pantothenic Acid Deficiency 395 10. Pantothenic Acid in Health and Disease 396 11. Pantothenic Acid Toxicity 397 12. Case Study 397 13. Study Questions and Exercises 398 Recommended Reading 398 17. Folate 1. The Significance of Folate 400 2. Properties of Folate 400 3. Sources of Folate 402 4. Absorption of Folate 404 5. Transport of Folate 406 6. Metabolism of Folate 408 7. Metabolic Functions of Folate 413 8. Biomarkers of Folate Status 419 9. Folate Deficiency 420 10. Folate in Health and Disease 425 11. Folate Toxicity 427 12. Case Study 427 13. Study Questions and Exercises 428 Recommended Reading 428 18. Vitamin B12 1. Significance of Vitamin B12 432 2. Properties of Vitamin B12 432 3. Sources of Vitamin B12 433 4. Absorption of Vitamin B12 435 5. Transport of Vitamin B12 436 6. Metabolism of Vitamin B12 439 7. Metabolic Functions of Vitamin B12 440 8. Biomarkers of Vitamin B12 Status 443 9. Vitamin B12 Deficiency 444 10. Vitamin B12 in Health and Disease 450 11. Vitamin B12 Toxicity 450 12. Case Study 450 13. Study Questions and Exercises 451 Recommended Reading 452 19. Vitamin-Like Factors 1. Is the List of Vitamins Complete? 454 2. Choline 455 3. Carnitine 462 4. Myo-Inositol 469 5. Ubiquinones 474 6. Lipoic Acid 477 7. Nonprovitamin A Carotenoids 480 8. Flavonoids 487 9. Orotic Acid 494 10. Unidentified Factors 495 11. Case Study 496 12. Study Questions and Exercises 496 Recommended Reading 497 x Contents Part III Using Current Knowledge of the Vitamins 20. Sources of the Vitamins 1. Vitamins in Foods and Feedstuffs 501 2. Vitamin Bioavailability 508 3. Vitamin Losses in Foods 509 4. Vitamin Fortification 511 5. Biofortification 513 6. Vitamin Labeling of Foods 516 7. Vitamins in Human Diets 517 8. Vitamin Supplementation 521 9. Vitamins in Livestock Feeding 523 10. Case Study 528 11. Study Questions and Exercises 530 Recommended Reading 530 21. Assessing Vitamin Status 1. Nutritional Assessment 531 2. Biomarkers of Vitamin Status 533 3. Vitamin Status of Human Populations 534 4. Global Undernutrition 541 5. Study Questions and Exercises 543 Recommended Reading 543 Appendix A: Current and Obsolete Designations of Vitamins (Bolded) and Other Vitamin-Like Factors 545 Appendix B: Original Reports for Case Studies 549 Appendix C: A Core of Current Vitamin Literature 551 Appendix D: Vitamin Contents of Foods (units per 100 g Edible Portion) 559 Appendix E: Vitamin Contents of Feedstuffs (units per kg) 589 Index 593 xi Preface to the Fifth Edition Understanding the vitamins is key to understanding nutrition. The history of their discovery and the continuing elucidation of their roles in health is the history of the emergence of nutrition as a science from the areas of physiology, bio- chemistry, medicine, and agriculture. Capturing the understanding that grew out of that history is both a challenge and a privilege. For us, it involved months of reviewing thousands of publications and look- ing for clear ways to present complex information without overstating present understanding. Producing this fifth edition of The Vitamins benefitted from the inclusion of a coauthor, which we believe brought a new prospective to the text. James studied the first edition of the The Vitamins as a masters student at the University of New Hampshire in 1997. He encountered the second edition of the text as Jerry’s student at Cornell University in 2001. We are hopeful that the dynamic relationship we have enjoyed, as student/mentor, colleagues, friends, and now coauthors, has resulted in the most effective edition of this text, as both a reference and a teaching aid. In writing this fifth edition of The Vitamins, we were mindful of comments from users of previous editions, which prompted several changes that we believe enhanced the book. We reorganized several chapters, which reduced their number. We emphasized roles of the gut microbiome in several places of importance. We added sections on biomarkers of vitamin status and modestly expanded the section on biofortification. We added, redrew, and updated several tables and figures. We used extensive footnoting as a means of including explanatory notes as well as for citing primary sources. We are grateful for the professional assistance from editors, Ms. Jaclyn Truesdell, Ms. Megan Ball, and Ms. Caroline Johnson of Elsevier. We enjoyed writing this fifth edition of The Vitamins together. We hope you will find it useful. Gerald F. Combs, Jr. Topsham, Maine James P. McClung Westborough, Massachusetts June 2016 This page intentionally left blank xiii How to Use This Book TO THE HEALTH PROFESSIONAL The Vitamins is designed as a one-stop source of compre- hensive, current information on the vitamins. In it you will find information on the history of vitamin discovery, the chemical properties of the vitamins and their isomers and metabolites, the utilization and metabolism of vitamins, the consequences of their deficient and excessive intakes, biomarkers of vitamin status, and the health roles if particular vitamins in beyond the traditional deficiencies. You will find examples of classical and current research findings as well as citations to recent key publications in the footnotes. You may find Appendix particularly useful, as it lists the vitamin contents of a most common foods. Please let us know of any ways you see we might enhance The Vitamins. TO STUDENTS AND INSTRUCTORS The Vitamins is also intended as a teaching text for an upper- level college course within a nutrition or health-related cur- riculum; however, it will also be useful as a workbook for self-paced study of the vitamins. It has several features that are designed to enhance its usefulness to students as well as instructors. Here is how we suggest using it. To the student When you use this text, make sure to have by your side a notebook, pencil (not pen—you may want to make changes in the notes you take). Then, before reading each chapter, take a few moments to go over the “Anchoring Concepts and Learning Objectives” on the chapter title page. Anchoring Concepts are the ideas fundamental to the subject matter of the chapter, the concepts to which the new ones presented in the chapter will be related. Those in the first several chapters should already be very familiar to you; if not, then it will be necessary for you to do some background reading or discussion until you feel comfortable in your understanding of these basic ideas. You will find that most chapters are designed to build upon the understanding gained through previous chapters; in most cases, the Anchoring Concepts of a chapter relate to the Learning Objectives of previous chapters. Pay attention to the Learning Objectives; they are the key elements of understanding what the chapter is intended to support. Keeping the Learning Objectives in mind as you go through each chapter will help you maintain focus on those elements. Next, read through the Vocabulary list and mark any terms that are unfamiliar or about which you feel unsure. Then, make a list of your own questions about the topic of the chapter. As you read through the text, look for items related to your questions and for unfamiliar terms. You will be able to find key terms in bold-faced type, and you should be able to get a good feel for their meanings from the contexts of their uses. If this is not sufficient for any particular term, then look it up in a medical dictionary. Do not wait to do this. Cultivate the habit of being bothered by not understanding something—this will help you enormously in years to come. As you proceed through the text, note what information the layout is designed to convey. First, note that the major sections of each chapter are indicated with a bold heading. This is done to help you scan for particular information. Also note that the footnoted information is largely supple- mentary and not essential to the understanding of the key concepts presented. Therefore, the text may be read at two levels: at the basic level, one should be able to ignore the footnotes and still get the key concepts; at the more detailed level, one should be able to pick up more background, particularly key citations to the primary literature, from the footnotes. Refer back frequently to your own list of questions and “target” vocabulary words; when you find an answer or can make a deduction, make a note. Do not be reluctant to write in the book, particularly to put a concept into your own words, or to note something you find impor- tant or do not fully understand. Studies show that to be an effective learning technique. When you have completed a chapter, take sometime to list what you see as the key points—those that you would cover in a formal presentation. Then, skim back over the chapter. You will find that Chapters 6–19 each have one or more Case Studies comprised of more clinical case reports abstracted from the medical literature. For each, use the associated questions to focus your thinking on the features that relate to vitamin functions. As you do so, try to ignore the obvious connection with the subject of the chapter; put yourself in the position of the attending physician who was called upon to diagnose the problem without prior xiv How to Use This Book knowledge that it involved any particular nutrient, much less a certain vitamin. The Case Study in Chapter 21 is dif- ferent; it is a fictional but highly plausible scenario that calls for a nonobvious decision. Additional case studies are listed in Appendix B. Take sometime and go through the Study Questions and Exercises at the end of each chapter. These, too, are designed to direct your thinking back to the key concepts of the respective chapter and to facilitate integration of those concepts with those you already have. We have made a point in Chapter 1 of using the technique of concept mapping do demonstrate the integration of complex subject matter. We have found the concept map to be a powerful teaching/learning tool. If you have had no previous experience with this device, then it will be worth your while to consult Learning How to Learn.1 When you have done all of this for a chapter, then deal with your questions. Discuss them with fellow students or look them up. To assist you in the latter, a short reading list is included at the end of each chapter. With the exception of Chapter 2, which lists papers of landmark significance to the discovery of the vitamins, the reading lists consist of key reviews in prominent scientific journals. These reviews and the papers cited in the footnotes will help you find primary research papers on topics of specific interest. After you have followed all of these steps, reread the chapter. You will find this last step to be extraordinarily useful in gaining a command of the material. Last, but certainly not least, have fun with this fascinat- ing aspect of the field of nutrition! To the instructor The format of this text reflects the way GFC taught a course called “The Vitamins” for some 29 years at Cornell University. To that end, some experiences in using The Vitamins as a text for my course may be of interest to you. I have found that every student comes to the study of the vitamins with some background knowledge of the subject, although those backgrounds are generally incomplete and frequently include areas of misinformation. This is true for upper-level nutrition majors and for students from other fields, the difference being largely one of magnitude. This is also true for instructors, most of whom come to the field with specific expertise that relates to only a subset of the subject matter. You can demonstrate this in the following exercise, best done of the first day of class. Raise your index finger (best done with a bit of dramatic flair) and say “vitamin A.” Hold that pose for 10 s and then ask “What came to mind when I said ‘vitamin A’?” Without fail, someone will say “vision” or “carrots,” and then an older graduate student may add “toxic.” When it looks safe to chime in, others will add what 1. Novak, J.D., Gowin, D.B., 1984. Learning How to Learn. Cambridge, University Press, New York, NY, pp. 199 will build to an array of descriptors that, collectively, are more relevant to vitamin A than any is individually. Most of the answers, by far, will relate to the clinical symptoms of vitamin A deficiency and the sources of vitamin A in diets. Catch each answer by dashing it on to a large sticky note and then stick the note haphazardly to a blackboard or wall. If you hear something complex or a cluster of concepts, make sure to question the contributor until you hear one or more individual concepts, which you can record on individual sticky notes. This approach never fails to stimulate further answers, and it is common that a group of 15–20 students will generate a list of twice that number of concepts before the momentum fades. Having used sticky notes, it is easy to move them into clusters and, thus, to use the activity to construct a concept map of “Vitamin A” based solely on the knowledge that the students, collectively, brought into the room. This exercise can demonstrate an empowering idea that, having at least some background on the subject and being motivated (by any of a number of reasons) to learn more, every learner brings to the study of the vitamins a unique perspective which may not be readily apparent. We are convinced that meaningful learning is served when both instructor and students come to understand each others’ various perspectives. This has two benefits in teaching the vitamins. First, it is in the instructor’s interest to know the students’ ideas and levels of understanding con- cerning issues of vitamin need, vitamin function, etc., such that these can be built upon and modified as may be appro- priate. Second, many upper-level students have interesting experiences (through personal or family histories, their own research, information from other courses, etc.) that can be valuable contributions to classroom discussions. These experiences are assets that can reduce the temptation to fall back on the “instructor knows all” notion, which we all know to be false. To identify student perspectives, it is useful to assign on the first class period, for submission at the second class, a written autobiographical sketch. Distribute your own as a model, and ask each student to write “as much or as little” as he or she cares to, recognizing that you will distribute to the class copies of whatever is submitted. The biographical sketches will range from a few sentences that reveal little of a personal nature to longer ones that provide many good insights about their authors; everyone will help you to get to know your students personally and to get a bet- ter idea of their understandings of the vitamins and of their expectations of the course. The exercise serves the students in a similar manner, thus promoting a group dynamic that facilitates classroom discussions. The Vitamins can be used as a typical text from which you can make regular reading assignments as preparation for each class. This will free you of the need for lecturing in favor of an open discussion format. In fact, this approach allows more information to be covered, as even a brilliant lecturer simply cannot cover the vitamins in any real depth